Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Hum Hered 2011;71:97–105 DOI: 10.1159/000319536 Attempted Replication of 50 Reported Asthma Risk Genes Identifies a SNP in RAD50 as Associated with Childhood Atopic Asthma William Murk   a Kyle Walsh   a Ling-I Hsu   a Linlu Zhao   a Michael B. Bracken   b Andrew T. DeWan   a a  Department of Epidemiology and Public Health, Yale University, and b  Center for Perinatal, Pediatric and Environmental Epidemiology, Yale University School of Public Health, New Haven, Conn., USA sociated with asthma. SNPs in frequently replicated asthma risk genes, including TNF , IL13, ADAM33, TGFB1 , and MS4A2, revealed no association. Conclusion: RAD50 may be a prom- ising candidate asthma risk gene. Lack of evidence of highly reported polymorphisms in the present study highlights the genetic heterogeneity of asthma and emphasizes the need for robust replication of candidate genes. Copyright © 2011 S. Karger AG, Basel Introduction Asthma is one of the most common diseases of child- hood, with an estimated global prevalence of 10% among children aged 6–7 [1]. It is a condition characterized by chronic inflammation of the lungs, presenting with air- way hyperreactivity, excessive mucous formation, and re- spiratory obstruction. Hereditary factors have been im- plicated in asthma pathogenesis as early as 1860 [2], a hy- pothesis that has been borne out in numerous twin and family studies [3]. However, asthma is an inherently com- plex, heterogeneous disease influenced by both genetic and environmental factors, and few robustly replicated asthma risk genes have emerged [4]. To date, numerous candidate risk genes have been reported for asthma, asth- Key Words Association analysis  Asthma  Atopy  Candidate gene analysis Abstract Objectives: Asthma is a childhood disease that is strongly influenced by genetic factors. We sought to replicate an as- sociation between single nucleotide polymorphisms (SNPs) of the top-ranked candidate genes and childhood atopic asthma in Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study subjects. Methods: Using data from a systematic literature search and an exploratory genome- wide association study conducted in a subset of the PRAM cohort, we followed a strict procedure to generate a ranked list of candidate genes. SNPs in the top 50 genes were ge- notyped in the full PRAM cohort (n = 103 cases with doc- tor-diagnosed atopic asthma at age 6, and n = 499 controls). Results: The literature search identified 251 prior risk genes from 469 publications. RAD50 (rs2706347) and PTPRE (rs10830196) revealed crude associations with asthma at a Bonferroni-corrected level of significance (p ! 0.0011). IL4R (rs1801275), CCL5 (rs2280788), and TBXA2R (rs4523) revealed nominal significance (p ! 0.05). When adjusted for race and gender, only rs2706347 in RAD50 remained significantly as- Published online: July 6, 2011 Andrew T. DeWan, PhD, MPH Department of Epidemiology and Public Health Yale University, 60 College Street New Haven, CT 06520 (USA) Tel. +1 203 785 3528, E-Mail andrew.dewan  @  yale.edu © 2011 S. Karger AG, Basel 0001–5652/11/0712–0097$38.00/0 Accessible online at: www.karger.com/hhe