Interaction of an S100A9 gene variant with saturated fat and carbohydrates to modulate insulin resistance in 3 populations of different ancestries

Abstract

Background: S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses in other populations and ancestries.

Objectives: We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations.

Design: We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155).

Results: Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low.

Conclusions: The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS).

Keywords: SFA:carbohydrate ratio; S100A9 gene; gene-diet interaction; insulin resistance; type 2 diabetes.

© 2016 American Society for Nutrition.

Figures

FIGURE 1

Meta-analysis of associations between rs3014866 and T2D risk in the 3 populations. A fixed-effect model was used to get the overall effect estimate. Black squares indicated βs, square sizes reflect corresponding weights, and horizontal bars denote 95% CIs. Heterogeneity was tested by Cochran’s Q statistic and quantified with the use of I2. BPRHS, Boston Puerto Rican Health Study; CORDIOPREV, Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; GOLDN, Genetics of Lipids Lowering Drugs and Diet Network.

FIGURE 2

Estimated mean ± SEM interactions between the S100A9 variant (rs3014866) and SFA intake (percentage of total energy) on HOMA-IR. (A) For the CORDIOPREV, low and high SFA intakes indicate median intakes (≤8.8% and >8.8%). (B) For the GOLDN, low and high SFA intakes indicate median intakes (≤11.8% and >11.8%). (C) In the BPRHS, low SFA and high SFA indicate SFA median intakes (≤9.3% and >9.3%). The number inside each bar indicates the number of subjects in that group with data available for HOMA-IR. Analyses were adjusted for age, sex, BMI, smoking status, alcohol use, diabetes medication use, and physical activity. In addition, we adjusted the model for the study center and family relationships in the GOLDN and for the population structure in the BPRHS. P-interactions between SFA intake (as dichotomous) and the S100A9 variant in each population were obtained with the use of a univariate model analysis. *P < 0.05 for mean comparisons of HOMA-IR values between CC and TT+CT genotypes with high SFA intake (univariate model analysis). BPRHS, Boston Puerto Rican Health Study; CORDIOPREV, Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; GOLDN, Genetics of Lipids Lowering Drugs and Diet Network; S100A9, S100 calcium-binding protein A9 gene.

FIGURE 3

Estimated mean ± SEM interactions between the S100A9 variant (rs3014866) and SFA/CHO ratio intake on HOMA-IR. (A) For the CORDIOPREV, low and high SFA/CHO ratios indicate median intakes (≤0.21 and >0.22). (B) For the GOLDN, low and high SFA/CHO ratios indicate median intakes (≤0.24 and >0.25). (C) In the BPRHS, low and high SFA/CHO ratios indicate median intakes (≤0.19 and >0.20). The number inside each bar indicates the number of subjects in that group with data available for HOMA-IR. Analyses were adjusted for age, sex, BMI, smoking status, alcohol use, diabetes medication use, and physical activity. In addition, we adjusted the model for the study center and family relationships in the GOLDN and for the population structure in the BPRHS. P-interactions between the SFA/CHO ratio (as dichotomous) and the S100A9 variant in each population were obtained with the use of a univariate model analysis. *P < 0.05 for mean comparisons of HOMA-IR values between CC and TT+CT genotypes with high SFA/CHO ratio intake (univariate model analysis). BPRHS, Boston Puerto Rican Health Study; CHO, carbohydrate; CORDIOPREV, Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; GOLDN, Genetics of Lipids Lowering Drugs and Diet Network; S100A9, S100 calcium-binding protein A9 gene.