Variants Near MC4R Are Associated With Obesity and Influence Obesity-Related Quantitative Traits in a Population of Middle-Aged People: Studies of 14,940 Danes

OBJECTIVE: Variants downstream of the melanocortin-4 receptor gene (MC4R) have been reported to associate with obesity. We examined rs17782313, rs17700633, rs12970134, rs477181, rs502933, and rs4450508 near MC4R for association with obesity-related quantitative traits, obesity, and type 2 diabetes in Danish individuals. RESEARCH DESIGN AND METHODS: The variants were investigated for association with obesity-related quantitative traits in 5,807 population-based sampled individuals, obesity in 14,940 individuals, and type 2 diabetes in 8,821 individuals. RESULTS: The minor risk alleles of rs17782313, rs17700633, and rs12970134 were associated with BMI (effect per allele 0.25 kg/m2, P = 0.01; 0.23, P = 0.01; and 0.31, P = 7 x 10(-4), respectively), waist circumference (0.67 cm, P = 0.006; 0.53, P = 0.02; and 0.85, P = 3 x 10(-4)), and body weight (1.04 kg, P = 6 x 10(-4); 0.71, P = 0.01; and 1.16, P = 8 x 10(-5)). In case-control studies of obesity defined by BMI, the minor C-allele of rs17782313 was associated with overweight/obesity and obesity (odds ratio [OR] 1.09, P = 0.006 and OR 1.12, P = 0.003, respectively). Similarly, the minor A-allele of rs17700633 was associated with overweight/obesity and obesity (1.12, P = 8 x 10(-5) and 1.16, P = 2 x 10(-5)), and the minor A-allele of rs12970134 was also associated with overweight/obesity and obesity (1.13, P = 2 x 10(-5) and 1.15, P = 6 x 10(-5)). rs477181, rs502933, and rs4450508 were not significantly associated with obesity in the Danish population. The frequency of the minor risk alleles of rs17782313 and rs12970134 was higher among patients with type 2 diabetes than among glucose-tolerant individuals (OR 1.08, P = 0.08 and 1.08, P = 0.06, respectively); however, these borderline associations were abolished after adjustment for BMI. CONCLUSIONS: rs17782313, rs17700633, and rs12970134 near MC4R associate with measures of obesity in Danish individuals.