Journal Article

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

Gut, Ivo G., Cookson, William O. C., Depner, Martin, Heinzmann, Andrea, Liang, Liming, Strachan, David, Willis-Owen, Saffron A. G., Abecasis, Gonçalo R., Simma, Burkard, Rietschel, Ernst, Dixon, Anna L., Illig, Thomas, Kabesch, Michael, Moffatt, Miriam F., Lathrop, G. Mark, Bufe, Albrecht, Wong, Kenny C. C., Vogelberg, Christian, Weiland, Stephan K., Farrall, Martin, von Berg, Andrea, Frischer, Thomas, Heath, Simon, von Mutius, Erika

2007

Overview

Childhood asthma genes Rates of childhood asthma diagnosis are rising: 6% of children in the United States are sufferers. Both genetic and environmental factors are clearly important. To discover more about the genetic element, Moffatt et al . looked for genes linked to asthma in a genome-wide association scan. More than a third of children with asthma of onset below the age of seven showed variations in expression of the ORMDL3 gene on chromosome 17. Similar genes are found in yeast and other primitive organisms, suggesting that they may be components of an ancient and conserved immune mechanism. Variations in expression of the gene ORMDL3 were found to be associated with development of childhood asthma, suggesting this gene should be examined in more patient groups. Asthma is caused by a combination of poorly understood genetic and environmental factors 1 , 2 . 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 3 . The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Age of Onset / Asthma / Asthma - epidemiology / Asthma - genetics / Asthma in children / Biological and medical sciences / Case-Control Studies / Causes of / Child / Chromosomes, Human, Pair 17 - genetics / Chronic obstructive pulmonary disease, asthma / Deoxyribonucleic acid / DNA / Environmental aspects / Environmental factors / Epstein-Barr virus / Gene expression / Gene Expression Regulation - genetics / Genetic aspects / Genetic markers / Genetic Predisposition to Disease / Genetic susceptibility / Genetic variance / Genomics / Germany / Humanities and Social Sciences / Humans / letter / Medical sciences / Membrane Proteins - genetics / multidisciplinary / Pediatrics / Pneumology / Polymorphism, Single Nucleotide - genetics / Risk factors / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / United Kingdom