research article dna repair gene polymorphism and the risk...

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Research Article DNA Repair Gene Polymorphism and the Risk of Mitral Chordae Tendineae Rupture Aysel Kalayci Yigin, 1 Mehmet Bulent Vatan, 2 Ramazan Akdemir, 2 Muhammed Necati Murat Aksoy, 2 Mehmet Akif Cakar, 2 Harun Kilic, 2 Unal Erkorkmaz, 3 Keziban Karacan, 4 and Suleyman Kaleli 1 1 Department of Medical Biology and Genetics, Faculty of Medicine, Sakarya University, 54290 Sakarya, Turkey 2 Department of Cardiology, Faculty of Medicine, Sakarya University, 54290 Sakarya, Turkey 3 Department of Biostatistics, Faculty of Medicine, Sakarya University, 54290 Sakarya, Turkey 4 Department of Anatomy, Faculty of Medicine, Sakarya University, 54290 Sakarya, Turkey Correspondence should be addressed to Ramazan Akdemir; [email protected] Received 24 July 2015; Revised 21 September 2015; Accepted 22 September 2015 Academic Editor: Gad Rennert Copyright © 2015 Aysel Kalayci Yigin et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Polymorphisms in Lys939Gln XPC gene may diminish DNA repair capacity, eventually increasing the risk of carcinogenesis. e aim of the present study was to evaluate the significance of polymorphism Lys939Gln in XPC gene in patients with mitral chordae tendinea rupture (MCTR). Twenty-one patients with MCTR and thirty-seven age and sex matched controls were enrolled in the study. Genotyping of XPC gene Lys939Gln polymorphism was carried out using polymerase chain reaction- (PCR-) restriction fragment length polymorphism (RFLP). e frequencies of the heterozygote genotype (Lys/Gln-AC) and homozygote genotype (Gln/Gln-CC) were significantly different in MCTR as compared to control group, respectively (52.4% versus 43.2%, = 0.049; 38.15% versus 16.2%, = 0.018). Homozygote variant (Gln/Gln) genotype was significantly associated with increased risk of MCTR (OR = 2.059; 95% CI: 1.097–3.863; = 0.018). Heterozygote variant (Lys/Gln) genotype was also highly significantly associated with increased risk of MCTR (OR = 1.489; 95% CI: 1.041–2.129; = 0.049). e variant allele C was found to be significantly associated with MCTR (OR = 1.481; 95% CI: 1.101–1.992; = 0.011). is study has demonstrated the association of XPC gene Lys939Gln polymorphism with MCTR, which is significantly associated with increased risk of MCTR. 1. Introduction Although definite cause of chordae tendineae rupture remains confusing, primary rupture is thought to be more frequent cause than the other underlying situations such as mitral valve prolapse, subacute bacterial endocarditis, local myxomatous degeneration, rheumatic heart disease (mostly during the chronic stage), systemic or generalized connective tissue abnormality (such as in Marfan syndrome, osteoge- nesis imperfecta, and Ehler-Danlos syndrome), blunt chest trauma, hypertrophic cardiomyopathy, other (nonmitral) heart and valvular abnormalities (such as aortic stenosis and aortic regurgitation), ischemic heart disease in general, and myocardial infarction in particular [1]. Primary or idiopathic mitral chordae tendineae rupture (MCTR) is a progressive condition that may eventually require mitral valve surgery, as the patients treated medically suffer a high (6.3%) mortality rate. e vast majority of patients with idiopathic MCTR experience the separation of multiple chords, leading to severe mitral regurgitation and requiring immediate surgical intervention [2, 3]. Under- standing the underlying mechanisms involved in the patho- genesis of idiopathic MCTR is vital in the development of novel therapeutic strategies [3, 4]. Despite its clinical importance, the precise pathophysiologic mechanisms of MCTR have not been established. However, it is evident that the altered expression of genes encoding signal cascade which instigate apoptosis, cell differentiation, cardiac remodeling, Hindawi Publishing Corporation Disease Markers Volume 2015, Article ID 825020, 6 pages http://dx.doi.org/10.1155/2015/825020

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Page 1: Research Article DNA Repair Gene Polymorphism and the Risk ...downloads.hindawi.com/journals/dm/2015/825020.pdf · Research Article DNA Repair Gene Polymorphism and the Risk of Mitral

Research ArticleDNA Repair Gene Polymorphism and the Risk of MitralChordae Tendineae Rupture

Aysel Kalayci Yigin1 Mehmet Bulent Vatan2 Ramazan Akdemir2

Muhammed Necati Murat Aksoy2 Mehmet Akif Cakar2 Harun Kilic2

Unal Erkorkmaz3 Keziban Karacan4 and Suleyman Kaleli1

1Department of Medical Biology and Genetics Faculty of Medicine Sakarya University 54290 Sakarya Turkey2Department of Cardiology Faculty of Medicine Sakarya University 54290 Sakarya Turkey3Department of Biostatistics Faculty of Medicine Sakarya University 54290 Sakarya Turkey4Department of Anatomy Faculty of Medicine Sakarya University 54290 Sakarya Turkey

Correspondence should be addressed to Ramazan Akdemir ramazanakdemirgmailcom

Received 24 July 2015 Revised 21 September 2015 Accepted 22 September 2015

Academic Editor Gad Rennert

Copyright copy 2015 Aysel Kalayci Yigin et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Polymorphisms in Lys939Gln XPC gene may diminish DNA repair capacity eventually increasing the risk of carcinogenesis Theaim of the present study was to evaluate the significance of polymorphism Lys939Gln in XPC gene in patients with mitral chordaetendinea rupture (MCTR) Twenty-one patients with MCTR and thirty-seven age and sex matched controls were enrolled in thestudy Genotyping of XPC gene Lys939Gln polymorphism was carried out using polymerase chain reaction- (PCR-) restrictionfragment length polymorphism (RFLP) The frequencies of the heterozygote genotype (LysGln-AC) and homozygote genotype(GlnGln-CC) were significantly different in MCTR as compared to control group respectively (524 versus 432 119901 = 00493815 versus 162 119901 = 0018) Homozygote variant (GlnGln) genotype was significantly associated with increased risk ofMCTR(OR= 2059 95CI 1097ndash3863119901 = 0018) Heterozygote variant (LysGln) genotype was also highly significantly associated withincreased risk of MCTR (OR = 1489 95 CI 1041ndash2129 119901 = 0049) The variant allele C was found to be significantly associatedwith MCTR (OR = 1481 95 CI 1101ndash1992 119901 = 0011) This study has demonstrated the association of XPC gene Lys939Glnpolymorphism with MCTR which is significantly associated with increased risk of MCTR

1 Introduction

Although definite cause of chordae tendineae ruptureremains confusing primary rupture is thought to be morefrequent cause than the other underlying situations such asmitral valve prolapse subacute bacterial endocarditis localmyxomatous degeneration rheumatic heart disease (mostlyduring the chronic stage) systemic or generalized connectivetissue abnormality (such as in Marfan syndrome osteoge-nesis imperfecta and Ehler-Danlos syndrome) blunt chesttrauma hypertrophic cardiomyopathy other (nonmitral)heart and valvular abnormalities (such as aortic stenosis andaortic regurgitation) ischemic heart disease in general andmyocardial infarction in particular [1]

Primary or idiopathic mitral chordae tendineae rupture(MCTR) is a progressive condition that may eventuallyrequire mitral valve surgery as the patients treated medicallysuffer a high (63) mortality rate The vast majority ofpatients with idiopathic MCTR experience the separationof multiple chords leading to severe mitral regurgitationand requiring immediate surgical intervention [2 3] Under-standing the underlying mechanisms involved in the patho-genesis of idiopathic MCTR is vital in the developmentof novel therapeutic strategies [3 4] Despite its clinicalimportance the precise pathophysiologic mechanisms ofMCTR have not been established However it is evident thatthe altered expression of genes encoding signal cascadewhichinstigate apoptosis cell differentiation cardiac remodeling

Hindawi Publishing CorporationDisease MarkersVolume 2015 Article ID 825020 6 pageshttpdxdoiorg1011552015825020

2 Disease Markers

angiogenesis and fibrosis may have an important role in thepathogenesis ofMCTR [5 6] Recently Kimura et al revealedthat downregulation of tissue inhibitor of metalloproteinase(TIMP) 2 and tenomodulin and upregulation of vascularendothelial growth factor- (VEG) A and matrix metallopro-teinases (MMP) likely play a major role in the molecularmechanism underlying the pathophysiology of MCTR [5] Inaddition Lin et al also showed that MMP 1 gene expressionand MMP 1-1607-1626 gene polymorphism were indepen-dently associated with MCTR [6] These preliminary studieshave demonstrated that genetic factors have an influence onindividual susceptibility to MCTR

The Xeroderma Pigmentosum Complementation GroupC (XPC) made up one of the eight core genes (ie ERCC1XPA XPB XPC XPD XPE XPF and XPG) and serves as theprimary initiating factor in the genome nucleotide excisionrepair pathway (NER) [7ndash9] The XPC gene encodes a 940-amino acid protein spanning 33 kb on chromosome 3p25and contains 16 exons and 15 introns [10] The XPC geneplays a crucial role in maintaining a balance between cellproliferation and apoptosis [11ndash13] The XPC gene polymor-phism enhances DNA damage-induced apoptosis throughthe activation of p53 or p53-independent apoptotic pathway[14ndash16] Increasing evidence has provided support for theexistence of apoptotic pathways and their regulators in theheart [17] The relationship between the pathways of apop-tosis and various valvular disorders such as degenerativeaortic valve disease andmyxomatousmitral valve disease hasbeen demonstrated in previous studies [18 19] However therole of pathways of apoptosis in MCTR remains unknownThis study has been conducted to investigate the role orassociation of XPC polymorphisms in the pathogenesis ofidiopathic MCTR patients

2 Methods

21 Study Subjects Twenty-one patients with idiopathicMCTR and thirty-seven subjects without valvular heartdisease were recruited from files of the Department of Cardi-ology of Sakarya University All subjects in the MCTR groupunderwent transesophageal echocardiography to confirm thediagnosis The Ethical Committee of Sakarya UniversitySchool of Medicine provided ethical approval for this studyThe study conformed to the ethical principles of the Decla-ration of Helsinki Informed written consent was obtainedfrom each subject included in the present study Patientswith infective endocarditis rheumatic heart disease mitralvalve prolapse myxomatous degeneration connective tissuedisease blunt chest trauma hypertrophic cardiomyopathyand acute coronary syndromes including acute myocardialinfarction chronic renal failure chronic congestive heartfailure known or suspected infiltrative cardiac diseasesconstrictive andor restrictive cardiomyopathy and chronic-active inflammatory disease current smokers and thosediagnosed with any cancer were excluded from the studyClinical and demographical data such as age gender heightand weight were recorded on patient charts Measures of car-diovascular risk including hypertension diabetes mellitusand medication use were also evaluated

22 Echocardiographic Examination In all subjects trans-thoracic two-dimensional and Doppler echocardiographicexaminations performed by a Vivid 5 echocardiography sys-tem (General Electric Vingmed USG Israel) using 25MHztransducers were carried out according to standards ofthe American Society of Echocardiography Transesophagealechocardiography (TEE) was performed in all patients withMCTR Left atrial (LA) diameter was measured from theparasternal left heart long-axis view Pulmonary artery trunkand pulmonary flow were measured from the aortic short-axis view Mitral inflow and aortic valve flow were alsomeasured Pulmonary artery systolic pressure was calculatedaccording to velocity of tricuspid regurgitation using theBernoulli equation The left ventricular end diastolic diam-eter (LVEDd) and ejection fractions (EF) were calculated bythe M-mode method The quantification of mitral regurgita-tion (MR) is made according to the echocardiographic meth-ods including vena contracta width the flow convergencemethod and color Doppler characteristics of regurgitantjet penetration The mitral valve and its chordae tendineaewere observed in the left ventricular midesophageal and MVtransgastric views using rotation of the TEE probe to achievethe clearest view MCTR diagnosis was made on the basisof flail mitral valve associated with chordal elongation andchordal swinging with or without chordal remnant root

