Association of Obesity Susceptibility Gene Variants With Cardiometabolic Phenotypes in Morbid Obesity

Introduction: Genome-wide association studies (GWAs) have identified several gene variants strongly associated with increased body mass index (BMI) and obesity. However, their association with the cardiometabolic consequences of obesity is unclear. We performed a study of 40 validated variants recently identified in two large metaanalysis GWAS and analyzed their association with related cardiovascular and metabolic traits of severe obesity. Methods: Genotyping was performed in 320 deeply-phenotyped obese subjects (mean BMI 41±9 kg/m2, aged 44±12 years), participating in a standardized weight reduction program. Anthropometric parameters, parameters of glucose/insulin metabolism, oxidative stress and early atherogenesis, adipokines, adhesion molecules, apolipoproteins, cardiac function and structure, intima media thickness and arterial elasticity were assessed standardized after 12h fast. Results: The transmembran protein TMEM18 rs939583 variant was significantly related to several parameters of adiposity (i.e. BMI β-estimate 1/2 risk alleles vs. no risk allele: 3.7±2.2/ 5.5±1.9, p=0.0009), epicardial fat thickness (p=0.023), insulin (p=0.002), fasting glucose (p=0.007), HOMA-IR (p=0.0008), and leptin (p=0.008) levels, systolic (p=0.007) and diastolic (p=0.009) blood pressure, arterial hypertension (frequency in subjects with 0/1/2 risk allele(s): 14/30/46%, p=0.001), and the metabolic syndrome (29/29/48%, p=0.029). Moreover, the BDNF rs10767664 variant was significantly associated with ApoA1, ApoA2, HDL cholesterol and soluble CD40L levels. Conclusion: TMEM18 and BDNF variants increased the risk of metabolic syndrome components, probably through their effect of abdominal obesity. However, several gene variants that have been found to be associated with BMI with small effects in large scale GWAS, did not seriously alter obesity related cardiometabolic traits.