The MC4R p.Ile269Asn mutation confers a high risk for type 2 diabetes in the Mexican population via obesity dependent and independent effects

We investigated the association between the loss-of-function mutation MC4R p.Ile269Asn and T2D risk in the Mexican population. We enrolled 6929 adults [3175 T2D cases and 3754 normal glucose tolerant (NGT) controls] and 994 NGT children in the study. Anthropometric data and T2D-related quantitative traits were studied in 994 NGT children and 3754 NGT adults. The MC4R p.Ile269Asn mutation was genotyped using TaqMan. The MC4R p.Ile269Asn mutation was associated with T2D [OR=2.00, 95% confidence interval (CI) 1.35-2.97, p=0.00057] in Mexican adults. Additional adjustment for body-mass index (BMI) attenuated but did not remove the association (OR=1.70, 95% CI 1.13-2.56, p=0.011). The MC4R p.Ile269Asn mutation was associated with T2D (OR=1.88, 95% CI 1.14-3.08, p=0.013) in a subset of 1269 T2D cases and 1269 NGT controls matched for sex, age, and BMI. A mediation analysis estimated that BMI accounts for 22.7% of the association between MC4R p.Ile269Asn mutation and T2D risk (p=4.55x10(-6)). An association was observed between the MC4R p.Ile269Asn mutation and BMI in NGT children and adults (children: beta=3.731 +/- 0.958, p=0.0001; adults: beta=2.269 +/- 0.536, p=2.3x10(-5)). In contrast, the mutation was not associated with T2D-related quantitative traits. We demonstrate that the MC4R p.Ile269Asn mutation predisposes to T2D via obesity-dependent and independent effects in the Mexican population.

Automated summary

The MC4R p.Ile269Asn mutation is associated with an increased risk of T2D in Mexican adults, even after adjusting for BMI. Mediation analysis showed that BMI accounts for 22.7% of the association between the mutation and T2D risk.