Common variants near MC4R in relation to body fat, body fat distribution, metabolic traits and energy expenditure

Objective: Common variants near melanocortin receptor 4 (MC4R) have been related to fatness and type 2 diabetes. We examined the associations of rs17782313 and rs17700633 in relation to body fat, body fat distribution, metabolic traits, weight development and energy expenditure. Methods: Obese young men (n = 753, BMI >= 31.0 kg m(-2)) and a randomly selected group (n = 874) identified from a population of 174 800 men were re-examined in three surveys at mean ages 35, 46 and 49 years (S-35, S-46 and S-49). Measurements were available at upto eight times from birth to adulthood. Logistic regression analysis was used to assess odds ratio (OR) for the presence of the carrier allele for a given difference in phenotypic values. Results: Rs17782313 minor C-allele was associated with overall, abdominal and peripheral fatness (range of OR 1.06-1.14 per z-score units) at all three surveys, although only consistently significant at S-35 and S-46. Rs17700633 minor A-allele was also associated with the fatness measures, but significantly so only at S-49 for overall and abdominal fatness (range of OR 1.03-1.15 per z-score units), and peripheral fatness (OR 1.15-1.20 per z-score units). There were only few significant associations with metabolic traits. The rs17782313 C-allele and the rs17700633 A-allele were both associated with lower high-density lipoprotein cholesterol (range of OR 0.64-0.84 per mol l(-1)), significantly at S-46. The rs17700633 A-allele was significantly associated with insulin (OR 1.25 per 50 pmol l(-1)), leptin (OR 1.42 per 10 ng mu l(-1)) and insulin sensitivity (OR 0.81 per model unit). The rs17782313 C-allele and the rs17700633 A-allele were both associated with BMI in childhood and adolescence (range of OR 1.04-1.17 per z-score units), significant for the rs17782313 C-allele at the age of 13-19 years and for rs17700633 A-allele at age 7, 10, 13 and 19 years. No significant associations were found for energy expenditure. Conclusion: Near MC4R variants appear to contribute to body fat, body fat distribution, some metabolic traits, weight development during childhood, but not to energy expenditure. International Journal of Obesity (2010) 34, 182-189; doi:10.1038/ijo.2009.215; published online 20 October 2009