Circulating Fatty Acids and Genetic Predisposition to Type 2 Diabetes: Gene-Nutrient Interaction Analysis

<b>OBJECTIVE</b>: To assess the relationship of circulating fatty acids (FAs) with risk of type 2 diabetes (T2D) and potential interactions with genetic risk. <p><a><b>RESEARCH DESIGN AND METHODS:</b></a><b> </b><a>95,854</a> participants with complete data on plasma FAs from the UK Biobank, were enrolled between 2006 and 2010, and were followed up to the end of 2020. Plasma concentrations of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were analyzed by a high-throughput NMR-based biomarker profiling platform. The genetic risk score (GRS) was calculated on the basis of 424 variants associated with T2D. Pathway-specific GRSs were calculated based on robust clusters of T2D loci.</p> <p><b>RESULTS:</b> 3,052 T2D cases were documented after an average follow-up of 11.6 years. Plasma concentrations of SFAs and MUFAs were positively associated with T2D risk while plasma PUFAs were inversely associated. After adjustment for major risk factors, HRs (95% CIs) of T2D for 1 SD increment were 1.03 (1.02-1.04) for SFAs, 1.03 (1.02-1.05) for MUFAs, 0.62 (0.56-0.68) for PUFAs, 0.67 (0.61-0.73) for n-6 PUFAs, 0.90 (0.85-0.95) for n-3 PUFAs, and 1.01 (0.98-1.04) for n-6/n-3 ratio. Plasma MUFAs had significant interactions with the overall GRS and GRSs for Proinsulin and Liver/Lipid clusters on T2D risk. The protective associations of n-3 PUFAs with T2D risk were weaker among individuals with higher Obesity GRS (P interaction=0.040) and Liver/Lipid GRS (P interaction=0.012). Additionally, increased plasma n-3 PUFA concentration was associated with more reductions in T2D risk among participants carrying more docosapentaenoic acid-associated alleles (P interaction=0.007).</p> <b>CONCLUSIONS: </b>Plasma concentrations of SFAs and MUFAs were associated with a higher T2D risk whereas plasma PUFAs and n-6 and n-3 PUFAs were related to a lower risk. Circulating MUFAs and n-3 PUFAs had significant interactions with genetic predisposition to T2D and FA-associated variants.