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 affects 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 6929 Mexican adults (3175 T2D cases and 3754 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 TaqMan technology.

RESULTS:

The MC4R p.Ile269Asn mutation was associated with T2D in 6929 Mexican adults (Ncontrols = 3754, Ncases = 3175, 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). Although a strong association between the mutation and T2D was observed in men (Ncontrols = 2418, Ncases = 1807, OR = 2.63, 95% CI, 1.62-4.28, P = 9.3 × 10-5), results were not significant in women (Ncontrols = 1336, Ncases = 1368, 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.

• Authors: Miguel Vázquez-Moreno, Daniel Locia-Morales, Adan Valladares-Salgado, Tanmay Sharma, Niels Wacher-Rodarte, Miguel Cruz, David Meyre
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 106 Issue 1 Pg. e112-e117 (01 01 2021) ISSN: 1945-7197 [Electronic] United States
• PMID: 33045043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• MC4R protein, human
• Receptor, Melanocortin, Type 4
• Isoleucine
• Asparagine

Topics

• Adult
• Aged
• Amino Acid Substitution
• Asparagine (genetics)
• Case-Control Studies
• Cross-Sectional Studies
• Diabetes Mellitus, Type 2 (epidemiology, genetics)
• Effect Modifier, Epidemiologic
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genotype
• Humans
• Isoleucine (genetics)
• Male
• Mexico (epidemiology)
• Middle Aged
• Polymorphism, Single Nucleotide
• Receptor, Melanocortin, Type 4 (genetics)
• Risk Factors
• Sex Factors