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