23 DNA Isolation and Genotyping Genomic DNA wasextracted from whole blood samples using a special isolationkit (Roche Diagnostics DNA Isolation Kit for MammalianBloodGermany) All isolation stepswere carefully performedaccording to the manufacturerrsquos instructions Genotypingof XPC Lys939Gln polymorphism was carried out usingpolymerase chain reaction- (PCR-) restriction fragmentlength polymorphism PCR amplification was performed ina 30 120583L PCR volume containing 100 ng template DNA 0750units Taq polymerase (Fermentas) 1x Mg++ free PCR buffer(Fermentas) 200mM dNTP (Fermentas) 15mM MgCl++10 pMol of each F 51015840-GGCTTCCTGGTATCTGATTACT-31015840R 51015840-CTCAGTTTGCCTTCTCAGCA-31015840 (GenBank acces-sion number NC 00000312) The incubation process of thetouchdown-PCR (Sensoquest Thermocycler Germany) wasperformed as follows 4min at 95∘C followed by 16 cyclesfor 30 sec at 95∘C 30 sec at 60∘C and 45 sec at 72∘C adding05 seccycle Then 30 cycles of the triple steps were per-formed for 30 sec at 94∘C 30 sec at 52∘C and 2min at 72∘Cthe final elongation step was achieved after 10min at 72∘CAfter agarose gel electrophoresis the 10 120583L PCR-amplifiedDNA was digested with PvuII restriction enzyme for 20minutes at 37∘C and electrophoresed on 2 agarose gel Thehomozygote wild-type genotype was identified by a singleband at 402 bp level the heterozygote genotype by 3 bandsat 402 276 and 126 bp levels and the homozygote variant by2 bands at 276 and 126 bp levels (Figure 1)

24 Statistical Methods Distributions of genotype weresuited to the Hardy-Weinberg equilibrium in both controland case groups (119901 = 0623 and 119901 = 0519 resp) Pear-sonrsquos and Fisherrsquos Chi-Square tests were used to comparethe genotypes alleles and other categorical data between

Disease Markers 3

500bp400bp250bp

100 bp50bp

M 1 2 3 4 5 6 7 8 9 10

Figure 1 Genotypes were generated from 402 bp PCR productacquired from 9 individuals using specific primers after digestionwith PvuII restriction enzyme The lanes were as follows M DNAladder lanes 1 and 7 CC genotype homozygote variant lanes 2 and8 AA genotype homozygote wild type lanes 3 4 5 6 9 and 10 ACgenotype heterozygote

control and case groups Categorical data were expressed ascount and percentages According to Kolmogorov-Smirnovnormality test two independent-sample 119905-tests were usedto compare the continuous variables between two groupsContinuous data were expressed as mean and standard devi-ation A multiple logistic regression model was implementedto determine genotypes and other covariates associated withXPC The odds ratio was calculated for heterozygous andmutant individuals in the assessment of risk status accordingto the normal group A 119901 value lt005 was consideredsignificant Analyses were performed using commercial soft-ware (IBM SPSS Statistics Version 220 Armonk NY IBMCorp)

3 Results

This study contains 21 MCTR patients with 57 plusmn 16 meanage and 37 control groups with 52 plusmn 16 mean age Of the21 MCTR patients 15 (714) were male and 6 (286) werefemale Of the 37 control groups 19 (513) were male and18 (487) were female Demographic echocardiographiclaboratory and genotypeallele frequencies of the XPCLys939Gln polymorphisms between MCTR patients andcontrols are summarized in Tables 1 and 2 The frequenciesof the heterozygote genotype (LysGln-AC) and homozygotegenotype (GlnGln-CC)were significantly different inMCTRas compared to control group respectively (524 versus432 119901 = 0049 3815 versus 162 119901 = 0018) The oddsratio for heterozygous and mutant individuals was calculatedin the risk status assessment which is prepared regarding thenormal group Homozygote variant (GlnGln) genotype wassignificantly associated with increased risk of MCTR (OR =2059 95 CI 1097ndash3863 119901 = 0018) Heterozygote variant(LysGln) genotype was also highly significantly associatedwith increased risk of MCTR (OR = 1489 95 CI 1041ndash2129 119901 = 0049) The variant allele C was found to besignificantly associated with MCTR (OR = 1481 95 CI1101ndash1992 119901 = 0011) (Table 3)

Table 1 Baseline characteristics and laboratory findings of case andcontrol groups

Control (119899 = 37) Case (119899 = 21) 119901

GenotypeAA 15 (4054) 2 (952)

0026AC 16 (4324) 11 (5238)CC 6 (1622) 8 (381)

Age 4749 plusmn 1521 57 plusmn 1612 0029HTNo 19 (5135) 13 (619) 0616Yes 18 (4865) 8 (381)

DMNo 31 (8378) 20 (9524) 0403Yes 6 (1622) 1 (476)

CADNo 34 (9189) 20 (9524) 1000Yes 3 (811) 1 (476)

Crea 093 plusmn 017 096 plusmn 037 0703LDL 12465 plusmn 282 10852 plusmn 316 0049HDL 4214 plusmn 96 4143 plusmn 1244 0810CRP 285 plusmn 165 416 plusmn 281 0061UA 525 plusmn 11 577 plusmn 151 0134HT hypertension DM diabetes mellitus CAD coronary artery diseaseCrea creatinine HDL high-density lipoprotein LDL low-density lipopro-tein CRP C-reactive protein and UA uric acid

Table 2 Echocardiographic findings of case and control groups

Control (119899 = 37) Case (119899 = 21) 119901

LAD 349 plusmn 018 475 plusmn 047 lt0001AOD 325 plusmn 019 334 plusmn 014 0057LVSD 33 plusmn 027 428 plusmn 033 lt0001LVDD 488 plusmn 024 541 plusmn 031 lt0001LVEF 063 plusmn 004 055 plusmn 006 lt0001IVST 114 plusmn 008 117 plusmn 01 0224PWT 114 plusmn 008 117 plusmn 01 0156MPAP 1876 plusmn 209 4029 plusmn 73 lt0001MR gradingModerate 9 (4286) mdashSevere 12 (5714)

Vena contracta width 065 plusmn 011 mdashLAD left atrial diameter AOD aortic root diameter LVSD left ventricularsystolic diameter LVDD left ventricular diastolic diameter LVEF leftventricular ejection fraction IVST interventricular septal thickness PWTposterior wall thickness MPAP mean pulmonary artery pressure MRmitral regurgitation and VCW vena contracta width

Table 3Multiple logistic regressionmodels for genotypes and othercovariates associated with XPC

120573SE of120573

Wald 119901 OR 95 CI for ORLower Upper

Genotype 677 0034Genotype(AC) 327 130 634 0012 2637 207 33673

Genotype(CC) 323 135 570 0017 2536 179 36037

Age 013 005 858 0003 114 104 124HT minus212 108 381 0051 012 001 101DM minus317 162 380 0051 004 000 102CAD minus388 176 488 0027 002 000 065LDL minus005 002 683 0009 095 091 099Constant minus227 213 113 0287 010

4 Disease Markers

4 Discussion

There are currently no published reports in the literature onthe XP polymorphisms profile of MCTR Thus this is toour knowledge the first study demonstrating a link betweenthe XPC polymorphisms and MCTR This study showedthat increased heterozygote genotype (AC) and homozygotegenotype (CC) frequencies of the XPC Lys939Gln polymor-phisms might result in increased genetic susceptibility toMCTR Furthermore the variant allele C genotype was alsohighly associated with increased risk of MCTR

MCTR is an increasingly important cause of mitralregurgitation and is more common in male adults over 50[1] Rupture of a single structure of chordae leads to limitedhemodynamic effect and usually requires neither interven-tion nor treatment Significant rupture of amultiple structureof chordae tendineae usually results in acute severe mitralregurgitation andhemodynamic instability requiring promptsurgical intervention [2 3] The leading underlying causesin the literature were blunt thoracic trauma connective tis-sue diseases coronary artery disease infective endocarditisrheumatic mitral stenosis and mitral valve prolapse Unde-termined cases are defined as primary (idiopathic) chordaerupture in which there is obviously no underlying cause In arecent systematic review the prevalence of idiopathic MCTRwas 512 [1 20 21]

The pathophysiologic mechanism that results in idio-pathic MCTR is still unclear Recently the investigators haveattempted to establish genetic factors which are thought toplay a key role inMCTR occurrence Evidence for these stud-ies demonstrated that inflammation increased expressionof genes encoding signal cascade which instigate apoptoticbalance and cell differentiation may have an important rolein the pathogenesis of MCTR [5 6]

DNA repair genes protect genomic integrity and they arebasic components of normal cell homeostasis necessary tocell growth differentiation and apoptosis [21 22] It is knownthat diminished DNA repair capacity due to various DNArepair gene polymorphisms is associated with increasedrisk and susceptibility to human solid tumors [23ndash25] XPCis a key member in the nucleotide excision repair (NER)pathway It is involved in the recognition and initiation ofthe genome repair of NER pathway [7ndash9] Polymorphismsin the XPC gene may alter DNA repair capacity of the NERpathway which further play a critical role in carcinogenesisSeveral polymorphic variants in the XPC gene have beenidentified The most common polymorphisms of XPC geneare Ala499Val (CrarrT) PAT (minus+) and Lys939Gln (ArarrC)[25ndash28] Increasing evidence has accumulated suggesting thatXPC gene polymorphism can cause replication blockagewhich also enhances unregulated apoptosis induced by DNAdamage [11ndash13] Recent studies support the claim that apop-tosis does occur in the heart [17] Data obtained from numer-ous studies have suggested a possible role for apoptosis inheart failure ischemiareperfusion injury idiopathic dilatedcardiomyopathy ischemic cardiomyopathy arrhythmogenic

right ventricular dysplasia hypertrophic cardiomyopathyand viral myocarditis [17 29 30]

In this study we hypothesized that unregulated apoptosisinduced by reduced DNA repair capacities due to inheritedXPC gene polymorphisms may contribute to the develop-ment of MCTR Because of the unique architect and tissuecomponents of chordae tendineae any changes in DNAdamage may eventually lead to MCTR Recently experi-mental and clinical studies also showed a close associationbetween apoptosis and valvular heart disease [18 19] Astudy by Galeone demonstrated that TNF-related apoptosis-inducing ligand is characteristically present within calcificaortic valves and mediates the calcification of aortic valveinterstitial cells in culture through mechanism involvingapoptosis Another study by Torigoe et al has revealed thatapoptotic regulatory genes and antiapoptotic mechanismmay play a role in the pathogenesis of canine myxomatousmitral valve disease [19] As yet the role of apoptosis in thepathogenesis of MCTR has not been evaluated Howeversome evidence has supported the possible role of apoptosison MCTRThis evidence suggests that upregulation of MMPand downregulation of tissue inhibitor of metalloproteinase(TIMP) 2 genes predispose patients to ruptured chordaetendineae [5 6] It has become known that MMPs and TIMP2 may be potential regulators of apoptosis MMPs cleavecell surface receptors they release apoptotic ligands like FASligandMMPs affectmany behavioral patterns of the cell suchas proliferation differentiation migration and apoptosisTIMP 2 is an endogenous inhibitor for MMPs In contrastTIMP-2 is able to promote cell proliferation in a wide range ofcell types andmay also have an antiapoptotic function Basedon the above observations we intended to investigate XPCLys939Gln polymorphisms and the risk of mitral chordaetendineae ruptureWemay report that heterozygote genotype(AC) and homozygote genotype (CC) of XPC gene werehighly associated with MCTR It has also been found thatapoptosis induced by DNA damage as a consequence ofXPC polymorphism makes people more prone to developMCTR as well as cancers This study provides preliminaryresults for further studies of the relatively large number ofparticipants It is hoped that a better understanding of themolecular mechanisms of MCTR may yield novel diagnosticand therapeutic targets

