Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci

Abstract

Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10−6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10−8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition.

Associations between Omega-3 Index, Dopaminergic Genetic Variants and Aggressive and Metacognitive Traits: A Study in Adult Male Prisoners

“…Although there is a growing body of literature showing the beneficial effect of fish-oil consumption (such as a higher level of n-3 LCPUFA in the blood associated with a lower risk of heart disease), high blood levels of n-3 LCPUFA can be detrimental for some individuals depending on their genotype in the context of lipid profiles [ 70 ]. A recent study reported that omega-3 supplementation can either aid in reducing blood triglycerides or increase blood triglycerides depending on the genotypes of four variants for the GJB2 , SLC12A3 , ABCA6 , and MLXIPL genes in individuals [ 70 ].…”

Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers

“…Our approach identified 846 significant GEIs, many of which involved a set of highly correlated exposures (discussed further below). The large sample size of UKB provides the statistical power needed to identify interactions and has supported genome-wide GEI discovery in investigations of anthropometric and cardiometabolic phenotypes [21][22][23][24] . However, the scale of this population also means that spurious GEIs induced by even small statistical artifacts or biological confounders may reach statistical significance, as demonstrated by Tyrell and colleagues 25 .…”

Biomarkers of geroprotection and cardiovascular health: An overview of omics studies and established clinical biomarkers in the context of diet

“…These gene expression changes were accompanied by a decrease in circulatory cytokines, adhesion molecules, and acute-phase proteins and an increase in pro-resolving mediators, indicating an anti-inflammatory effect elicited by the omega-3 fatty acids. GWAS of fish oil supplementation effects recently revealed new gene-diet interaction loci, some of which implicated in LDL metabolism (Francis et al 2021).…”