Sex-specific interactions between the IRS1 polymorphism and intakes of carbohydrates and fat on incident type 2 diabetes

Abstract

The minor T allele of rs2943641 near the gene encoding for insulin receptor substrate 1 (IRS1) has been associated with decreased risk of type 2 diabetes (T2D) and adiposity in genome-wide association studies. Dietary intake can influence the regulation of IRS1, and studies have indicated sex-specific associations between IRS1 and adiposity. The objective was to examine the interaction between IRS1 rs2943641 and macronutrient intakes on incident T2D and percentage body fat in the Malmö Diet and Cancer cohort. The study included 15,227 women and 9614 men aged 45-74 y without prevalent diabetes. Dietary data were collected with a modified diet history method. During 12 y of follow-up, 1567 incident T2D cases were identified. The T allele was associated with lower incidence of T2D (P-trend = 0.003) and, in men, with higher percentage body fat (P-trend = 0.00002). We observed 3-way interactions between sex, rs2943641, and carbohydrate intake (P = 0.01) as well as between sex, rs2943641, and fat intake (P = 0.01) on incident T2D. Among women, the T allele was associated with decreased risk only in the lower tertiles of carbohydrate intake (P-trend = 0.01, P-interaction = 0.01). In contrast, among men, the T allele was associated with decreased risk in the lowest tertile of fat intake (P-trend = 0.01, P-interaction = 0.02). No interaction was observed between macronutrient intakes and rs2943641 on percentage body fat. Our results indicate that IRS1 rs2943641 interacts with carbohydrate and fat intakes on incident T2D in a sex-specific fashion. A protective association between the rs2943641 T allele and T2D was restricted to women with low carbohydrate intake and to men with low fat intake.