5 Limitations

Our study has some limitations The major limitation of thepresent study is its small sample size Therefore although theresults of our study are interesting they should be interpretedcautiously until further studies including a greater number ofpatients may be conducted

6 Conclusion

Our study has shown that XPC Lys939Gln gene polymor-phism is correlatedwith an increased risk of theMCTRdevel-opment Abnormal regulation of apoptosis and diminished

Disease Markers 5

DNA repair capacity may be present in the molecular mech-anism of MCTR Further studies with a larger number ofpatients are warranted to validate these findings

Conflict of Interests

All other authors have no conflict of interests to declare

References

[1] U Gabbay and C Yosefy ldquoThe underlying causes of chordaetendinae rupture a systematic reviewrdquo International Journal ofCardiology vol 143 no 2 pp 113ndash118 2010

[2] D B G Oliveira K D Dawkins P H Kay and M PanethldquoChordal rupture I aetiology and natural historyrdquo British HeartJournal vol 50 no 4 pp 312ndash317 1983

[3] L H Ling M Enriquez-Sarano J B Seward et al ldquoClinicaloutcome of mitral regurgitation due to flail leafletrdquo The NewEngland Journal ofMedicine vol 335 no 19 pp 1417ndash1423 1996

[4] W R Mills J E Barber N B Ratliff D M Cosgrove III IVesely and B P Griffin ldquoBiomechanical and echocardiographiccharacterization of flail mitral leaflet due to myxomatous dis-ease further evidence for early surgical interventionrdquoAmericanHeart Journal vol 148 no 1 pp 144ndash150 2004

[5] N Kimura C Shukunami D Hakuno et al ldquoLocal tenomod-ulin absence angiogenesis and matrix metalloproteinase acti-vation are associated with the rupture of the chordae tendineaecordisrdquo Circulation vol 118 no 17 pp 1737ndash1747 2008

[6] T-H Lin S-F Yang C-C Chiu et al ldquoMatrix metallo-proteinase-1 mitral expression and -1607 1G2G gene promoterpolymorphism in mitral chordae tendinae rupturerdquo Transla-tional Research vol 161 no 5 pp 406ndash413 2013

[7] K Sugasawa J M Y Ng C Masutani et al ldquoXeroderma pig-mentosum group C protein complex is the initiator of globalgenome nucleotide excision repairrdquoMolecular Cell vol 2 no 2pp 223ndash232 1998

[8] R Legerski and C Peterson ldquoExpression cloning of a humanDNA repair gene involved in xeroderma pigmentosum groupCrdquo Nature vol 359 no 6390 pp 70ndash73 1992

[9] L Li C Peterson and R Legerski ldquoSequence of themouse XPCcDNA and genomic structure of the human XPC generdquo NucleicAcids Research vol 24 no 6 pp 1026ndash1028 1996

[10] W K Kaufmann and R S Paules ldquoDNA damage and cell cyclecheckpointsrdquo The FASEB Journal vol 10 no 2 pp 238ndash2471996

[11] G J StoutMOosten F Z Acherrat et al ldquoSelectiveDNAdam-age responses in murine Xpaminusminus Xpcminusminus and Csbminusminus keratino-cyte culturesrdquo DNA Repair vol 4 no 11 pp 1337ndash1344 2005

[12] G Wang A Dombkowski L Chuang and X X S Xu ldquoTheinvolvement of XPC protein in the cisplatin DNA damagingtreatment-mediated cellular responserdquo Cell research vol 14 no4 pp 303ndash314 2004

[13] Z Chen J Yang GWang B Song J Li and Z Xu ldquoAttenuatedexpression of xeroderma pigmentosum group C is associatedwith critical events in human bladder cancer carcinogenesis andprogressionrdquo Cancer Research vol 67 no 10 pp 4578ndash45852007

[14] S Adimoolam and J M Ford ldquop53 andDNA damage-inducibleexpression of the xeroderma pigmentosum group C generdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12985ndash12990 2002

[15] Q-E Wang C Han B Zhang K Sabapathy and A A WanildquoNucleotide excision repair factor XPC enhancesDNAdamage-induced apoptosis by downregulating the antiapoptotic shortisoform of caspase-2rdquo Cancer Research vol 72 no 3 pp 666ndash675 2012

[16] C Gill R Mestril and A Samali ldquoLosing heart the role ofapoptosis in heart diseasemdasha novel therapeutic targetrdquo TheFASEB Journal vol 16 no 2 pp 135ndash146 2002

[17] I Tuleta A KAlGhaddioui G Bauriedel et al ldquoThe imbalancebetween proliferation and apoptosis contributes to degenera-tion of aortic valves and bioprosthesesrdquo Cardiology Journal vol20 no 3 pp 268ndash276 2013

[18] T Jiranantasak A Rungsipipat and S Surachetpong ldquoHisto-pathological changes and apoptosis detection in canine myxo-matous mitral valve disease using tissue microarray techniquerdquoComparative Clinical Pathology vol 23 pp 1173ndash1178 2014

[19] T Torigoe H Sakaguchi M Kitano et al ldquoClinical charac-teristics of acute mitral regurgitation due to ruptured chordaetendineae in infancymdashexperience at a single institutionrdquo Euro-pean Journal of Pediatrics vol 171 no 2 pp 259ndash265 2012

[20] A J Hickey D E L Wilcken J S Wright and B A WarrenldquoPrimary (spontaneous) chordal rupture relation to myxoma-tous valve disease and mitral valve prolapserdquo Journal of theAmerican College of Cardiology vol 5 no 6 pp 1341ndash1346 1985

[21] M H Sherman C H Bassing and M A Teitell ldquoRegulationof cell differentiation by the DNA damage responserdquo Trends inCell Biology vol 21 no 5 pp 312ndash319 2011

[22] H Shen E M Sturgis S G Khan et al ldquoAn intronic poly(AT) polymorphism of the DNA repair gene XPC and risk ofsquamous cell carcinoma of the head and neck a case-controlstudyrdquo Cancer Research vol 61 no 8 pp 3321ndash3325 2001

[23] U Vogel K Overvad H Wallin A Tjoslashnneland B A Nexoslashand O Raaschou-Nielsen ldquoCombinations of polymorphisms inXPD XPC and XPA in relation to risk of lung cancerrdquo CancerLetters vol 222 no 1 pp 67ndash74 2005

[24] C Liu Q Yin M Ying et al ldquoXPC Lys939Gln and Ala499Valpolymorphisms in colorectal cancer susceptibility a meta-analysis of case-control studiesrdquoMolecular Biology Reports vol41 no 2 pp 1171ndash1178 2014

[25] S Blankenburg I R Konig R Moessner et al ldquoAssessment of3 xeroderma pigmentosum group C gene polymorphisms andrisk of cutaneous melanoma a case-control studyrdquo Carcinogen-esis vol 26 no 6 pp 1085ndash1090 2005

[26] R A Gottlieb K O Burleson R A Kloner B M Babior andR L Engler ldquoReperfusion injury induces apoptosis in rabbitcardiomyocytesrdquo Journal of Clinical Investigation vol 94 no 4pp 1621ndash1628 1994

[27] J Narula NHaider R Virmani et al ldquoApoptosis inmyocytes inend-stage heart failurerdquo The New England Journal of Medicinevol 335 no 16 pp 1182ndash1189 1996

[28] R L Debiasi B A Robinson J S Leser R D Brown C SLong and P Clarke ldquoCritical role for death-receptor mediatedapoptotic signaling in viral myocarditisrdquo Journal of CardiacFailure vol 16 no 11 pp 901ndash910 2010

6 Disease Markers

[29] A Galeone G Brunetti A Oranger et al ldquoAortic valvularinterstitial cells apoptosis and calcification are mediated byTNF-related apoptosis-inducing ligandrdquo International Journalof Cardiology vol 169 no 4 pp 296ndash304 2013

[30] P Valente G Fassina A Melchiori et al ldquoTIMP-2 over-expression reduces invasion and angiogenesis and protectsB16F10 melanoma cells from apoptosisrdquo International Journalof Cancer vol 75 no 2 pp 246ndash253 1998

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Page 2: Research Article DNA Repair Gene Polymorphism and the Risk ...downloads.hindawi.com/journals/dm/2015/825020.pdf · Research Article DNA Repair Gene Polymorphism and the Risk of Mitral

2 Disease Markers

angiogenesis and fibrosis may have an important role in thepathogenesis ofMCTR [5 6] Recently Kimura et al revealedthat downregulation of tissue inhibitor of metalloproteinase(TIMP) 2 and tenomodulin and upregulation of vascularendothelial growth factor- (VEG) A and matrix metallopro-teinases (MMP) likely play a major role in the molecularmechanism underlying the pathophysiology of MCTR [5] Inaddition Lin et al also showed that MMP 1 gene expressionand MMP 1-1607-1626 gene polymorphism were indepen-dently associated with MCTR [6] These preliminary studieshave demonstrated that genetic factors have an influence onindividual susceptibility to MCTR

The Xeroderma Pigmentosum Complementation GroupC (XPC) made up one of the eight core genes (ie ERCC1XPA XPB XPC XPD XPE XPF and XPG) and serves as theprimary initiating factor in the genome nucleotide excisionrepair pathway (NER) [7ndash9] The XPC gene encodes a 940-amino acid protein spanning 33 kb on chromosome 3p25and contains 16 exons and 15 introns [10] The XPC geneplays a crucial role in maintaining a balance between cellproliferation and apoptosis [11ndash13] The XPC gene polymor-phism enhances DNA damage-induced apoptosis throughthe activation of p53 or p53-independent apoptotic pathway[14ndash16] Increasing evidence has provided support for theexistence of apoptotic pathways and their regulators in theheart [17] The relationship between the pathways of apop-tosis and various valvular disorders such as degenerativeaortic valve disease andmyxomatousmitral valve disease hasbeen demonstrated in previous studies [18 19] However therole of pathways of apoptosis in MCTR remains unknownThis study has been conducted to investigate the role orassociation of XPC polymorphisms in the pathogenesis ofidiopathic MCTR patients

2 Methods

21 Study Subjects Twenty-one patients with idiopathicMCTR and thirty-seven subjects without valvular heartdisease were recruited from files of the Department of Cardi-ology of Sakarya University All subjects in the MCTR groupunderwent transesophageal echocardiography to confirm thediagnosis The Ethical Committee of Sakarya UniversitySchool of Medicine provided ethical approval for this studyThe study conformed to the ethical principles of the Decla-ration of Helsinki Informed written consent was obtainedfrom each subject included in the present study Patientswith infective endocarditis rheumatic heart disease mitralvalve prolapse myxomatous degeneration connective tissuedisease blunt chest trauma hypertrophic cardiomyopathyand acute coronary syndromes including acute myocardialinfarction chronic renal failure chronic congestive heartfailure known or suspected infiltrative cardiac diseasesconstrictive andor restrictive cardiomyopathy and chronic-active inflammatory disease current smokers and thosediagnosed with any cancer were excluded from the studyClinical and demographical data such as age gender heightand weight were recorded on patient charts Measures of car-diovascular risk including hypertension diabetes mellitusand medication use were also evaluated

22 Echocardiographic Examination In all subjects trans-thoracic two-dimensional and Doppler echocardiographicexaminations performed by a Vivid 5 echocardiography sys-tem (General Electric Vingmed USG Israel) using 25MHztransducers were carried out according to standards ofthe American Society of Echocardiography Transesophagealechocardiography (TEE) was performed in all patients withMCTR Left atrial (LA) diameter was measured from theparasternal left heart long-axis view Pulmonary artery trunkand pulmonary flow were measured from the aortic short-axis view Mitral inflow and aortic valve flow were alsomeasured Pulmonary artery systolic pressure was calculatedaccording to velocity of tricuspid regurgitation using theBernoulli equation The left ventricular end diastolic diam-eter (LVEDd) and ejection fractions (EF) were calculated bythe M-mode method The quantification of mitral regurgita-tion (MR) is made according to the echocardiographic meth-ods including vena contracta width the flow convergencemethod and color Doppler characteristics of regurgitantjet penetration The mitral valve and its chordae tendineaewere observed in the left ventricular midesophageal and MVtransgastric views using rotation of the TEE probe to achievethe clearest view MCTR diagnosis was made on the basisof flail mitral valve associated with chordal elongation andchordal swinging with or without chordal remnant root

