Sex/gender modifies the association between the MC4R p.Ile269Asn mutation and type 2 diabetes in the Mexican population

Abstract

Context: Studies in mice and humans suggest that melanocortin-4 receptor (MC4R) deficiency impacts body weight in a sex/gender-dependent manner. However, similar evidence for type 2 diabetes (T2D) is scarce.

Objective and design: We investigated whether sex/gender modifies the association between the loss-of-function MC4R p.Ile269Asn mutation and T2D in 6,929 Mexican adults (3,175 T2D cases and 3,754 normal glucose tolerance (NGT) controls). The 2003 American Diabetes Association criteria were used to define NGT and T2D. The MC4R p.Ile269Asn mutation was genotyped in all participants using the TaqMan technology.

Results: The MC4R p.Ile269Asn mutation was associated with T2D in 6,929 Mexican adults (Ncontrols=3,754, Ncases=3,175, odds ratio (OR)=2.00, 95% confidence interval (CI) [1.35-2.97], p=5.7×10 -4). The MC4R p.Ile269Asn mutation had a frequency of 0.86 and 1.05% in women with NGT and T2D, and 0.78 and 1.32% in men with NGT and T2D, respectively. We identified a significant interaction between the MC4R p.Ile269Asn mutation and sex/gender on T2D risk (p=0.049). While a strong association between the mutation and T2D was observed in men (Ncontrols=2,418, Ncases=1,807, OR=2.63, 95%CI [1.62-4.28], p=9.3×10 -5), results were not significant in women (Ncontrols=1,336, Ncases=1,368, OR=1.16, 95%CI [0.60-2.26], p=0.65). Further adjustment for body mass index in the logistic regression model did not alter the sex/gender-specific pattern of association (men: OR=2.22, 95%CI [1.34-3.67], p=0.0019; women: OR = 1.02, 95%CI [0.51-2.02], p=0.95).

Conclusion: This is the first report of a male-specific association between the MC4R p.Ile269Asn loss-of-function mutation and T2D in the Mexican population.

Keywords: Mexican population; human genetics; melanocortin-4 receptor; sex/gender-specific effect; type 2 diabetes.

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