2 research outputs found
Evidence for Large-Scale Gene-by-Smoking Interaction Effects on Pulmonary Function
Background: Smoking is the strongest environmental risk factor for reduced pulmonary
function. The genetic component of various pulmonary traits has also been demonstrated, and
at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in
1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and
genetic loci are well established, the question of potential gene-by-smoking interaction effect
remains unanswered. The aim of the present study was to assess, using a genetic risk score
approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.
Methods: We evaluated the interaction between smoking exposure, considered as either ever
vs. never or pack-years, and a 26 SNPs genetic risk score in relation to FEV1 or FEV1/FVC in 50
047 participants of European ancestry from the CHARGE and SpiroMeta consortia.
Results: We identified an interaction ( = −0.036, 95% confidence interval, -0.040 – -0.032,
P=0.00057) between an unweighted 26 SNPs genetic risk score and smoking status (ever/never)
on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling
below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher
among ever smokers than among never smokers.
Conclusions: This study highlights the benefit of using genetic risk scores for identifying
interactions missed when studying individual SNPs, and shows for the first time that persons
with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious
effects of smoking
Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance