Common Variants Near MC4R: Exploring Gender Effects in Overweight and Obese Children and Adolescents Participating in a Lifestyle Intervention

Objective: Association with obesity and increased insulin levels have been reported for two variants (rs17782313 and rs12970134) located downstream of the melanocortin-4 receptor gene (MC4R). Methods: We investigated whether these variants have sex-specific effects on overweight, obesity and 14 related phenotypes in 889 overweight and obese children and adolescents. We also explored the impact of the variants on weight change in 367 of the 889 cases who participated in an intervention program. Prior to these analyses we showed that both variants were associated with overweight/ obesity in the analyzed 889 cases versus 442 normal-weight and lean controls (case-control study). Results: In explorative analyses we observed higher diastolic blood pressure levels in males (rs17782313: beta = 2.52 mm Hg per risk allele; p = 0.003) but reduced blood pressure level in females for the same risk allele (beta = -1.72 mm Hg; p = 0.039). We also detected a greater BMI standard deviation score (BMI-SDS) reduction in females with the risk allele at rs17782313 (beta = 0.086 per risk allele; p = 0.021). Additionally, we observed evidence for an association of the same risk allele with insulin levels (beta = 0.029 log (mu U/ml); p = 0.044) with no sex-specific effect. For the remaining 11 phenotypes, we observed no evidence for a (sex-specific) association. Conclusions: In sum, our data support the associations of variants rs17782313 and rs12970134 near MC4R with early onset obesity and increased insulin levels. Exploratory evidence for sex-specific effects of the risk alleles were observed for diastolic blood pressure and BMI-SDS reduction.