title: Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy.
abstract: 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 = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively), and NOS1 in African Americans (p = 2.3x10-11). 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.
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Dara G
authors.initials: DG
authors.lastname: Torgerson
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Tusar
authors.initials: T
authors.lastname: Giri
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Druley
authors.affiliation: Department of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Huntsman
authors.affiliation: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America.
authors.forename: Max A
authors.initials: MA
authors.lastname: Seibold
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Young
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Toni
authors.initials: T
authors.lastname: Schweiger
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Yin-Declue
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Geneline D
authors.initials: GD
authors.lastname: Sajol
authors.affiliation: Department of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Schechtman
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute of Human Genetics, and California Institute of Quantitative Biosciences (QB3), University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hernandez
authors.affiliation: Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Adrienne G
authors.initials: AG
authors.lastname: Randolph
authors.affiliation: Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri, United States of America.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Bacharier
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
mesh_terms: D001741:Black or African American / Q000235:genetics; D001249:Asthma / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000821:virology; D001990:Bronchiolitis, Viral / Q000150:complications / Q000235:genetics* / Q000473:pathology; D019002:CD56 Antigen / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D000091344:Filaggrin Proteins; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012136:Respiratory Syncytial Viruses / Q000472:pathogenicity; D009418:S100 Proteins / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C553443:ADRB2 protein, human; D019002:CD56 Antigen; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C522918:NCAM1 protein, human; D018343:Receptors, Adrenergic, beta-2; D009418:S100 Proteins