23 DNA Isolation and Genotyping Genomic DNA wasextracted from whole blood samples using a special isolationkit (Roche Diagnostics DNA Isolation Kit for MammalianBloodGermany) All isolation stepswere carefully performedaccording to the manufacturerrsquos instructions Genotypingof XPC Lys939Gln polymorphism was carried out usingpolymerase chain reaction- (PCR-) restriction fragmentlength polymorphism PCR amplification was performed ina 30 120583L PCR volume containing 100 ng template DNA 0750units Taq polymerase (Fermentas) 1x Mg++ free PCR buffer(Fermentas) 200mM dNTP (Fermentas) 15mM MgCl++10 pMol of each F 51015840-GGCTTCCTGGTATCTGATTACT-31015840R 51015840-CTCAGTTTGCCTTCTCAGCA-31015840 (GenBank acces-sion number NC 00000312) The incubation process of thetouchdown-PCR (Sensoquest Thermocycler Germany) wasperformed as follows 4min at 95∘C followed by 16 cyclesfor 30 sec at 95∘C 30 sec at 60∘C and 45 sec at 72∘C adding05 seccycle Then 30 cycles of the triple steps were per-formed for 30 sec at 94∘C 30 sec at 52∘C and 2min at 72∘Cthe final elongation step was achieved after 10min at 72∘CAfter agarose gel electrophoresis the 10 120583L PCR-amplifiedDNA was digested with PvuII restriction enzyme for 20minutes at 37∘C and electrophoresed on 2 agarose gel Thehomozygote wild-type genotype was identified by a singleband at 402 bp level the heterozygote genotype by 3 bandsat 402 276 and 126 bp levels and the homozygote variant by2 bands at 276 and 126 bp levels (Figure 1)

24 Statistical Methods Distributions of genotype weresuited to the Hardy-Weinberg equilibrium in both controland case groups (119901 = 0623 and 119901 = 0519 resp) Pear-sonrsquos and Fisherrsquos Chi-Square tests were used to comparethe genotypes alleles and other categorical data between

Disease Markers 3

500bp400bp250bp

100 bp50bp

M 1 2 3 4 5 6 7 8 9 10

Figure 1 Genotypes were generated from 402 bp PCR productacquired from 9 individuals using specific primers after digestionwith PvuII restriction enzyme The lanes were as follows M DNAladder lanes 1 and 7 CC genotype homozygote variant lanes 2 and8 AA genotype homozygote wild type lanes 3 4 5 6 9 and 10 ACgenotype heterozygote

control and case groups Categorical data were expressed ascount and percentages According to Kolmogorov-Smirnovnormality test two independent-sample 119905-tests were usedto compare the continuous variables between two groupsContinuous data were expressed as mean and standard devi-ation A multiple logistic regression model was implementedto determine genotypes and other covariates associated withXPC The odds ratio was calculated for heterozygous andmutant individuals in the assessment of risk status accordingto the normal group A 119901 value lt005 was consideredsignificant Analyses were performed using commercial soft-ware (IBM SPSS Statistics Version 220 Armonk NY IBMCorp)

3 Results

This study contains 21 MCTR patients with 57 plusmn 16 meanage and 37 control groups with 52 plusmn 16 mean age Of the21 MCTR patients 15 (714) were male and 6 (286) werefemale Of the 37 control groups 19 (513) were male and18 (487) were female Demographic echocardiographiclaboratory and genotypeallele frequencies of the XPCLys939Gln polymorphisms between MCTR patients andcontrols are summarized in Tables 1 and 2 The frequenciesof the heterozygote genotype (LysGln-AC) and homozygotegenotype (GlnGln-CC)were significantly different inMCTRas compared to control group respectively (524 versus432 119901 = 0049 3815 versus 162 119901 = 0018) The oddsratio for heterozygous and mutant individuals was calculatedin the risk status assessment which is prepared regarding thenormal group Homozygote variant (GlnGln) genotype wassignificantly associated with increased risk of MCTR (OR =2059 95 CI 1097ndash3863 119901 = 0018) Heterozygote variant(LysGln) genotype was also highly significantly associatedwith increased risk of MCTR (OR = 1489 95 CI 1041ndash2129 119901 = 0049) The variant allele C was found to besignificantly associated with MCTR (OR = 1481 95 CI1101ndash1992 119901 = 0011) (Table 3)

Table 1 Baseline characteristics and laboratory findings of case andcontrol groups

Control (119899 = 37) Case (119899 = 21) 119901

GenotypeAA 15 (4054) 2 (952)

0026AC 16 (4324) 11 (5238)CC 6 (1622) 8 (381)

Age 4749 plusmn 1521 57 plusmn 1612 0029HTNo 19 (5135) 13 (619) 0616Yes 18 (4865) 8 (381)

DMNo 31 (8378) 20 (9524) 0403Yes 6 (1622) 1 (476)

CADNo 34 (9189) 20 (9524) 1000Yes 3 (811) 1 (476)

Crea 093 plusmn 017 096 plusmn 037 0703LDL 12465 plusmn 282 10852 plusmn 316 0049HDL 4214 plusmn 96 4143 plusmn 1244 0810CRP 285 plusmn 165 416 plusmn 281 0061UA 525 plusmn 11 577 plusmn 151 0134HT hypertension DM diabetes mellitus CAD coronary artery diseaseCrea creatinine HDL high-density lipoprotein LDL low-density lipopro-tein CRP C-reactive protein and UA uric acid

Table 2 Echocardiographic findings of case and control groups

Control (119899 = 37) Case (119899 = 21) 119901

LAD 349 plusmn 018 475 plusmn 047 lt0001AOD 325 plusmn 019 334 plusmn 014 0057LVSD 33 plusmn 027 428 plusmn 033 lt0001LVDD 488 plusmn 024 541 plusmn 031 lt0001LVEF 063 plusmn 004 055 plusmn 006 lt0001IVST 114 plusmn 008 117 plusmn 01 0224PWT 114 plusmn 008 117 plusmn 01 0156MPAP 1876 plusmn 209 4029 plusmn 73 lt0001MR gradingModerate 9 (4286) mdashSevere 12 (5714)

Vena contracta width 065 plusmn 011 mdashLAD left atrial diameter AOD aortic root diameter LVSD left ventricularsystolic diameter LVDD left ventricular diastolic diameter LVEF leftventricular ejection fraction IVST interventricular septal thickness PWTposterior wall thickness MPAP mean pulmonary artery pressure MRmitral regurgitation and VCW vena contracta width

Table 3Multiple logistic regressionmodels for genotypes and othercovariates associated with XPC

120573SE of120573

Wald 119901 OR 95 CI for ORLower Upper

Genotype 677 0034Genotype(AC) 327 130 634 0012 2637 207 33673

Genotype(CC) 323 135 570 0017 2536 179 36037

Age 013 005 858 0003 114 104 124HT minus212 108 381 0051 012 001 101DM minus317 162 380 0051 004 000 102CAD minus388 176 488 0027 002 000 065LDL minus005 002 683 0009 095 091 099Constant minus227 213 113 0287 010

4 Disease Markers

4 Discussion

There are currently no published reports in the literature onthe XP polymorphisms profile of MCTR Thus this is toour knowledge the first study demonstrating a link betweenthe XPC polymorphisms and MCTR This study showedthat increased heterozygote genotype (AC) and homozygotegenotype (CC) frequencies of the XPC Lys939Gln polymor-phisms might result in increased genetic susceptibility toMCTR Furthermore the variant allele C genotype was alsohighly associated with increased risk of MCTR

MCTR is an increasingly important cause of mitralregurgitation and is more common in male adults over 50[1] Rupture of a single structure of chordae leads to limitedhemodynamic effect and usually requires neither interven-tion nor treatment Significant rupture of amultiple structureof chordae tendineae usually results in acute severe mitralregurgitation andhemodynamic instability requiring promptsurgical intervention [2 3] The leading underlying causesin the literature were blunt thoracic trauma connective tis-sue diseases coronary artery disease infective endocarditisrheumatic mitral stenosis and mitral valve prolapse Unde-termined cases are defined as primary (idiopathic) chordaerupture in which there is obviously no underlying cause In arecent systematic review the prevalence of idiopathic MCTRwas 512 [1 20 21]

The pathophysiologic mechanism that results in idio-pathic MCTR is still unclear Recently the investigators haveattempted to establish genetic factors which are thought toplay a key role inMCTR occurrence Evidence for these stud-ies demonstrated that inflammation increased expressionof genes encoding signal cascade which instigate apoptoticbalance and cell differentiation may have an important rolein the pathogenesis of MCTR [5 6]

DNA repair genes protect genomic integrity and they arebasic components of normal cell homeostasis necessary tocell growth differentiation and apoptosis [21 22] It is knownthat diminished DNA repair capacity due to various DNArepair gene polymorphisms is associated with increasedrisk and susceptibility to human solid tumors [23ndash25] XPCis a key member in the nucleotide excision repair (NER)pathway It is involved in the recognition and initiation ofthe genome repair of NER pathway [7ndash9] Polymorphismsin the XPC gene may alter DNA repair capacity of the NERpathway which further play a critical role in carcinogenesisSeveral polymorphic variants in the XPC gene have beenidentified The most common polymorphisms of XPC geneare Ala499Val (CrarrT) PAT (minus+) and Lys939Gln (ArarrC)[25ndash28] Increasing evidence has accumulated suggesting thatXPC gene polymorphism can cause replication blockagewhich also enhances unregulated apoptosis induced by DNAdamage [11ndash13] Recent studies support the claim that apop-tosis does occur in the heart [17] Data obtained from numer-ous studies have suggested a possible role for apoptosis inheart failure ischemiareperfusion injury idiopathic dilatedcardiomyopathy ischemic cardiomyopathy arrhythmogenic

right ventricular dysplasia hypertrophic cardiomyopathyand viral myocarditis [17 29 30]

In this study we hypothesized that unregulated apoptosisinduced by reduced DNA repair capacities due to inheritedXPC gene polymorphisms may contribute to the develop-ment of MCTR Because of the unique architect and tissuecomponents of chordae tendineae any changes in DNAdamage may eventually lead to MCTR Recently experi-mental and clinical studies also showed a close associationbetween apoptosis and valvular heart disease [18 19] Astudy by Galeone demonstrated that TNF-related apoptosis-inducing ligand is characteristically present within calcificaortic valves and mediates the calcification of aortic valveinterstitial cells in culture through mechanism involvingapoptosis Another study by Torigoe et al has revealed thatapoptotic regulatory genes and antiapoptotic mechanismmay play a role in the pathogenesis of canine myxomatousmitral valve disease [19] As yet the role of apoptosis in thepathogenesis of MCTR has not been evaluated Howeversome evidence has supported the possible role of apoptosison MCTRThis evidence suggests that upregulation of MMPand downregulation of tissue inhibitor of metalloproteinase(TIMP) 2 genes predispose patients to ruptured chordaetendineae [5 6] It has become known that MMPs and TIMP2 may be potential regulators of apoptosis MMPs cleavecell surface receptors they release apoptotic ligands like FASligandMMPs affectmany behavioral patterns of the cell suchas proliferation differentiation migration and apoptosisTIMP 2 is an endogenous inhibitor for MMPs In contrastTIMP-2 is able to promote cell proliferation in a wide range ofcell types andmay also have an antiapoptotic function Basedon the above observations we intended to investigate XPCLys939Gln polymorphisms and the risk of mitral chordaetendineae ruptureWemay report that heterozygote genotype(AC) and homozygote genotype (CC) of XPC gene werehighly associated with MCTR It has also been found thatapoptosis induced by DNA damage as a consequence ofXPC polymorphism makes people more prone to developMCTR as well as cancers This study provides preliminaryresults for further studies of the relatively large number ofparticipants It is hoped that a better understanding of themolecular mechanisms of MCTR may yield novel diagnosticand therapeutic targets

