prostacyclin promoter polymorphism is associated with severity of infant respiratory viral infection...
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Prostacyclin Promoter Polymorphism is Associated with Severity of Infant Respiratory Viral Infection
S Van Driest1, T Gebretsadik3, P Moore2, S Reiss2, T Hartert4,5
Vanderbilt University School of Medicine, Departments of Pediatrics1, Division of Allergy, Immunology and Pulmonary Medicine2; Biostatistics3; and Medicine4, Division of Allergy, Pulmonary, and Critical Care Medicine5
Results
Background• Bronchiolitis is the leading cause of
infant hospitalization in the US and a major cause of infant mortality worldwide
• Treatment is limited to supportive care• In mice with RSV bronchiolitis,
prostacyclin synthetase expression protected against severe infection
• A variable number of tandem repeats (VNTR) modulates human prostacyclin production
• VNTR length inversely correlated with severity of RSV bronchiolitis in Japanese infants
Objectives• Determine the relationship of VNTR
length to bronchiolitis severity in a larger cohort representing multiple ethnicities and viral etiologies
• Assess whether VNTR length is associated with risk for bronchiolitis vs. upper respiratory infection (URI)
Methods• Population: 674 term, non-low birth weight,
previously healthy infants with either URI or bronchiolitis recruited for the parent study (Tennessee Children’s Respiratory Initiative)
• Outcome Measure: Questionnaires and medical record data were used to determine the Bronchiolitis Severity Score
• DNA source: DNA extracted from infant whole blood or buccal swabs from a subset of 233 infants
• Genotyping: The prostacyclin VNTR region was amplified by PCR and analyzed for length via gel electrophoresis
• Analysis: Wicoxon rank-sum or Kruskal-Wallis (for continuous variables) and Pearson (for categorical variables) tests were used to assess for differences between categories
Characteristics of Cohort (n=674) Bronchiolitis Severity Score and Prostacyclin VNTR Length Among
Genotyped Patients with Bronchiolitis (n=134)
Conclusions• Among infants with bronchiolitis
there was no statistically significant difference in Bronchiolitis Severity Score by prostacyclin VNTR genotype, though a trend is evident
• Increasing prostacyclin VNTR length is associated with less severe respiratory disease as measured by final diagnosis (URI vs. bronchiolitis)
Limitations• Subgroup of whole cohort
genotyped to date• Small group size for some
genotypes• VNTR length may be marker for
linked polymorphism in prostacyclin or nearby gene
References
Hashimoto K, et al. 2004. J Virol. 78:10303;
Iwai N, et al. 1999. Circulation 100:2231;
Hashimoto K, et al. 2008. J Med Virol. 80:2015This study was supported by Thrasher Research Fund Grants (TVH and SVD), NIH K24 AI 77930, and Vanderbilt CTSA NIH RR24975.
Future Directions• Examine role of ethnicity,
environment and viral etiology• Functional correlation via urine
prostacyclin metabolite• Identification of other genetic
polymorphisms that may influence susceptibility to severe bronchiolitis, enabling more accurate prediction of infants at risk for severe respiratory illness
• Pharmacologic intervention with prostacyclin may treat or prevent severe bronchiolitis
20 (9)26 (6)Other
148 (64)306 (69)BronchiolitisFinal Diagnosis
93 (40)201 (46)Supplemental Oxygen
144 (62)309 (70)Hospital Admission^
4 [1,7]5 [2,8]Bronchiolitis Severity Score*^
13 [6,31]12 [6,26]Age (weeks)*
3345 [3033,3657]
3289 [2977,3629]
Birth Weight (grams)*
51 (22)124 (28)Other
50 (21)97 (22) Black
132 (57) 219 (50) WhiteRace
98 (42)194 (44)Female
135 (58)247 (56)MaleGender
Genotyped
n=233
n (%)
Not Genotyped
n=441
n (%)
65 (28)109 (25)URI
*Median [interquartile range]; ^P<0.05
Prostacyclin VNTR Genotypes*
(n=233)
Frequency of Bronchiolitis vs. URI Inversely Correlates with Prostacyclin VNTR length
(n=191, P = 0.034)
The Tennessee
Children’sRespiratory Initiative
Bro
nch
iolit
is S
ever
ity
Sco
re
Prostacyclin VNTR Genotype
4R/6R
n=33
5R/6R
n=18
6R/6R
n=77
7R/6R
n=6
Prostacyclin VNTR Genotype
4R/6R
n=40
5R/6R
n=32
6R/6R
n=106
7R/6R
n=13
83% 59% 73% 46%
17% 41% 27% 54%
Respiratory Rate
Flaring or Retractions
Oxygen Saturation
Wheezing Score
≤ 30 None ≥ 95% None 0
31-45 Mild 90-94% End Expiratory 1
46-60 Moderate 85-89% Full Expiratory 2
> 60 Severe < 85%Audible without
stethoscope3
Bronchiolitis Severity Score (BSS)
49%
16%
7%
9%
18%
4R/4R n=1
5R/4R n=8
5R/5R n=6
7R/5R n=4
8R/6R n=3
6R/6Rn=114
5R/6Rn=38
4R/6Rn=43
7R/6Rn=16
Othern=22
*Genotypes identified as •#repeats shorter allele / #repeats longer allele