Joint Association of Nicotinic Acetylcholine Receptor Variants with Abdominal Obesity in American Indians: The Strong Heart Family Study

<div><p>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 <i>per se</i>. 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 <i>per se</i>.</p></div

Gene-based and gene-family association of nAChRs variants with obesity (n = 3,640).

<p>P-values in bold indicates significant association after adjusting for multiple testing by FDR.</p

Characteristics of study participants according to smoking status (n = 3,640).

<p>^*P values were obtained by GEE, adjusting for age and sex when appropriate; ^‡ Former plus current smokers.</p

Baseline Characteristics of Strong Heart Study Participants with Complete Scr Data at All Three Exams (<i>N</i> = 2,264).

<p>Abbreviations: CVD = cardiovascular disease; Scr = serum creatinine.</p><p>Baseline Characteristics of Strong Heart Study Participants with Complete Scr Data at All Three Exams (<i>N</i> = 2,264).</p

Mean and SD of Scr Values Stratified by Imputation Method and Model.

<p>Abbreviations: AV = imputation using adjacent value; LD = listwise deletion; Mean = imputation using the mean; MI = multiple imputation; NMAR = not missing at random; PM = pattern mixture.</p><p>Model 1 = data with randomly missing values</p><p>Model 2 = autoregressive missing</p><p>Model 3 = autoregressive +gender + age</p><p>Model 4 = NMAR data.</p><p>Mean and SD of Scr Values Stratified by Imputation Method and Model.</p

Adjusted Hazard Ratios With 95% Confidence Intervals for Cardiovascular Disease Risk.

<p>^& Cox proportional regression models adjusted for age, gender, and diabetes.</p><p>*Significant at 5%.</p><p>Abbreviations: LD = listwise deletion; Mean = imputation using the mean; AV = imputation using adjacent value; MI = multiple imputation; NMAR = not missing at random; PM = pattern mixture.</p><p>Complete Data: data with no missing values</p><p>Model 1: data with randomly missing values</p><p>Model 2: autoregressive missing</p><p>Model 3: autoregressive +gender + age</p><p>Model 4: NMAR data.</p><p>Adjusted Hazard Ratios With 95% Confidence Intervals for Cardiovascular Disease Risk.</p

Clinical characteristics of the study participants according to obesity (N = 431).

<p>Clinical characteristics of the study participants according to obesity (N = 431).</p

Metabolites associated with body mass index in American Indians.

<p>Metabolites associated with body mass index in American Indians.</p

Separation of individuals with normal body weight versus those with abdominal obesity by a multi-metabolites score comprising of all metabolites significantly associated with waist circumference using sparse partial least-squares discriminant analysis.

<p>Separation of individuals with normal body weight versus those with abdominal obesity by a multi-metabolites score comprising of all metabolites significantly associated with waist circumference using sparse partial least-squares discriminant analysis.</p