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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/m^sup 2^, P = 0.01; 0.23, P = 0.01; and 0.31, P = 7 × 10^sup -4^, respectively), waist circumference (0.67 cm, P = 0.006; 0.53, P = 0.02; and 0.85, P = 3 × 10^sup -4^), and body weight (1.04 kg, P = 6 × 10^sup -4^; 0.71, P = 0.01; and 1.16, P = 8 × 10^sup -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 × 10^sup -5^ and 1.16, P = 2 × 10^sup -5^), and the minor A-allele of rs12970134 was also associated with overweight/obesity and obesity (1.13, P = 2 × 10^sup -5^ and 1.15, P = 6 × 10^sup -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. Diabetes 58:757-764, 2009
Obesity and the accompanying risk of common diseases such as type 2 diabetes and premature cardiovascular morbidity and mortality are increasing global health burdens. Multiple variations in genes are likely to contribute to the pathogenesis of obesity. Monogenic forms of obesity have been identified, with mutations in the gene encoding the melanocortin-4 receptor (MC4R) being the most prevalent (1-3). MC4R is located on chromosome 18q22...