The combined effects of FADS gene variation and dietary fats in obesity-related traits in a population from the far north of Sweden: the GLACIER Study

BACKGROUND: Recent analyses in Greenlandic Inuit identified six genetic polymorphisms (rs74771917, rs3168072, rs12577276, rs7115739, rs174602, and rs174570) in the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) that are associated with multiple metabolic and anthropometric traits. Our objectives were to systematically assess whether dietary polyunsaturated fat acid (PUFA) intake modifies the associations between genetic variants in the FADS gene cluster and cardiometabolic traits and to functionally annotate top ranking candidates to estimate their regulatory potential. METHODS: Data analyses consisted: interaction analyses between the six candidate genetic variants and dietary PUFA intake; gene-centric joint analyses to detect interaction signals in the FADS region; haplotype block-centric joint tests across 30 haplotype blocks in the FADS region to refine interaction signals; functional annotation of top loci. These analyses were undertaken in Swedish adults from the GLACIER Study (N=5,160); data on genetic variation and eight cardiometabolic traits was used. RESULTS: Interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (P(int)=0.005) and between rs174602 and n-3 PUFA intake on total cholesterol (P(int)=0.001). Gene-centric analyses demonstrated a statistically significant interaction effect for FADS and n-3 PUFA on triglycerides (P=0.005) considering genetic main effects as random. Haplotype analyses revealed three blocks (P(int)<0.011) that could drive the interaction between FADS and n-3 PUFA on triglycerides; Functional annotation of these regions showed that each block harbours a number of highly functional regulatory variants; FADS2 rs5792235 demonstrated the highest functionality score. CONCLUSIONS: The association between FADS variants and triglycerides may be modified by PUFA intake. The intronic FADS2 rs5792235 variant is a potential causal variant in the region having the highest regulatory potential. However, our results suggest that haplotypes may harbour multiple functional variants in a region, rather than a single variant.