Abstract 010: Favorable Associations of a Healthy Diet with Fasting Glucose or Insulin are Not Modified by Fasting Glucose- or Insulin-Associated Genotypes in 51,289 Non-Diabetic Individuals from 15 Cohorts

Background: Genome-wide association studies (GWAS) have identified several genetic loci that influence fasting glucose (FG) and insulin (FI). Whether the favorable relation between eating a healthy diet and FG or FI is the same regardless of genetic risk is unknown. Objective: We studied 15 well-characterized U.S., Northern European and Mediterranean cohorts that had dietary and genetic data (maximum N = 51,289) to test whether genotype and healthy diet interact to influence FG or FI concentrations. Design: Within each cohort, we constructed a healthy diet score comprising foods with previous evidence of associations with metabolic risk: whole grains, fish, fruits, vegetables, nuts/seeds (favorable food groups) and red meat, sweets, sugared beverages, fried potatoes (unfavorable food groups). Intakes of each food group were categorized in quartiles and assigned ascending values (0, 1, 2, 3) for favorable foods and descending values (3, 2, 1, 0) for unfavorable foods. These values were summed to generate an overall diet score (range: 0 to 27 points), with higher scores representing healthier diets. We used multivariable linear regression including an additive genetic model within cohorts followed by inverse weighted meta-analysis of all cohorts to quantify 1) associations between healthy diet and FG and FI and 2) interactions of healthy diet with 16 established FG- or two FI-associated loci on FG and FI concentrations. Results: Healthier diets (per additional diet score unit) were associated with lower FG (β: -0.004; 95% CI: -0.005, -0.003 mmol/L, p: <0.001) and lower ln(FI) (β: -0.008; 95% CI: -0.009, -0.007 pmol/L, p: <0.001) with adjustment for demographic, lifestyle and physiological factors including body mass index. The relations between healthy diet and FG and FI were the same regardless of genotype for any individual SNP (interaction p: 0.22 - 0.99) or the sum of risk alleles across the 16 FG-related SNPs (unweighted genetic risk score, p: 0.71). We estimated that modest differences in diet score could offset the small genetic risk associated with per risk allele increases in common variants associated with FG. For example, the mean effect size across all 16 FG-raising alleles was ∼0.03 mmol/L greater FG per FG-raising allele, which compares in magnitude to the effect size of an approximate 1.5-SD increase in diet score, i.e., towards a healthier diet: ∼7 score units x diet score β -0.004 = -0.028 mmol/L lower FG). Conclusions: A healthy diet score allowing summarization of dietary intake as an environmental exposure across diverse cohorts is favorably associated with FG and FI concentrations regardless of genotype at FG or FI-associated loci. Modest dietary differences are far larger than an individual’s apparent genetic risk at these loci.

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