Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry

Abstract

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist–hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006–0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

The importance of gene–environment interactions in human obesity

“…Data from 177330 adults (87 % Whites, 10 % Asian, 3 % African American) did not indicate any significant interactions between the FTO variant and dietary intake of total energy, fat, protein or carbohydrate on BMI [137]. A second meta-analysis of 68317 Europeans did not detect an interaction between a 32 SNP genetic risk score and a multifactorial diet score on BMI [136]. The diet score moderated the impact of two SNPs in/near LRRN6C and MTIF3 on BMI), although these effects were nominal and the impact of these risk variants appeared to be greater among those consuming healthier diets [136].…”

“…Despite the many studies demonstrating that diet patterns can moderate the genetic risk for obesity, two recent meta-analyses did not detect significant interactions between diet patterns and obesity-associated gene variants [136,137]. Data from 177330 adults (87 % Whites, 10 % Asian, 3 % African American) did not indicate any significant interactions between the FTO variant and dietary intake of total energy, fat, protein or carbohydrate on BMI [137].…”

“…A second meta-analysis of 68317 Europeans did not detect an interaction between a 32 SNP genetic risk score and a multifactorial diet score on BMI [136]. The diet score moderated the impact of two SNPs in/near LRRN6C and MTIF3 on BMI), although these effects were nominal and the impact of these risk variants appeared to be greater among those consuming healthier diets [136]. The authors speculate that the broad diet assessment in their analysis may have masked interactions of varying directions and magnitudes that were identified in previous studies [136].…”

The heritable basis of gene–environment interactions in cardiometabolic traits

“…Approaches include quantitative genetics studies, usually undertaken in twin or familybased cohorts [4,6,7,[34][35][36][37][38] and candidate gene studies, focused on individual genetic variants, haplotypes, or genetic risk scores constructed from variants with high biological priors for interactions or those conveying genome-wide < p < 5x10 TC, total cholesterol; TG, triacylglycerol significant marginal effects [39][40][41][42][43][44][45][46][47]. Several quantitative genetic studies have shown that physical activity attenuates the influence of genetic effects on cardiometabolic traits [4,6,34,35,37,38].…”

“…Although several candidate gene studies have focused on gene-diet interactions (e.g. [43][44][45][46][47] ) are marked with an asterisk (SBP for class 1 interactions, and weight for class 2 interactions). α G , γ G and λ parameters were calculated based on individuals 30-60 years of age, as this was the age range in the dataset.…”