Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis

Abstract

Objective: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

Research design and methods: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

Results: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

Conclusions: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

FIG. 1.

Mean dietary and total zinc intake across cohorts. Values are presented as means (SD) and expressed as milligrams per day of dietary (food sources) and total (food sources and supplements) zinc intake. ●, dietary zinc; ○, total zinc.

FIG. 2.

Forest plots of the effect associations of zinc intake with fasting glucose. A: The effect association of total zinc (food sources and supplements) intake (per 1 mg/day) (summary P value = 0.0003, n = 34,533). B: Effect association of dietary zinc (food sources) intake (per 1 mg/day) (summary P value = 0.52, N = 46,021). Fasting blood glucose is expressed in micromoles per liter, and all associations are adjusted for age and sex, field center (in the CHS, the InCHIANTI study, the ARIC study, and the Health ABC study), and family structure by principal components (in the FHS and the FamHS).

FIG. 3.

Forest plot of the interaction between SLC30A8 rs11558471 and total zinc intake on fasting glucose. The rs11558471 effect is expressed per A allele, total zinc (food sources and supplements) intake per 1 mg/day, and fasting blood glucose in micromoles per liter. Associations are adjusted for age and sex, field center (in the CHS and the ARIC study), and family structure by principal components (in the FHS) (summary P value = 0.0051, N = 34,150).

FIG. 4.

Forest plots of the SLC30A8 rs11558471 interaction with zinc intake on glucose, by zinc supplement use. The rs11558471 effect is expressed per A allele, zinc intake per 1 mg/day, and fasting blood glucose in micromoles per liter. Associations are adjusted for age and sex, field center (in the CHS and the ARIC study), and family structure by principal components (in the FHS) (summary P value = 0.0077, N = 4,986 for zinc supplement users and summary P value = 0.65, n = 29,164 for zinc supplement nonusers).