Polymorphisms in Genes Involved in the Leptin-Melanocortin Pathway are Associated with Obesity-Related Cardiometabolic Alterations in a Southern Chilean Population.

Abstract

Polymorphisms in genes encoding proteins of the leptin-melanocortin pathway have been associated with obesity. The involvement of these polymorphisms with changes in body mass index (BMI) and anthropometric measures could also imply a contribution to the risk of metabolic syndrome (MetS) and metabolic alterations. We evaluated the relationship of leptin-melanocortin system polymorphisms with obesity, MetS, and other metabolic alterations in Southern Chilean individuals. Two-hundred individuals were grouped as normoweight (BMI 18.0-24.9kg/m2), overweight (BMI 25.0-29.9kg/m2), and obese (BMI≥30kg/m2) or according to MetS status. Anthropometric measures (BMI, abdominal circumference, waist-to-hip ratio [WHR]) and biochemical parameters (glycemia and lipid profile) were evaluated. Polymorphisms LEP rs7799039, LEPR rs1137101, MC3R rs3746619 and rs3827103, and MC4R rs17782313 were evaluated by real-time PCR using allelic discrimination assays. LEPR rs1137101 GG genotype was related to reduced risk of obesity (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.08-0.79; p=0.018) and MetS (OR 0.36, 95% CI 0.15-0.88; p=0.024), but it was not significant after Bonferroni correction for multiple tests as compared to the AA genotype (p>0.01). Moreover, LEPR rs1137101 allele G (AG+GG) was related to lower BMI and WHR (p<0.01). Further multiple linear regression analysis demonstrated that this genotype was also responsible for reduced BMI in 2.44kg/m2 and WHR in 0.033 units. MC4R rs17782313 allele C (TC+CC) was slightly associated with diminished risk of MetS (OR 0.48, 95% CI 0.23-0.98; p=0.040) and reduced BMI values in 1.95kg/m2 (p<0.05). Regarding lipid profile, LEPR rs1137101 allele G carriers had lower triglycerides and very-low-density lipoprotein (VLDL) cholesterol, whereas individuals carrying the MC4R rs17782313 allele C had higher high-density lipoprotein (HDL) cholesterol (p<0.01). LEP rs7799039 allele A (GA+AA) was slightly associated with reduced total and low-density lipoprotein (LDL) cholesterol (p<0.05). These results suggest that polymorphisms at LEP, LEPR, and MC4R may be useful biomarkers of obesity-related cardiometabolic alterations in our population.