predisposition to asthma among the utah population
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Predisposition to asthma among the Utah population. Craig Teerlink University of Utah Department of Biomedical Informatics Asthma Genomics Conference Utah Department of Health Asthma Program June 7, 2007. Introduction. Asthma is a common disorder Effects 7% of US population 1 - PowerPoint PPT PresentationTRANSCRIPT
Predisposition to asthma among the Predisposition to asthma among the Utah populationUtah population
Craig TeerlinkCraig TeerlinkUniversity of UtahUniversity of Utah
Department of Biomedical InformaticsDepartment of Biomedical Informatics
Asthma Genomics ConferenceAsthma Genomics ConferenceUtah Department of Health Asthma ProgramUtah Department of Health Asthma Program
June 7, 2007June 7, 2007
IntroductionIntroductionAsthma is a common disorderAsthma is a common disorder Effects 7% of US populationEffects 7% of US population11
Increased global incidence observed in the last few Increased global incidence observed in the last few decadesdecades22
Complicated etiologyComplicated etiology Both environmental and genetic factors are Both environmental and genetic factors are
recognizedrecognized33
Heritable nature of asthmaHeritable nature of asthmaDiscordance observed between MZ and DZ twinsDiscordance observed between MZ and DZ twins44
Familial aggregation studies and risk factor analyses provide Familial aggregation studies and risk factor analyses provide evidence that asthma clusters in familiesevidence that asthma clusters in families5,65,6
A better understanding of predisposing factors A better understanding of predisposing factors may help improve treatment outcomesmay help improve treatment outcomes
Introduction to familial analysis studyIntroduction to familial analysis study
Such studies have been restricted to first degree Such studies have been restricted to first degree relatives relatives It is difficult to distinguish between evidence for It is difficult to distinguish between evidence for common genetic factors and common common genetic factors and common environmental factors among close relatives environmental factors among close relatives since close relatives often share their immediate since close relatives often share their immediate environmentenvironmentIn contrast, using a unique Utah resource, we In contrast, using a unique Utah resource, we were able to observe increased risk to distant were able to observe increased risk to distant relatives for a severe asthma phenotype relatives for a severe asthma phenotype definitiondefinition77
The Utah Population DatabaseThe Utah Population Database
Computerized genealogy recordsComputerized genealogy records
2.2 million Utah pioneers and their descendents2.2 million Utah pioneers and their descendents
Some genealogies have up to 10 generationsSome genealogies have up to 10 generations
Has been linked to 440,000+ death certificates from UtahHas been linked to 440,000+ death certificates from Utah
The combined resource allows us to identify individuals The combined resource allows us to identify individuals who died from asthma (cases) and investigate their who died from asthma (cases) and investigate their ‘relatedness’‘relatedness’
Benefits of genealogical approach to Benefits of genealogical approach to familialityfamiliality
Well-established methodsWell-established methods The resource has previously been used to The resource has previously been used to
provide evidence for a heritable component in provide evidence for a heritable component in other disease settingsother disease settings
Can extend analyses to distant relatives Can extend analyses to distant relatives (i.e., 2(i.e., 2ndnd or 3 or 3rdrd degree relatives), providing degree relatives), providing potentially more meaningful resultspotentially more meaningful results
Two types of analysisTwo types of analysis
Relative riskRelative risk If asthma mortality is familial, a higher risk of If asthma mortality is familial, a higher risk of
asthma mortality will be found among relatives asthma mortality will be found among relatives of individuals who died from asthma than of individuals who died from asthma than would be found for random controlswould be found for random controls
Average relatednessAverage relatedness If asthma mortality is familial, more If asthma mortality is familial, more
relationships between cases will be found relationships between cases will be found than would be found for random controlsthan would be found for random controls
Relative risk analysisRelative risk analysis
MethodMethod Compare the rate of asthma death in relatives of Compare the rate of asthma death in relatives of
asthma death cases with the rate of asthma death asthma death cases with the rate of asthma death in the population (UPDB)in the population (UPDB)
