Abstract
Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se.
Highlights
The global epidemics of overweight and obesity, and the resulting impact on diabetes, cardiovascular disease (CVD), and certain types of cancer [1,2,3,4,5,6] pose a great burden on public health
Results for sensitivity analysis Given the strong correlation between obesity and diabetes, we examined the potential impact of diabetes on the association of the nicotine acetylcholine receptors (nAChRs) gene family with obesity measures by excluding participants with diabetes (Tables S1)
It shows that the nAChRs gene family remained to be significantly associated with abdominal obesity among normoglycemic subjects, suggesting that the observed genetic association was not driven by diabetes
Summary
The global epidemics of overweight and obesity, and the resulting impact on diabetes, cardiovascular disease (CVD), and certain types of cancer [1,2,3,4,5,6] pose a great burden on public health. The loci identified so far explain only a small proportion of disease variability, suggesting that additional genes with important roles remained to be discovered. It is well-accepted that the etiology of obesity is multifactorial involving multiple genes in biologically related pathways. A single gene with small or weak individual effect may not cause disease individually; instead, they act jointly in the context of networks or pathways in leading to disease susceptibility.[14] a gene-family or pathwaybased approach combining information from multiple genetic variants may capture a large proportion of the causal variants, and should have higher power than studying single gene alone in dissecting the complex genetic architecture of obesity or its related traits
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