5 Limitations

Our study has some limitations The major limitation of thepresent study is its small sample size Therefore although theresults of our study are interesting they should be interpretedcautiously until further studies including a greater number ofpatients may be conducted

6 Conclusion

Our study has shown that XPC Lys939Gln gene polymor-phism is correlatedwith an increased risk of theMCTRdevel-opment Abnormal regulation of apoptosis and diminished

Disease Markers 5

DNA repair capacity may be present in the molecular mech-anism of MCTR Further studies with a larger number ofpatients are warranted to validate these findings

Conflict of Interests

All other authors have no conflict of interests to declare

References

[1] U Gabbay and C Yosefy ldquoThe underlying causes of chordaetendinae rupture a systematic reviewrdquo International Journal ofCardiology vol 143 no 2 pp 113ndash118 2010

[2] D B G Oliveira K D Dawkins P H Kay and M PanethldquoChordal rupture I aetiology and natural historyrdquo British HeartJournal vol 50 no 4 pp 312ndash317 1983

[3] L H Ling M Enriquez-Sarano J B Seward et al ldquoClinicaloutcome of mitral regurgitation due to flail leafletrdquo The NewEngland Journal ofMedicine vol 335 no 19 pp 1417ndash1423 1996

[4] W R Mills J E Barber N B Ratliff D M Cosgrove III IVesely and B P Griffin ldquoBiomechanical and echocardiographiccharacterization of flail mitral leaflet due to myxomatous dis-ease further evidence for early surgical interventionrdquoAmericanHeart Journal vol 148 no 1 pp 144ndash150 2004

[5] N Kimura C Shukunami D Hakuno et al ldquoLocal tenomod-ulin absence angiogenesis and matrix metalloproteinase acti-vation are associated with the rupture of the chordae tendineaecordisrdquo Circulation vol 118 no 17 pp 1737ndash1747 2008

[6] T-H Lin S-F Yang C-C Chiu et al ldquoMatrix metallo-proteinase-1 mitral expression and -1607 1G2G gene promoterpolymorphism in mitral chordae tendinae rupturerdquo Transla-tional Research vol 161 no 5 pp 406ndash413 2013

[7] K Sugasawa J M Y Ng C Masutani et al ldquoXeroderma pig-mentosum group C protein complex is the initiator of globalgenome nucleotide excision repairrdquoMolecular Cell vol 2 no 2pp 223ndash232 1998

[8] R Legerski and C Peterson ldquoExpression cloning of a humanDNA repair gene involved in xeroderma pigmentosum groupCrdquo Nature vol 359 no 6390 pp 70ndash73 1992

[9] L Li C Peterson and R Legerski ldquoSequence of themouse XPCcDNA and genomic structure of the human XPC generdquo NucleicAcids Research vol 24 no 6 pp 1026ndash1028 1996

[10] W K Kaufmann and R S Paules ldquoDNA damage and cell cyclecheckpointsrdquo The FASEB Journal vol 10 no 2 pp 238ndash2471996

[11] G J StoutMOosten F Z Acherrat et al ldquoSelectiveDNAdam-age responses in murine Xpaminusminus Xpcminusminus and Csbminusminus keratino-cyte culturesrdquo DNA Repair vol 4 no 11 pp 1337ndash1344 2005

[12] G Wang A Dombkowski L Chuang and X X S Xu ldquoTheinvolvement of XPC protein in the cisplatin DNA damagingtreatment-mediated cellular responserdquo Cell research vol 14 no4 pp 303ndash314 2004

[13] Z Chen J Yang GWang B Song J Li and Z Xu ldquoAttenuatedexpression of xeroderma pigmentosum group C is associatedwith critical events in human bladder cancer carcinogenesis andprogressionrdquo Cancer Research vol 67 no 10 pp 4578ndash45852007

[14] S Adimoolam and J M Ford ldquop53 andDNA damage-inducibleexpression of the xeroderma pigmentosum group C generdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12985ndash12990 2002

[15] Q-E Wang C Han B Zhang K Sabapathy and A A WanildquoNucleotide excision repair factor XPC enhancesDNAdamage-induced apoptosis by downregulating the antiapoptotic shortisoform of caspase-2rdquo Cancer Research vol 72 no 3 pp 666ndash675 2012

[16] C Gill R Mestril and A Samali ldquoLosing heart the role ofapoptosis in heart diseasemdasha novel therapeutic targetrdquo TheFASEB Journal vol 16 no 2 pp 135ndash146 2002

[17] I Tuleta A KAlGhaddioui G Bauriedel et al ldquoThe imbalancebetween proliferation and apoptosis contributes to degenera-tion of aortic valves and bioprosthesesrdquo Cardiology Journal vol20 no 3 pp 268ndash276 2013

[18] T Jiranantasak A Rungsipipat and S Surachetpong ldquoHisto-pathological changes and apoptosis detection in canine myxo-matous mitral valve disease using tissue microarray techniquerdquoComparative Clinical Pathology vol 23 pp 1173ndash1178 2014

[19] T Torigoe H Sakaguchi M Kitano et al ldquoClinical charac-teristics of acute mitral regurgitation due to ruptured chordaetendineae in infancymdashexperience at a single institutionrdquo Euro-pean Journal of Pediatrics vol 171 no 2 pp 259ndash265 2012

[20] A J Hickey D E L Wilcken J S Wright and B A WarrenldquoPrimary (spontaneous) chordal rupture relation to myxoma-tous valve disease and mitral valve prolapserdquo Journal of theAmerican College of Cardiology vol 5 no 6 pp 1341ndash1346 1985

[21] M H Sherman C H Bassing and M A Teitell ldquoRegulationof cell differentiation by the DNA damage responserdquo Trends inCell Biology vol 21 no 5 pp 312ndash319 2011

[22] H Shen E M Sturgis S G Khan et al ldquoAn intronic poly(AT) polymorphism of the DNA repair gene XPC and risk ofsquamous cell carcinoma of the head and neck a case-controlstudyrdquo Cancer Research vol 61 no 8 pp 3321ndash3325 2001

[23] U Vogel K Overvad H Wallin A Tjoslashnneland B A Nexoslashand O Raaschou-Nielsen ldquoCombinations of polymorphisms inXPD XPC and XPA in relation to risk of lung cancerrdquo CancerLetters vol 222 no 1 pp 67ndash74 2005

[24] C Liu Q Yin M Ying et al ldquoXPC Lys939Gln and Ala499Valpolymorphisms in colorectal cancer susceptibility a meta-analysis of case-control studiesrdquoMolecular Biology Reports vol41 no 2 pp 1171ndash1178 2014

[25] S Blankenburg I R Konig R Moessner et al ldquoAssessment of3 xeroderma pigmentosum group C gene polymorphisms andrisk of cutaneous melanoma a case-control studyrdquo Carcinogen-esis vol 26 no 6 pp 1085ndash1090 2005

[26] R A Gottlieb K O Burleson R A Kloner B M Babior andR L Engler ldquoReperfusion injury induces apoptosis in rabbitcardiomyocytesrdquo Journal of Clinical Investigation vol 94 no 4pp 1621ndash1628 1994

[27] J Narula NHaider R Virmani et al ldquoApoptosis inmyocytes inend-stage heart failurerdquo The New England Journal of Medicinevol 335 no 16 pp 1182ndash1189 1996

[28] R L Debiasi B A Robinson J S Leser R D Brown C SLong and P Clarke ldquoCritical role for death-receptor mediatedapoptotic signaling in viral myocarditisrdquo Journal of CardiacFailure vol 16 no 11 pp 901ndash910 2010

6 Disease Markers

[29] A Galeone G Brunetti A Oranger et al ldquoAortic valvularinterstitial cells apoptosis and calcification are mediated byTNF-related apoptosis-inducing ligandrdquo International Journalof Cardiology vol 169 no 4 pp 296ndash304 2013

[30] P Valente G Fassina A Melchiori et al ldquoTIMP-2 over-expression reduces invasion and angiogenesis and protectsB16F10 melanoma cells from apoptosisrdquo International Journalof Cancer vol 75 no 2 pp 246ndash253 1998

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 3: Research Article DNA Repair Gene Polymorphism and the Risk ...downloads.hindawi.com/journals/dm/2015/825020.pdf · Research Article DNA Repair Gene Polymorphism and the Risk of Mitral

Disease Markers 3

500bp400bp250bp

100 bp50bp

M 1 2 3 4 5 6 7 8 9 10

Figure 1 Genotypes were generated from 402 bp PCR productacquired from 9 individuals using specific primers after digestionwith PvuII restriction enzyme The lanes were as follows M DNAladder lanes 1 and 7 CC genotype homozygote variant lanes 2 and8 AA genotype homozygote wild type lanes 3 4 5 6 9 and 10 ACgenotype heterozygote

control and case groups Categorical data were expressed ascount and percentages According to Kolmogorov-Smirnovnormality test two independent-sample 119905-tests were usedto compare the continuous variables between two groupsContinuous data were expressed as mean and standard devi-ation A multiple logistic regression model was implementedto determine genotypes and other covariates associated withXPC The odds ratio was calculated for heterozygous andmutant individuals in the assessment of risk status accordingto the normal group A 119901 value lt005 was consideredsignificant Analyses were performed using commercial soft-ware (IBM SPSS Statistics Version 220 Armonk NY IBMCorp)

3 Results

This study contains 21 MCTR patients with 57 plusmn 16 meanage and 37 control groups with 52 plusmn 16 mean age Of the21 MCTR patients 15 (714) were male and 6 (286) werefemale Of the 37 control groups 19 (513) were male and18 (487) were female Demographic echocardiographiclaboratory and genotypeallele frequencies of the XPCLys939Gln polymorphisms between MCTR patients andcontrols are summarized in Tables 1 and 2 The frequenciesof the heterozygote genotype (LysGln-AC) and homozygotegenotype (GlnGln-CC)were significantly different inMCTRas compared to control group respectively (524 versus432 119901 = 0049 3815 versus 162 119901 = 0018) The oddsratio for heterozygous and mutant individuals was calculatedin the risk status assessment which is prepared regarding thenormal group Homozygote variant (GlnGln) genotype wassignificantly associated with increased risk of MCTR (OR =2059 95 CI 1097ndash3863 119901 = 0018) Heterozygote variant(LysGln) genotype was also highly significantly associatedwith increased risk of MCTR (OR = 1489 95 CI 1041ndash2129 119901 = 0049) The variant allele C was found to besignificantly associated with MCTR (OR = 1481 95 CI1101ndash1992 119901 = 0011) (Table 3)

Table 1 Baseline characteristics and laboratory findings of case andcontrol groups

Control (119899 = 37) Case (119899 = 21) 119901

GenotypeAA 15 (4054) 2 (952)

0026AC 16 (4324) 11 (5238)CC 6 (1622) 8 (381)

Age 4749 plusmn 1521 57 plusmn 1612 0029HTNo 19 (5135) 13 (619) 0616Yes 18 (4865) 8 (381)

DMNo 31 (8378) 20 (9524) 0403Yes 6 (1622) 1 (476)

CADNo 34 (9189) 20 (9524) 1000Yes 3 (811) 1 (476)

Crea 093 plusmn 017 096 plusmn 037 0703LDL 12465 plusmn 282 10852 plusmn 316 0049HDL 4214 plusmn 96 4143 plusmn 1244 0810CRP 285 plusmn 165 416 plusmn 281 0061UA 525 plusmn 11 577 plusmn 151 0134HT hypertension DM diabetes mellitus CAD coronary artery diseaseCrea creatinine HDL high-density lipoprotein LDL low-density lipopro-tein CRP C-reactive protein and UA uric acid

Table 2 Echocardiographic findings of case and control groups

Control (119899 = 37) Case (119899 = 21) 119901

LAD 349 plusmn 018 475 plusmn 047 lt0001AOD 325 plusmn 019 334 plusmn 014 0057LVSD 33 plusmn 027 428 plusmn 033 lt0001LVDD 488 plusmn 024 541 plusmn 031 lt0001LVEF 063 plusmn 004 055 plusmn 006 lt0001IVST 114 plusmn 008 117 plusmn 01 0224PWT 114 plusmn 008 117 plusmn 01 0156MPAP 1876 plusmn 209 4029 plusmn 73 lt0001MR gradingModerate 9 (4286) mdashSevere 12 (5714)