Results for 1,553 asthma deathsResults for 1,553 asthma deaths
No. of relativesNo. of relatives ObservedObserved ExpectedExpected RRRR P-valueP-value
11stst degree relatives degree relatives 7,9367,936 5252 30.730.7 1.691.69 <0.001<0.001
22ndnd degree relatives degree relatives 19,31919,319 100100 74.874.8 1.341.34 0.0030.003
33rdrd degree relatives degree relatives 28,60128,601 129129 112.2112.2 1.151.15 0.0650.065
Average relatedness analysisAverage relatedness analysisMethodMethod
Calculate the genetic distance between every pair of cases (i.e., Calculate the genetic distance between every pair of cases (i.e., degree of ‘relatedness’)degree of ‘relatedness’)
Calculate the average relatedness of all cases (GIF statistic)Calculate the average relatedness of all cases (GIF statistic) Repeat for 1000 sets of matched controlsRepeat for 1000 sets of matched controls
Results for 1,553 asthma deathsResults for 1,553 asthma deathsAll casesAll cases Ignoring 1Ignoring 1stst and 2 and 2ndnd
degree relativesdegree relatives
Case GIFCase GIF 3.163.16 1.951.95
Control GIFControl GIF 2.422.42 1.731.73
P-ValueP-Value <0.0001<0.0001 0.0260.026
Contribution to the GIF statisticContribution to the GIF statistic
Contribution to the Contribution to the GIF statistic by GIF statistic by genetic distance genetic distance between pairs of between pairs of individuals for asthma individuals for asthma mortalitymortality1,553 cases and 1000 1,553 cases and 1000 sets of matched sets of matched controls controls
genetic distance
cont
ribut
ion
to G
IF
1 2 3 4 5 6 7 8 9 10 12 14
0.0
0.1
0.2
0.3
0.4
0.5
asthma casesmatched controls
Summary of familial investigationSummary of familial investigation
Used a population based genealogy linked Used a population based genealogy linked to death certificatesto death certificatesObserved significantly increased risk to Observed significantly increased risk to relatives of individuals who died from relatives of individuals who died from asthma asthma Cases are significantly more related than Cases are significantly more related than expected by chance expected by chance Both analyses were significant in close Both analyses were significant in close and distant relativesand distant relatives
ImplicationsImplicationsImplications vary according to interest…Implications vary according to interest…Genetic epidemiologist:Genetic epidemiologist: Highly specific phenotype definition and significant Highly specific phenotype definition and significant
results among distant relatives suggests heritable results among distant relatives suggests heritable factorfactor
Department of health:Department of health: Risk estimates are on a population basis, so apply Risk estimates are on a population basis, so apply
well to an entire populationwell to an entire populationAn individual:An individual: Asthma mortality is rare Asthma mortality is rare Increased risk is low and not likely to apply at the Increased risk is low and not likely to apply at the
individual levelindividual level
Next stepNext step
Use of clinical data (instead of mortality) to Use of clinical data (instead of mortality) to distinguish asthma cases within the distinguish asthma cases within the genealogy database may produce more genealogy database may produce more meaningful risk estimates to clinicians, meaningful risk estimates to clinicians, public health practitioners, and individuals.public health practitioners, and individuals.
Utah Asthma Program community mini-Utah Asthma Program community mini-grant may help to perform the next stepgrant may help to perform the next step
Acknowledgements, 1Acknowledgements, 1
PeoplePeople Lisa Cannon-AlbrightLisa Cannon-Albright Matt HegewaldMatt Hegewald
InstitutionsInstitutions Resource for Genetic and Epidemiologic Resource for Genetic and Epidemiologic
Research (Utah Population Database)Research (Utah Population Database) Utah Department of Health Asthma ProgramUtah Department of Health Asthma Program
Introduction to linkage analysis studyIntroduction to linkage analysis study
Linkage analysis Linkage analysis Attempts to identify disease predisposition loci in the genomeAttempts to identify disease predisposition loci in the genome Based on the phenomenon of chromosome recombination that Based on the phenomenon of chromosome recombination that
occur during meiosesoccur during meioses Utilizes inheritance information gathered in disease pedigreesUtilizes inheritance information gathered in disease pedigrees
Previous genome-wide scans for asthma have implicated Previous genome-wide scans for asthma have implicated almost every chromosomealmost every chromosome
22 study populations thus far22 study populations thus far88
> 30 suggestive or significant regions in the genome> 30 suggestive or significant regions in the genome88
