A prospective study of dietary and supplemental zinc intake and risk of type 2 diabetes depending on genetic variation in SLC30A8

Isabel Drake, George Hindy, Ulrika Ericson, Marju Orho-Melander

The solute carrier family 30 member 8 gene (SLC30A8) encodes a zinc transporter in the pancreatic beta cells and the major C-allele of a missense variant (rs13266634; C/T; R325W) in SLC30A8 is associated with an increased risk of type 2 diabetes (T2D). We hypothesized that the association between zinc intake and T2D may be modified by the SLC30A8 genotype. We carried out a prospective study among subjects with no history cardio-metabolic diseases in the Malmö Diet and Cancer Study cohort (N = 26,132, 38% men; 86% with genotype data). Zinc intake was assessed using a diet questionnaire and food record. During a median follow-up of 19 years, 3676 T2D cases occurred. A BMI-stratified Cox proportional hazards regression model with attained age as the time scale was used to model the association between total and dietary zinc intake, zinc supplement use, zinc to iron ratio, and risk of T2D adjusting for putative confounding factors.The median total zinc intake was 11.4 mg/day, and the median dietary zinc intake was 10.7 mg/day. Zinc supplement users (17%) had a median total zinc intake of 22.4 mg/day. Dietary zinc intake was associated with increased risk of T2D (Ptrend < 0.0001). In contrast, we observed a lower risk of T2D among zinc supplement users (HR = 0.79, 95% CI 0.70-0.89). The SLC30A8 CC genotype was associated with a higher risk of T2D (HR = 1.16, 95% CI 1.07-1.24), and the effect was stronger among subjects with higher BMI (Pinteraction = 0.007). We observed no significant modification of the zinc-T2D associations by SLC30A8 genotype. However, a three-way interaction between SLC30A8 genotype, BMI, and zinc to iron ratio was observed (Pinteraction = 0.007). A high zinc to iron ratio conferred a protective associated effect on T2D risk among obese subjects, and the effect was significantly more pronounced among T-allele carriers. Zinc supplementation and a high zinc to iron intake ratio may lower the risk of T2D, but these associations could be modified by obesity and the SLC30A8 genotype. The findings implicate that when considering zinc supplementation for T2D prevention, both obesity status and SLC30A8 genotype may need to be accounted for.