Journal Article

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Paternoster, Lavinia, Mercader, Josep M, Hollegaard, Mads V, Blicher, Thomas, Lackie, Peter M, Gupta, Ramneek, Duijts, Liesbeth, Thomsen, Philip F, Rasmussen, Morten A, Flaaten, Richard, Davies, Donna E, Bønnelykke, Klaus, Kreiner-Møller, Eskil, Holloway, John W, Faura-Tellez, Grissel, Simpson, Angela, Hakonarson, Hakon, den Dekker, Herman T, Sevelsted, Astrid, Torrents, David, Nielsen, Kasper, Mølgaard, Anne, Smart, David E, Sleiman, Patrick, Husby, Anders, Nohr, Ellen A, Yadav, Rachita, March, Michael E, Jaddoe, Vincent W V, Holst, Claus, Custovic, Adnan, Hougaard, David M, Mortensen, Li Juel, Bisgaard, Hans, Bonàs-Guarch, Silvia, Belgrave, Danielle

2014

Overview

Klaus Bønnelykke and colleagues identify a common variant in CDHR3 associated with early childhood asthma with severe exacerbations. CDHR3 encodes a cell adhesion protein expressed at high levels in airway epithelium, suggesting a role for altered epithelial integrity in asthma pathogenesis. Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB , IL33 , RAD50 and IL1RL1 , were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/43 / 631/208/205/2138 / 692/308/2056 / 692/699/249/2510/31 / Acid Anhydride Hydrolases / Age / Agriculture / Animal Genetics and Genomics / Asthma / Asthma - etiology / Asthma - genetics / Asthma in children / Biomedicine / Cadherin Related Proteins / Cadherins / Cadherins - chemistry / Cadherins - genetics / Cadherins - metabolism / Cancer Research / Case-Control Studies / Causes of / Child / Child, Preschool / Chromosomes, Human, Pair 17 / Confidence intervals / Denmark / Deoxyribonucleic acid / DNA / DNA Repair Enzymes - genetics / DNA-Binding Proteins - genetics / Female / Gene Function / Genealogy / Genetic aspects / Genetic Predisposition to Disease / Genetic susceptibility / Genome-Wide Association Study / Genomes / Genotype & phenotype / Hospitalization / Human Genetics / Humans / Interleukin-1 Receptor-Like 1 Protein / Interleukin-33 / Interleukins - genetics / letter / Male / Membrane Proteins - chemistry / Membrane Proteins - genetics / Membrane Proteins - metabolism / Models, Molecular / Neoplasm Proteins - genetics / Physiological aspects / Polymorphism, Single Nucleotide / Population / Protein Conformation / Receptors, Cell Surface - genetics / Studies