Several genes have been identified/hypothesized in Several genes have been identified/hypothesized in association studiesassociation studies99
Replication is needed for these genesReplication is needed for these genes Results are likely to be population-specificResults are likely to be population-specific
1 2
3 45 6
78
9 10 11 12
13 14 1516 17 18
19 2021 22
X
Previous results from genome-wide scans for asthma8
• previously published regions
A unique data resource for asthma linkageA unique data resource for asthma linkage
81 extended pedigrees ascertained for asthma between 81 extended pedigrees ascertained for asthma between 1996 and 20001996 and 2000
3 to 6 generations per pedigree3 to 6 generations per pedigree 6 to 97 individuals per pedigree6 to 97 individuals per pedigree 2 to 40 affected individuals per pedigree 2 to 40 affected individuals per pedigree
1880 individuals included in analysis1880 individuals included in analysis 744 affected (93% genotyped)744 affected (93% genotyped) 628 unaffected628 unaffected 508 undetermined phenotype status508 undetermined phenotype status
GenotypingGenotyping Subjects were genotyped on 540 florescent dye-labeled Subjects were genotyped on 540 florescent dye-labeled
microsatellite markers across the genomemicrosatellite markers across the genome Genotyping was performed by Myriad geneticsGenotyping was performed by Myriad genetics Average spacing of 6 cM between markersAverage spacing of 6 cM between markers
MethodsMethods
Phenotype definitionPhenotype definition Physician confirmed presence or absence of asthmaPhysician confirmed presence or absence of asthma Based on spirometry measures, medical records and Based on spirometry measures, medical records and
questionnairequestionnaire
Parametric analysesParametric analyses Mode of inheritance is not well-characterizedMode of inheritance is not well-characterized general dominant and recessive modelgeneral dominant and recessive model
Disease allele frequency of 0.005 (dom) and 0.05 (rec)Disease allele frequency of 0.005 (dom) and 0.05 (rec)Both models assumed penetrance of 50% for disease allele Both models assumed penetrance of 50% for disease allele carriers and 0.5% for non-disease carrierscarriers and 0.5% for non-disease carriers
Genome-wide resultsGenome-wide results
a.line1[, 1]
a.lin
e1[,
2]
1 2 3 4 5 6 7 8 90
1
2
3a.
line2
[, 2]
10 11 12 13 14 15 16 17 18 19 20 21 22 X0
1
2
3
Genome-wide results, cont.Genome-wide results, cont.A significantA significant1010 result occurred on chromosome 5 result occurred on chromosome 5 LOD = 3.75 LOD = 3.75 ~ 5600:1 odds in favor of linkage~ 5600:1 odds in favor of linkage Evidence from recessive modelEvidence from recessive model Not reported in other genome-wide scans for asthmaNot reported in other genome-wide scans for asthmaA nearly suggestive result occurred on A nearly suggestive result occurred on chromosome 6chromosome 6 LOD = 2.08LOD = 2.08 ~ 120:1 odds in favor of linkage~ 120:1 odds in favor of linkage Evidence from dominant modelEvidence from dominant model Reported in several other genome-wide scansReported in several other genome-wide scans1111
1 2
3 45 6
78
9 10 11 12
13 14 1516 17 18
19 2021 22
X
Our results in perspective to other published results
• previously published regions
ConclusionsConclusionsOur analysis of extended pedigrees identified a Our analysis of extended pedigrees identified a novel asthma susceptibility locus at chromosome novel asthma susceptibility locus at chromosome 5q215q21Our analysis confirmed another region of interest Our analysis confirmed another region of interest (with nearly suggestive evidence) for an asthma (with nearly suggestive evidence) for an asthma susceptibility locus at 6p21.susceptibility locus at 6p21.Inclusion of fine mapping markers in regions of Inclusion of fine mapping markers in regions of interest will improve localizationinterest will improve localizationFuture linkage analysis in this resource should Future linkage analysis in this resource should address phenotypic heterogeneity of asthmaaddress phenotypic heterogeneity of asthmaA better understanding of genetic factors for A better understanding of genetic factors for asthma may improve disease outcomesasthma may improve disease outcomes
Acknowledgements, 2Acknowledgements, 2People:People:
Alun ThomasAlun ThomasLisa Cannon-AlbrightLisa Cannon-AlbrightNicola CampNicola CampMatt HegewaldMatt HegewaldMarlene EggerMarlene EggerJim FarnhamJim FarnhamSteven BackusSteven Backus
Institutions:Institutions:The National Library of MedicineThe National Library of MedicineIntermountain HealthcareIntermountain HealthcareMyriad GeneticsMyriad GeneticsBayer PharmaceuticalsBayer Pharmaceuticals
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