Genetic Variation In ORM1-like 3 (ORMDL3) And Gasdermin-like (GSDML) And Childhood Asthma

Abstract

Asthma is a complex disease caused by multiple genetic and environmental factors. Moffatt et al. recently identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3) as a potential asthma candidate gene using genome-wide association and microarray approaches (1). Multiple single nucleotide polymorphisms (SNPs) on chromosome 17q21 were statistically significantly associated with childhood asthma in German and British populations (1). In a microarray analysis, SNPs that were related to asthma in the region containing the ORMDL3 gene on 17q21 were associated with expression levels of ORMDL3 in Epstein–Barr virus-transformed lymphoblastoid cell lines from asthmatic children (1). ORMDL3 belongs to a novel evolutionarily conserved gene family with unknown function (2). Genes in the ORMDL family encode transmembrane proteins located at the endoplasmic reticulum membrane (2). ORMDL3 is ubiquitously expressed in human tissues (2). Yeast double knockouts of the ORMDL genes show slower growth and higher sensitivity to toxic compounds (2). The function of ORMDL3 in humans is unclear (2). The gasdermin-like (GSDML) gene belongs to the cancer associated gasdermin-domain containing protein family, which has been related to cancer pathogenesis (3). GSDML is adjacent to ORMDL3 on chromosome 17. Moffatt et al. found that polymorphisms in GSDML were statistically significantly associated with childhood asthma and transcript levels of ORMDL3 (1) suggesting that GSDML SNPs may also modify ORMDL3 expression and thus contribute to asthma susceptibility. Several subsequent studies have confirmed associations between variants in ORMDL3 and GSDML and asthma (4–7). Given that these are the only published associations with asthma from genome-wide association studies to date and that the original study was modest in size relative to the magnitude of the association, confirmation in other populations remains crucial (8). We examined associations of polymorphisms in ORMDL3 and GSDML with childhood asthma and atopy in a case– parent triad study in Mexico City. Given that the asthma involves interactions between genetic susceptibility and environmental exposures, we also explored possible effect modification by two environmental risk factors for childhood asthma – ambient ozone concentrations (9), which are especially high in Mexico City and parental tobacco smoking (10). Evidence of gene by environment interaction in relation to asthma phenotypes exists for these two exposures (11–14). In addition, to put our findings and previous publications in perspective, we performed a meta-analysis of all published data on SNP rs7216389 which was associated with asthma and ORMDL3 expression with the highest degree of statistical significance in the original report (1) and examined in all subsequent studies (4–7).