Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma by Moffatt Miriam F, Kabesch Michael, Liang Liming, Dixon Anna L, Strachan David, Heath Simon, Depner Martin, von Berg Andrea, Bufe Albrecht, Rietschel Ernst, Heinzmann Andrea, Simma Burkard, Frischer Thomas, Willis-Owen Saffron A G, Wong Kenny C C, Illig Thomas, Vogelberg Christian, Weiland Stephan K, von Mutius Erika, Abecasis Gonçalo R, Farrall Martin, Gut Ivo G, Lathrop G Mark, Cookson William O C in Nature (2007). PubMed

Abstract

Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10(-12). In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10(-22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

[ hide abstract ]

Discussed In Paper