Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma

MF Moffatt, M Kabesch, L Liang, AL Dixon, D Strachan… - Nature, 2007 - nature.com
MF Moffatt, M Kabesch, L Liang, AL Dixon, D Strachan, S Heath, M Depner, A von Berg…
Nature, 2007nature.com
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 …
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.
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