TY - JOUR
T1 - Pooled sequencing of candidate genes implicates rare variants in the development of asthma following severe RSV bronchiolitis in infancy
AU - Torgerson, Dara G.
AU - Giri, Tusar
AU - Druley, Todd E.
AU - Zheng, Jie
AU - Huntsman, Scott
AU - Seibold, Max A.
AU - Young, Andrew L.
AU - Schweiger, Toni
AU - Yin-Declue, Huiqing
AU - Sajol, Geneline D.
AU - Schechtman, Kenneth B.
AU - Hernandez, Ryan D.
AU - Randolph, Adrienne G.
AU - Bacharier, Leonard B.
AU - Castro, Mario
N1 - Publisher Copyright:
© 2015 Torgerson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6×10-4, 1.9×10-13 and 5.0×10-5, respectively), and NOS1 in African Americans (p = 2.3×10-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.
AB - Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6×10-4, 1.9×10-13 and 5.0×10-5, respectively), and NOS1 in African Americans (p = 2.3×10-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.
UR - http://www.scopus.com/inward/record.url?scp=84957990160&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0142649
DO - 10.1371/journal.pone.0142649
M3 - Article
C2 - 26587832
AN - SCOPUS:84957990160
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 11
M1 - e0142649
ER -