Vena contracta width 065 plusmn 011 mdashLAD left atrial diameter AOD aortic root diameter LVSD left ventricularsystolic diameter LVDD left ventricular diastolic diameter LVEF leftventricular ejection fraction IVST interventricular septal thickness PWTposterior wall thickness MPAP mean pulmonary artery pressure MRmitral regurgitation and VCW vena contracta width

Table 3Multiple logistic regressionmodels for genotypes and othercovariates associated with XPC

120573SE of120573

Wald 119901 OR 95 CI for ORLower Upper

Genotype 677 0034Genotype(AC) 327 130 634 0012 2637 207 33673

Genotype(CC) 323 135 570 0017 2536 179 36037

Age 013 005 858 0003 114 104 124HT minus212 108 381 0051 012 001 101DM minus317 162 380 0051 004 000 102CAD minus388 176 488 0027 002 000 065LDL minus005 002 683 0009 095 091 099Constant minus227 213 113 0287 010

4 Disease Markers

4 Discussion

There are currently no published reports in the literature onthe XP polymorphisms profile of MCTR Thus this is toour knowledge the first study demonstrating a link betweenthe XPC polymorphisms and MCTR This study showedthat increased heterozygote genotype (AC) and homozygotegenotype (CC) frequencies of the XPC Lys939Gln polymor-phisms might result in increased genetic susceptibility toMCTR Furthermore the variant allele C genotype was alsohighly associated with increased risk of MCTR

MCTR is an increasingly important cause of mitralregurgitation and is more common in male adults over 50[1] Rupture of a single structure of chordae leads to limitedhemodynamic effect and usually requires neither interven-tion nor treatment Significant rupture of amultiple structureof chordae tendineae usually results in acute severe mitralregurgitation andhemodynamic instability requiring promptsurgical intervention [2 3] The leading underlying causesin the literature were blunt thoracic trauma connective tis-sue diseases coronary artery disease infective endocarditisrheumatic mitral stenosis and mitral valve prolapse Unde-termined cases are defined as primary (idiopathic) chordaerupture in which there is obviously no underlying cause In arecent systematic review the prevalence of idiopathic MCTRwas 512 [1 20 21]

The pathophysiologic mechanism that results in idio-pathic MCTR is still unclear Recently the investigators haveattempted to establish genetic factors which are thought toplay a key role inMCTR occurrence Evidence for these stud-ies demonstrated that inflammation increased expressionof genes encoding signal cascade which instigate apoptoticbalance and cell differentiation may have an important rolein the pathogenesis of MCTR [5 6]

DNA repair genes protect genomic integrity and they arebasic components of normal cell homeostasis necessary tocell growth differentiation and apoptosis [21 22] It is knownthat diminished DNA repair capacity due to various DNArepair gene polymorphisms is associated with increasedrisk and susceptibility to human solid tumors [23ndash25] XPCis a key member in the nucleotide excision repair (NER)pathway It is involved in the recognition and initiation ofthe genome repair of NER pathway [7ndash9] Polymorphismsin the XPC gene may alter DNA repair capacity of the NERpathway which further play a critical role in carcinogenesisSeveral polymorphic variants in the XPC gene have beenidentified The most common polymorphisms of XPC geneare Ala499Val (CrarrT) PAT (minus+) and Lys939Gln (ArarrC)[25ndash28] Increasing evidence has accumulated suggesting thatXPC gene polymorphism can cause replication blockagewhich also enhances unregulated apoptosis induced by DNAdamage [11ndash13] Recent studies support the claim that apop-tosis does occur in the heart [17] Data obtained from numer-ous studies have suggested a possible role for apoptosis inheart failure ischemiareperfusion injury idiopathic dilatedcardiomyopathy ischemic cardiomyopathy arrhythmogenic

right ventricular dysplasia hypertrophic cardiomyopathyand viral myocarditis [17 29 30]

In this study we hypothesized that unregulated apoptosisinduced by reduced DNA repair capacities due to inheritedXPC gene polymorphisms may contribute to the develop-ment of MCTR Because of the unique architect and tissuecomponents of chordae tendineae any changes in DNAdamage may eventually lead to MCTR Recently experi-mental and clinical studies also showed a close associationbetween apoptosis and valvular heart disease [18 19] Astudy by Galeone demonstrated that TNF-related apoptosis-inducing ligand is characteristically present within calcificaortic valves and mediates the calcification of aortic valveinterstitial cells in culture through mechanism involvingapoptosis Another study by Torigoe et al has revealed thatapoptotic regulatory genes and antiapoptotic mechanismmay play a role in the pathogenesis of canine myxomatousmitral valve disease [19] As yet the role of apoptosis in thepathogenesis of MCTR has not been evaluated Howeversome evidence has supported the possible role of apoptosison MCTRThis evidence suggests that upregulation of MMPand downregulation of tissue inhibitor of metalloproteinase(TIMP) 2 genes predispose patients to ruptured chordaetendineae [5 6] It has become known that MMPs and TIMP2 may be potential regulators of apoptosis MMPs cleavecell surface receptors they release apoptotic ligands like FASligandMMPs affectmany behavioral patterns of the cell suchas proliferation differentiation migration and apoptosisTIMP 2 is an endogenous inhibitor for MMPs In contrastTIMP-2 is able to promote cell proliferation in a wide range ofcell types andmay also have an antiapoptotic function Basedon the above observations we intended to investigate XPCLys939Gln polymorphisms and the risk of mitral chordaetendineae ruptureWemay report that heterozygote genotype(AC) and homozygote genotype (CC) of XPC gene werehighly associated with MCTR It has also been found thatapoptosis induced by DNA damage as a consequence ofXPC polymorphism makes people more prone to developMCTR as well as cancers This study provides preliminaryresults for further studies of the relatively large number ofparticipants It is hoped that a better understanding of themolecular mechanisms of MCTR may yield novel diagnosticand therapeutic targets

5 Limitations

Our study has some limitations The major limitation of thepresent study is its small sample size Therefore although theresults of our study are interesting they should be interpretedcautiously until further studies including a greater number ofpatients may be conducted

6 Conclusion

Our study has shown that XPC Lys939Gln gene polymor-phism is correlatedwith an increased risk of theMCTRdevel-opment Abnormal regulation of apoptosis and diminished

Disease Markers 5

DNA repair capacity may be present in the molecular mech-anism of MCTR Further studies with a larger number ofpatients are warranted to validate these findings

Conflict of Interests

All other authors have no conflict of interests to declare

References

[1] U Gabbay and C Yosefy ldquoThe underlying causes of chordaetendinae rupture a systematic reviewrdquo International Journal ofCardiology vol 143 no 2 pp 113ndash118 2010

[2] D B G Oliveira K D Dawkins P H Kay and M PanethldquoChordal rupture I aetiology and natural historyrdquo British HeartJournal vol 50 no 4 pp 312ndash317 1983

[3] L H Ling M Enriquez-Sarano J B Seward et al ldquoClinicaloutcome of mitral regurgitation due to flail leafletrdquo The NewEngland Journal ofMedicine vol 335 no 19 pp 1417ndash1423 1996

[4] W R Mills J E Barber N B Ratliff D M Cosgrove III IVesely and B P Griffin ldquoBiomechanical and echocardiographiccharacterization of flail mitral leaflet due to myxomatous dis-ease further evidence for early surgical interventionrdquoAmericanHeart Journal vol 148 no 1 pp 144ndash150 2004

[5] N Kimura C Shukunami D Hakuno et al ldquoLocal tenomod-ulin absence angiogenesis and matrix metalloproteinase acti-vation are associated with the rupture of the chordae tendineaecordisrdquo Circulation vol 118 no 17 pp 1737ndash1747 2008

[6] T-H Lin S-F Yang C-C Chiu et al ldquoMatrix metallo-proteinase-1 mitral expression and -1607 1G2G gene promoterpolymorphism in mitral chordae tendinae rupturerdquo Transla-tional Research vol 161 no 5 pp 406ndash413 2013

[7] K Sugasawa J M Y Ng C Masutani et al ldquoXeroderma pig-mentosum group C protein complex is the initiator of globalgenome nucleotide excision repairrdquoMolecular Cell vol 2 no 2pp 223ndash232 1998

[8] R Legerski and C Peterson ldquoExpression cloning of a humanDNA repair gene involved in xeroderma pigmentosum groupCrdquo Nature vol 359 no 6390 pp 70ndash73 1992

[9] L Li C Peterson and R Legerski ldquoSequence of themouse XPCcDNA and genomic structure of the human XPC generdquo NucleicAcids Research vol 24 no 6 pp 1026ndash1028 1996

[10] W K Kaufmann and R S Paules ldquoDNA damage and cell cyclecheckpointsrdquo The FASEB Journal vol 10 no 2 pp 238ndash2471996

[11] G J StoutMOosten F Z Acherrat et al ldquoSelectiveDNAdam-age responses in murine Xpaminusminus Xpcminusminus and Csbminusminus keratino-cyte culturesrdquo DNA Repair vol 4 no 11 pp 1337ndash1344 2005

[12] G Wang A Dombkowski L Chuang and X X S Xu ldquoTheinvolvement of XPC protein in the cisplatin DNA damagingtreatment-mediated cellular responserdquo Cell research vol 14 no4 pp 303ndash314 2004

[13] Z Chen J Yang GWang B Song J Li and Z Xu ldquoAttenuatedexpression of xeroderma pigmentosum group C is associatedwith critical events in human bladder cancer carcinogenesis andprogressionrdquo Cancer Research vol 67 no 10 pp 4578ndash45852007

[14] S Adimoolam and J M Ford ldquop53 andDNA damage-inducibleexpression of the xeroderma pigmentosum group C generdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12985ndash12990 2002

[15] Q-E Wang C Han B Zhang K Sabapathy and A A WanildquoNucleotide excision repair factor XPC enhancesDNAdamage-induced apoptosis by downregulating the antiapoptotic shortisoform of caspase-2rdquo Cancer Research vol 72 no 3 pp 666ndash675 2012

[16] C Gill R Mestril and A Samali ldquoLosing heart the role ofapoptosis in heart diseasemdasha novel therapeutic targetrdquo TheFASEB Journal vol 16 no 2 pp 135ndash146 2002

[17] I Tuleta A KAlGhaddioui G Bauriedel et al ldquoThe imbalancebetween proliferation and apoptosis contributes to degenera-tion of aortic valves and bioprosthesesrdquo Cardiology Journal vol20 no 3 pp 268ndash276 2013

[18] T Jiranantasak A Rungsipipat and S Surachetpong ldquoHisto-pathological changes and apoptosis detection in canine myxo-matous mitral valve disease using tissue microarray techniquerdquoComparative Clinical Pathology vol 23 pp 1173ndash1178 2014

[19] T Torigoe H Sakaguchi M Kitano et al ldquoClinical charac-teristics of acute mitral regurgitation due to ruptured chordaetendineae in infancymdashexperience at a single institutionrdquo Euro-pean Journal of Pediatrics vol 171 no 2 pp 259ndash265 2012

[20] A J Hickey D E L Wilcken J S Wright and B A WarrenldquoPrimary (spontaneous) chordal rupture relation to myxoma-tous valve disease and mitral valve prolapserdquo Journal of theAmerican College of Cardiology vol 5 no 6 pp 1341ndash1346 1985

[21] M H Sherman C H Bassing and M A Teitell ldquoRegulationof cell differentiation by the DNA damage responserdquo Trends inCell Biology vol 21 no 5 pp 312ndash319 2011

[22] H Shen E M Sturgis S G Khan et al ldquoAn intronic poly(AT) polymorphism of the DNA repair gene XPC and risk ofsquamous cell carcinoma of the head and neck a case-controlstudyrdquo Cancer Research vol 61 no 8 pp 3321ndash3325 2001

