Gene-diet interaction analysis, fine mapping and genomic annotation of the FADS1-2-3 gene cluster reveals regulatory potential in diabetes

• Background and aims: Polymorphisms at the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) have been associated with multiple metabolic and anthropometric traits in Greenlandic Inuit. We systematically assessed whether loci in the FADS region modify the association between dietary fat intake and cardiometabolic traits and functionally annotated top variants to estimate causal loci.Materials and methods: Data analyses consisted of: 1) interaction analyses between the six candidate genetic variants; 2) gene-centric joint analyses to detect interaction signals in the FADS region; 3) haplotype-centric joint tests across 30 haplotype blocks in the FADS1- 3 region to refine interaction signals: 4) functional annotation of top loci. These analyses were undertaken in Swedish adults from the GLACIER Study (N=5,160); data on gene variation (Metabochip array) and height, body weight, fasting and 2hr-glucose, triglycerides, and HDL-, LDL- and total cholesterol were available. Dietary intakes of n3, n-6 and total polyunsaturated fatty acids (PUFA) were calculated from food-frequency questionnaires. Results were adjusted for multiple testing.Results: SNP-level multiplicative interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (Pinteraction=0.007) and between rs174602 and n-3 PUFA intake on total cholesterol (Pinteraction=0.015). Gene-centric analyses demonstrated evidence for joint main and interaction effects for FADS on body weight (Pn-3.joint = 0.018, Pn-6.joint = 0.021, PPUFA.joint = 0.024) and on BMI (Pn-3.joint = 0.031, Pn-6.joint = 0.029, PPUFA.joint = 0.033) irrespective of types of fatty acid intake. An interaction was detected for FADS1-3 and n-3 PUFA on triglycerides (Pint=0.005). The haplotype analyses revealed three blocks (Pint ≤0.011) that drive the interaction between FADS1-3 and n-3 PUFA on triglycerides. Genomic annotation showed that the rs5792235 variant demonstrated the highest functionality score (Figure).Conclusion: The association between FADS1-3 variants and triglycerides may be modified by PUFA intake. The intronic rs5792235 variant is a potential causal variant in the region. It is likely that the region harbours multiple causal loci.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

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