Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility.

BACKGROUND: Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focussed almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs). OBJECTIVE: To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma-susceptibility variants at these loci. METHODS: We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20 092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT-CNV. RESULTS: Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In six instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried six asthma-candidate CNVs (range 1-29). However, the vast majority of identified CNVs were of rare frequency (< 5%) and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Although a substantial proportion of asthma-susceptibility genes harbour polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma-associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.

The interaction of glutathione S-transferase M1-null variants with tobacco smoke exposure and the development of childhood asthma.

BACKGROUND: The glutathione S-transferase M1 (GSTM1)-null variant is a common copy number variant associated with adverse pulmonary outcomes, including asthma and airflow obstruction, with evidence of important gene-by-environment interactions with exposures to oxidative stress. OBJECTIVE: To explore the joint interactive effects of GSTM1 copy number and tobacco smoke exposure on the development of asthma and asthma-related phenotypes in a family-based cohort of childhood asthmatics. METHODS: We performed quantitative PCR-based genotyping for GSTM1 copy number in children of self-reported white ancestry with mild to moderate asthma in the Childhood Asthma Management Program. Questionnaire data regarding intrauterine (IUS) and post-natal, longitudinal smoke exposure were available. We performed both family-based and population-based tests of association for the interaction between GSTM1 copy number and tobacco smoke exposure with asthma and asthma-related phenotypes. RESULTS: Associations of GSTM1-null variants with asthma (P=0.03), younger age of asthma symptom onset (P=0.03), and greater airflow obstruction (reduced forced expiratory volume in 1 s / forced vital capacity, P=0.01) were observed among the 50 children (10% of the cohort) with exposure to IUS. In contrast, no associations were observed between GSTM1-null variants and asthma-related phenotypes among children without IUS exposure. Presence of at least one copy of GSTM1 conferred protection. CONCLUSION: These findings support an important gene-by-environment interaction between two common factors: increased risk of asthma and asthma-related phenotypes conferred by GSTM1-null homozygosity in children is restricted to those with a history of IUS exposure.