[23] U Vogel K Overvad H Wallin A Tjoslashnneland B A Nexoslashand O Raaschou-Nielsen ldquoCombinations of polymorphisms inXPD XPC and XPA in relation to risk of lung cancerrdquo CancerLetters vol 222 no 1 pp 67ndash74 2005

[24] C Liu Q Yin M Ying et al ldquoXPC Lys939Gln and Ala499Valpolymorphisms in colorectal cancer susceptibility a meta-analysis of case-control studiesrdquoMolecular Biology Reports vol41 no 2 pp 1171ndash1178 2014

[25] S Blankenburg I R Konig R Moessner et al ldquoAssessment of3 xeroderma pigmentosum group C gene polymorphisms andrisk of cutaneous melanoma a case-control studyrdquo Carcinogen-esis vol 26 no 6 pp 1085ndash1090 2005

[26] R A Gottlieb K O Burleson R A Kloner B M Babior andR L Engler ldquoReperfusion injury induces apoptosis in rabbitcardiomyocytesrdquo Journal of Clinical Investigation vol 94 no 4pp 1621ndash1628 1994

[27] J Narula NHaider R Virmani et al ldquoApoptosis inmyocytes inend-stage heart failurerdquo The New England Journal of Medicinevol 335 no 16 pp 1182ndash1189 1996

[28] R L Debiasi B A Robinson J S Leser R D Brown C SLong and P Clarke ldquoCritical role for death-receptor mediatedapoptotic signaling in viral myocarditisrdquo Journal of CardiacFailure vol 16 no 11 pp 901ndash910 2010

6 Disease Markers

[29] A Galeone G Brunetti A Oranger et al ldquoAortic valvularinterstitial cells apoptosis and calcification are mediated byTNF-related apoptosis-inducing ligandrdquo International Journalof Cardiology vol 169 no 4 pp 296ndash304 2013

[30] P Valente G Fassina A Melchiori et al ldquoTIMP-2 over-expression reduces invasion and angiogenesis and protectsB16F10 melanoma cells from apoptosisrdquo International Journalof Cancer vol 75 no 2 pp 246ndash253 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 4: Research Article DNA Repair Gene Polymorphism and the Risk ...downloads.hindawi.com/journals/dm/2015/825020.pdf · Research Article DNA Repair Gene Polymorphism and the Risk of Mitral

4 Disease Markers

4 Discussion

There are currently no published reports in the literature onthe XP polymorphisms profile of MCTR Thus this is toour knowledge the first study demonstrating a link betweenthe XPC polymorphisms and MCTR This study showedthat increased heterozygote genotype (AC) and homozygotegenotype (CC) frequencies of the XPC Lys939Gln polymor-phisms might result in increased genetic susceptibility toMCTR Furthermore the variant allele C genotype was alsohighly associated with increased risk of MCTR

MCTR is an increasingly important cause of mitralregurgitation and is more common in male adults over 50[1] Rupture of a single structure of chordae leads to limitedhemodynamic effect and usually requires neither interven-tion nor treatment Significant rupture of amultiple structureof chordae tendineae usually results in acute severe mitralregurgitation andhemodynamic instability requiring promptsurgical intervention [2 3] The leading underlying causesin the literature were blunt thoracic trauma connective tis-sue diseases coronary artery disease infective endocarditisrheumatic mitral stenosis and mitral valve prolapse Unde-termined cases are defined as primary (idiopathic) chordaerupture in which there is obviously no underlying cause In arecent systematic review the prevalence of idiopathic MCTRwas 512 [1 20 21]

The pathophysiologic mechanism that results in idio-pathic MCTR is still unclear Recently the investigators haveattempted to establish genetic factors which are thought toplay a key role inMCTR occurrence Evidence for these stud-ies demonstrated that inflammation increased expressionof genes encoding signal cascade which instigate apoptoticbalance and cell differentiation may have an important rolein the pathogenesis of MCTR [5 6]

DNA repair genes protect genomic integrity and they arebasic components of normal cell homeostasis necessary tocell growth differentiation and apoptosis [21 22] It is knownthat diminished DNA repair capacity due to various DNArepair gene polymorphisms is associated with increasedrisk and susceptibility to human solid tumors [23ndash25] XPCis a key member in the nucleotide excision repair (NER)pathway It is involved in the recognition and initiation ofthe genome repair of NER pathway [7ndash9] Polymorphismsin the XPC gene may alter DNA repair capacity of the NERpathway which further play a critical role in carcinogenesisSeveral polymorphic variants in the XPC gene have beenidentified The most common polymorphisms of XPC geneare Ala499Val (CrarrT) PAT (minus+) and Lys939Gln (ArarrC)[25ndash28] Increasing evidence has accumulated suggesting thatXPC gene polymorphism can cause replication blockagewhich also enhances unregulated apoptosis induced by DNAdamage [11ndash13] Recent studies support the claim that apop-tosis does occur in the heart [17] Data obtained from numer-ous studies have suggested a possible role for apoptosis inheart failure ischemiareperfusion injury idiopathic dilatedcardiomyopathy ischemic cardiomyopathy arrhythmogenic

right ventricular dysplasia hypertrophic cardiomyopathyand viral myocarditis [17 29 30]

In this study we hypothesized that unregulated apoptosisinduced by reduced DNA repair capacities due to inheritedXPC gene polymorphisms may contribute to the develop-ment of MCTR Because of the unique architect and tissuecomponents of chordae tendineae any changes in DNAdamage may eventually lead to MCTR Recently experi-mental and clinical studies also showed a close associationbetween apoptosis and valvular heart disease [18 19] Astudy by Galeone demonstrated that TNF-related apoptosis-inducing ligand is characteristically present within calcificaortic valves and mediates the calcification of aortic valveinterstitial cells in culture through mechanism involvingapoptosis Another study by Torigoe et al has revealed thatapoptotic regulatory genes and antiapoptotic mechanismmay play a role in the pathogenesis of canine myxomatousmitral valve disease [19] As yet the role of apoptosis in thepathogenesis of MCTR has not been evaluated Howeversome evidence has supported the possible role of apoptosison MCTRThis evidence suggests that upregulation of MMPand downregulation of tissue inhibitor of metalloproteinase(TIMP) 2 genes predispose patients to ruptured chordaetendineae [5 6] It has become known that MMPs and TIMP2 may be potential regulators of apoptosis MMPs cleavecell surface receptors they release apoptotic ligands like FASligandMMPs affectmany behavioral patterns of the cell suchas proliferation differentiation migration and apoptosisTIMP 2 is an endogenous inhibitor for MMPs In contrastTIMP-2 is able to promote cell proliferation in a wide range ofcell types andmay also have an antiapoptotic function Basedon the above observations we intended to investigate XPCLys939Gln polymorphisms and the risk of mitral chordaetendineae ruptureWemay report that heterozygote genotype(AC) and homozygote genotype (CC) of XPC gene werehighly associated with MCTR It has also been found thatapoptosis induced by DNA damage as a consequence ofXPC polymorphism makes people more prone to developMCTR as well as cancers This study provides preliminaryresults for further studies of the relatively large number ofparticipants It is hoped that a better understanding of themolecular mechanisms of MCTR may yield novel diagnosticand therapeutic targets

5 Limitations

Our study has some limitations The major limitation of thepresent study is its small sample size Therefore although theresults of our study are interesting they should be interpretedcautiously until further studies including a greater number ofpatients may be conducted

6 Conclusion

Our study has shown that XPC Lys939Gln gene polymor-phism is correlatedwith an increased risk of theMCTRdevel-opment Abnormal regulation of apoptosis and diminished

Disease Markers 5

DNA repair capacity may be present in the molecular mech-anism of MCTR Further studies with a larger number ofpatients are warranted to validate these findings

Conflict of Interests

All other authors have no conflict of interests to declare

References

[1] U Gabbay and C Yosefy ldquoThe underlying causes of chordaetendinae rupture a systematic reviewrdquo International Journal ofCardiology vol 143 no 2 pp 113ndash118 2010

[2] D B G Oliveira K D Dawkins P H Kay and M PanethldquoChordal rupture I aetiology and natural historyrdquo British HeartJournal vol 50 no 4 pp 312ndash317 1983

[3] L H Ling M Enriquez-Sarano J B Seward et al ldquoClinicaloutcome of mitral regurgitation due to flail leafletrdquo The NewEngland Journal ofMedicine vol 335 no 19 pp 1417ndash1423 1996

[4] W R Mills J E Barber N B Ratliff D M Cosgrove III IVesely and B P Griffin ldquoBiomechanical and echocardiographiccharacterization of flail mitral leaflet due to myxomatous dis-ease further evidence for early surgical interventionrdquoAmericanHeart Journal vol 148 no 1 pp 144ndash150 2004

[5] N Kimura C Shukunami D Hakuno et al ldquoLocal tenomod-ulin absence angiogenesis and matrix metalloproteinase acti-vation are associated with the rupture of the chordae tendineaecordisrdquo Circulation vol 118 no 17 pp 1737ndash1747 2008

[6] T-H Lin S-F Yang C-C Chiu et al ldquoMatrix metallo-proteinase-1 mitral expression and -1607 1G2G gene promoterpolymorphism in mitral chordae tendinae rupturerdquo Transla-tional Research vol 161 no 5 pp 406ndash413 2013

[7] K Sugasawa J M Y Ng C Masutani et al ldquoXeroderma pig-mentosum group C protein complex is the initiator of globalgenome nucleotide excision repairrdquoMolecular Cell vol 2 no 2pp 223ndash232 1998

[8] R Legerski and C Peterson ldquoExpression cloning of a humanDNA repair gene involved in xeroderma pigmentosum groupCrdquo Nature vol 359 no 6390 pp 70ndash73 1992

[9] L Li C Peterson and R Legerski ldquoSequence of themouse XPCcDNA and genomic structure of the human XPC generdquo NucleicAcids Research vol 24 no 6 pp 1026ndash1028 1996

[10] W K Kaufmann and R S Paules ldquoDNA damage and cell cyclecheckpointsrdquo The FASEB Journal vol 10 no 2 pp 238ndash2471996

[11] G J StoutMOosten F Z Acherrat et al ldquoSelectiveDNAdam-age responses in murine Xpaminusminus Xpcminusminus and Csbminusminus keratino-cyte culturesrdquo DNA Repair vol 4 no 11 pp 1337ndash1344 2005

[12] G Wang A Dombkowski L Chuang and X X S Xu ldquoTheinvolvement of XPC protein in the cisplatin DNA damagingtreatment-mediated cellular responserdquo Cell research vol 14 no4 pp 303ndash314 2004

[13] Z Chen J Yang GWang B Song J Li and Z Xu ldquoAttenuatedexpression of xeroderma pigmentosum group C is associatedwith critical events in human bladder cancer carcinogenesis andprogressionrdquo Cancer Research vol 67 no 10 pp 4578ndash45852007

[14] S Adimoolam and J M Ford ldquop53 andDNA damage-inducibleexpression of the xeroderma pigmentosum group C generdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12985ndash12990 2002

[15] Q-E Wang C Han B Zhang K Sabapathy and A A WanildquoNucleotide excision repair factor XPC enhancesDNAdamage-induced apoptosis by downregulating the antiapoptotic shortisoform of caspase-2rdquo Cancer Research vol 72 no 3 pp 666ndash675 2012

[16] C Gill R Mestril and A Samali ldquoLosing heart the role ofapoptosis in heart diseasemdasha novel therapeutic targetrdquo TheFASEB Journal vol 16 no 2 pp 135ndash146 2002

[17] I Tuleta A KAlGhaddioui G Bauriedel et al ldquoThe imbalancebetween proliferation and apoptosis contributes to degenera-tion of aortic valves and bioprosthesesrdquo Cardiology Journal vol20 no 3 pp 268ndash276 2013

[18] T Jiranantasak A Rungsipipat and S Surachetpong ldquoHisto-pathological changes and apoptosis detection in canine myxo-matous mitral valve disease using tissue microarray techniquerdquoComparative Clinical Pathology vol 23 pp 1173ndash1178 2014

