Unravelling gene-by-environment effects in asthma and allergy: the glutathione pathway as an early success story

A. Rogers, S. Bunyavanich
2011 Clinical and Experimental Allergy  
The past 10 years have shown remarkable progress in identification of numerous, highly confident asthma genes. More than 50 genes have now been replicated in multiple large populations. Some of the most compelling genes were identified by GWAS studies (the ORMDL3/GSDMB locus, IL1RL1, and IL33, for example), identified in multi-group consortia involving tens of thousands of asthmatic subjects and controls. [1] Others emerged from the candidate gene literature, but have likewise been identified
more » ... playing a role in asthma and allergy in numerous cohorts, leading to high confidence that they represent bonafide asthma genes.[2, 3] Several genes in the anti-oxidant glutathione pathway, which scavenge oxygen free radicals by catalyzing the reaction between glutathione (GSH) and organic hydroperoxides fall into this latter category, notably the common Glutathione Stransferase deletion and Glutathione S-transferase Pi, two genes explored by Gerbase and colleagues in this issue of CEA. [4] The GSTM1 null mutation has an allele frequency of 70% in Caucasian individuals, meaning that fully ½ of Caucasian individuals lack a functional copy of the gene. The role of GSTM1 in asthma and lung disease has been studied in no fewer than 25 populations and summarized in several meta-analyses. As with other genes, results have not been uniformly significant, with many populations showing no association. Interestingly, however, given GSTM1's role as in the anti-oxidant pathway, the GSTM1-null mutation has frequently been found to be associated with increased disease severity in the setting of increased oxidative stress (such as exposure to environmental tobacco smoke, intra-uterine smoke, or ozone). We reviewed the GSTM1 in asthma literature in 2009 in CEA, and found that the majority of publications that evaluated a gene-by-environment affect for GSTM1 actually identified an interaction;[5] this is especially striking given the lower power inherent in gene-byenvironment studies. The GSTM1-null deletion and its interaction with increased
doi:10.1111/j.1365-2222.2011.03844.x pmid:22093009 pmcid:PMC5297891 fatcat:bkl3z7w7u5aszgkxw6isu5bv4q