[19] T Torigoe H Sakaguchi M Kitano et al ldquoClinical charac-teristics of acute mitral regurgitation due to ruptured chordaetendineae in infancymdashexperience at a single institutionrdquo Euro-pean Journal of Pediatrics vol 171 no 2 pp 259ndash265 2012

[20] A J Hickey D E L Wilcken J S Wright and B A WarrenldquoPrimary (spontaneous) chordal rupture relation to myxoma-tous valve disease and mitral valve prolapserdquo Journal of theAmerican College of Cardiology vol 5 no 6 pp 1341ndash1346 1985

[21] M H Sherman C H Bassing and M A Teitell ldquoRegulationof cell differentiation by the DNA damage responserdquo Trends inCell Biology vol 21 no 5 pp 312ndash319 2011

[22] H Shen E M Sturgis S G Khan et al ldquoAn intronic poly(AT) polymorphism of the DNA repair gene XPC and risk ofsquamous cell carcinoma of the head and neck a case-controlstudyrdquo Cancer Research vol 61 no 8 pp 3321ndash3325 2001

[23] U Vogel K Overvad H Wallin A Tjoslashnneland B A Nexoslashand O Raaschou-Nielsen ldquoCombinations of polymorphisms inXPD XPC and XPA in relation to risk of lung cancerrdquo CancerLetters vol 222 no 1 pp 67ndash74 2005

[24] C Liu Q Yin M Ying et al ldquoXPC Lys939Gln and Ala499Valpolymorphisms in colorectal cancer susceptibility a meta-analysis of case-control studiesrdquoMolecular Biology Reports vol41 no 2 pp 1171ndash1178 2014

[25] S Blankenburg I R Konig R Moessner et al ldquoAssessment of3 xeroderma pigmentosum group C gene polymorphisms andrisk of cutaneous melanoma a case-control studyrdquo Carcinogen-esis vol 26 no 6 pp 1085ndash1090 2005

[26] R A Gottlieb K O Burleson R A Kloner B M Babior andR L Engler ldquoReperfusion injury induces apoptosis in rabbitcardiomyocytesrdquo Journal of Clinical Investigation vol 94 no 4pp 1621ndash1628 1994

[27] J Narula NHaider R Virmani et al ldquoApoptosis inmyocytes inend-stage heart failurerdquo The New England Journal of Medicinevol 335 no 16 pp 1182ndash1189 1996

[28] R L Debiasi B A Robinson J S Leser R D Brown C SLong and P Clarke ldquoCritical role for death-receptor mediatedapoptotic signaling in viral myocarditisrdquo Journal of CardiacFailure vol 16 no 11 pp 901ndash910 2010

6 Disease Markers

[29] A Galeone G Brunetti A Oranger et al ldquoAortic valvularinterstitial cells apoptosis and calcification are mediated byTNF-related apoptosis-inducing ligandrdquo International Journalof Cardiology vol 169 no 4 pp 296ndash304 2013

[30] P Valente G Fassina A Melchiori et al ldquoTIMP-2 over-expression reduces invasion and angiogenesis and protectsB16F10 melanoma cells from apoptosisrdquo International Journalof Cancer vol 75 no 2 pp 246ndash253 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 5: Research Article DNA Repair Gene Polymorphism and the Risk ...downloads.hindawi.com/journals/dm/2015/825020.pdf · Research Article DNA Repair Gene Polymorphism and the Risk of Mitral

Disease Markers 5

DNA repair capacity may be present in the molecular mech-anism of MCTR Further studies with a larger number ofpatients are warranted to validate these findings

Conflict of Interests

All other authors have no conflict of interests to declare

References

[1] U Gabbay and C Yosefy ldquoThe underlying causes of chordaetendinae rupture a systematic reviewrdquo International Journal ofCardiology vol 143 no 2 pp 113ndash118 2010

[2] D B G Oliveira K D Dawkins P H Kay and M PanethldquoChordal rupture I aetiology and natural historyrdquo British HeartJournal vol 50 no 4 pp 312ndash317 1983

[3] L H Ling M Enriquez-Sarano J B Seward et al ldquoClinicaloutcome of mitral regurgitation due to flail leafletrdquo The NewEngland Journal ofMedicine vol 335 no 19 pp 1417ndash1423 1996

[4] W R Mills J E Barber N B Ratliff D M Cosgrove III IVesely and B P Griffin ldquoBiomechanical and echocardiographiccharacterization of flail mitral leaflet due to myxomatous dis-ease further evidence for early surgical interventionrdquoAmericanHeart Journal vol 148 no 1 pp 144ndash150 2004

[5] N Kimura C Shukunami D Hakuno et al ldquoLocal tenomod-ulin absence angiogenesis and matrix metalloproteinase acti-vation are associated with the rupture of the chordae tendineaecordisrdquo Circulation vol 118 no 17 pp 1737ndash1747 2008

[6] T-H Lin S-F Yang C-C Chiu et al ldquoMatrix metallo-proteinase-1 mitral expression and -1607 1G2G gene promoterpolymorphism in mitral chordae tendinae rupturerdquo Transla-tional Research vol 161 no 5 pp 406ndash413 2013

[7] K Sugasawa J M Y Ng C Masutani et al ldquoXeroderma pig-mentosum group C protein complex is the initiator of globalgenome nucleotide excision repairrdquoMolecular Cell vol 2 no 2pp 223ndash232 1998

[8] R Legerski and C Peterson ldquoExpression cloning of a humanDNA repair gene involved in xeroderma pigmentosum groupCrdquo Nature vol 359 no 6390 pp 70ndash73 1992

[9] L Li C Peterson and R Legerski ldquoSequence of themouse XPCcDNA and genomic structure of the human XPC generdquo NucleicAcids Research vol 24 no 6 pp 1026ndash1028 1996

[10] W K Kaufmann and R S Paules ldquoDNA damage and cell cyclecheckpointsrdquo The FASEB Journal vol 10 no 2 pp 238ndash2471996

[11] G J StoutMOosten F Z Acherrat et al ldquoSelectiveDNAdam-age responses in murine Xpaminusminus Xpcminusminus and Csbminusminus keratino-cyte culturesrdquo DNA Repair vol 4 no 11 pp 1337ndash1344 2005

[12] G Wang A Dombkowski L Chuang and X X S Xu ldquoTheinvolvement of XPC protein in the cisplatin DNA damagingtreatment-mediated cellular responserdquo Cell research vol 14 no4 pp 303ndash314 2004

[13] Z Chen J Yang GWang B Song J Li and Z Xu ldquoAttenuatedexpression of xeroderma pigmentosum group C is associatedwith critical events in human bladder cancer carcinogenesis andprogressionrdquo Cancer Research vol 67 no 10 pp 4578ndash45852007

[14] S Adimoolam and J M Ford ldquop53 andDNA damage-inducibleexpression of the xeroderma pigmentosum group C generdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 99 no 20 pp 12985ndash12990 2002

[15] Q-E Wang C Han B Zhang K Sabapathy and A A WanildquoNucleotide excision repair factor XPC enhancesDNAdamage-induced apoptosis by downregulating the antiapoptotic shortisoform of caspase-2rdquo Cancer Research vol 72 no 3 pp 666ndash675 2012

[16] C Gill R Mestril and A Samali ldquoLosing heart the role ofapoptosis in heart diseasemdasha novel therapeutic targetrdquo TheFASEB Journal vol 16 no 2 pp 135ndash146 2002

[17] I Tuleta A KAlGhaddioui G Bauriedel et al ldquoThe imbalancebetween proliferation and apoptosis contributes to degenera-tion of aortic valves and bioprosthesesrdquo Cardiology Journal vol20 no 3 pp 268ndash276 2013

[18] T Jiranantasak A Rungsipipat and S Surachetpong ldquoHisto-pathological changes and apoptosis detection in canine myxo-matous mitral valve disease using tissue microarray techniquerdquoComparative Clinical Pathology vol 23 pp 1173ndash1178 2014

[19] T Torigoe H Sakaguchi M Kitano et al ldquoClinical charac-teristics of acute mitral regurgitation due to ruptured chordaetendineae in infancymdashexperience at a single institutionrdquo Euro-pean Journal of Pediatrics vol 171 no 2 pp 259ndash265 2012

[20] A J Hickey D E L Wilcken J S Wright and B A WarrenldquoPrimary (spontaneous) chordal rupture relation to myxoma-tous valve disease and mitral valve prolapserdquo Journal of theAmerican College of Cardiology vol 5 no 6 pp 1341ndash1346 1985

[21] M H Sherman C H Bassing and M A Teitell ldquoRegulationof cell differentiation by the DNA damage responserdquo Trends inCell Biology vol 21 no 5 pp 312ndash319 2011

[22] H Shen E M Sturgis S G Khan et al ldquoAn intronic poly(AT) polymorphism of the DNA repair gene XPC and risk ofsquamous cell carcinoma of the head and neck a case-controlstudyrdquo Cancer Research vol 61 no 8 pp 3321ndash3325 2001

[23] U Vogel K Overvad H Wallin A Tjoslashnneland B A Nexoslashand O Raaschou-Nielsen ldquoCombinations of polymorphisms inXPD XPC and XPA in relation to risk of lung cancerrdquo CancerLetters vol 222 no 1 pp 67ndash74 2005

[24] C Liu Q Yin M Ying et al ldquoXPC Lys939Gln and Ala499Valpolymorphisms in colorectal cancer susceptibility a meta-analysis of case-control studiesrdquoMolecular Biology Reports vol41 no 2 pp 1171ndash1178 2014

[25] S Blankenburg I R Konig R Moessner et al ldquoAssessment of3 xeroderma pigmentosum group C gene polymorphisms andrisk of cutaneous melanoma a case-control studyrdquo Carcinogen-esis vol 26 no 6 pp 1085ndash1090 2005

[26] R A Gottlieb K O Burleson R A Kloner B M Babior andR L Engler ldquoReperfusion injury induces apoptosis in rabbitcardiomyocytesrdquo Journal of Clinical Investigation vol 94 no 4pp 1621ndash1628 1994

[27] J Narula NHaider R Virmani et al ldquoApoptosis inmyocytes inend-stage heart failurerdquo The New England Journal of Medicinevol 335 no 16 pp 1182ndash1189 1996

[28] R L Debiasi B A Robinson J S Leser R D Brown C SLong and P Clarke ldquoCritical role for death-receptor mediatedapoptotic signaling in viral myocarditisrdquo Journal of CardiacFailure vol 16 no 11 pp 901ndash910 2010

6 Disease Markers

[29] A Galeone G Brunetti A Oranger et al ldquoAortic valvularinterstitial cells apoptosis and calcification are mediated byTNF-related apoptosis-inducing ligandrdquo International Journalof Cardiology vol 169 no 4 pp 296ndash304 2013

[30] P Valente G Fassina A Melchiori et al ldquoTIMP-2 over-expression reduces invasion and angiogenesis and protectsB16F10 melanoma cells from apoptosisrdquo International Journalof Cancer vol 75 no 2 pp 246ndash253 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 6: Research Article DNA Repair Gene Polymorphism and the Risk ...downloads.hindawi.com/journals/dm/2015/825020.pdf · Research Article DNA Repair Gene Polymorphism and the Risk of Mitral

6 Disease Markers

[29] A Galeone G Brunetti A Oranger et al ldquoAortic valvularinterstitial cells apoptosis and calcification are mediated byTNF-related apoptosis-inducing ligandrdquo International Journalof Cardiology vol 169 no 4 pp 296ndash304 2013

[30] P Valente G Fassina A Melchiori et al ldquoTIMP-2 over-expression reduces invasion and angiogenesis and protectsB16F10 melanoma cells from apoptosisrdquo International Journalof Cancer vol 75 no 2 pp 246ndash253 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Page 7: Research Article DNA Repair Gene Polymorphism and the Risk ...downloads.hindawi.com/journals/dm/2015/825020.pdf · Research Article DNA Repair Gene Polymorphism and the Risk of Mitral

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom