Identification of Genetic Loci Associated with Plasma Long-chain Polyunsaturated Fatty Acids in Hispanic Children (P08-129-19)

Abstract

Abstract Objectives Long-chain polyunsaturated fatty acids (LC-PUFAs) are critical to the functioning of cell membranes as important constituents of phospholipids. They also serve as precursors for prostaglandins, leukotrienes and thromboxanes which affect metabolic processes such as vasodilation, inflammation and cell proliferation. The objective of this study was to identify genes that influence the plasma levels of LC-PUFAs in Hispanic children of the Viva La Familia study. Methods Plasma levels of LC-PUFAs, including eicosapentanoic acid (EPA, 20:5, n-3), docosahexanoic acid (DHA, 22:6, n-3), docosapentanoic acid (DPA, 22:5, n-3), arachidonic acid (20: 4 n-6) and docosapentanoic acid (DPA, 22:5 n-6), were measured as part of metabolomics profiling. Genome-wide single nucleotide polymorphisms (SNP) (array and exome sequence) association analysis (GWAS) were conducted using additive genetic models adjusting for kinships. Results GWAS identified several loci on chromosome 11 with significant evidence of association with LC-PUFAs. These include association of EPA and arachidonic acid with rs174548, rs174545, rs174546, rs174550, 1rs74538 of fatty acid desaturase 1 (FADS1), rs1535, rs174577, rs174568, 174570, 2072114, 2727270 of FADS2, rs174538 of flap structure-specific endonuclease 1 (FEN1), rs174535, rs174528, rs198462, rs174532, rs149803 and rs198464 of myelin regulatory factor (MYRF) and rs102275 and rs102274 of transmembrane protein 258 (TMEM258) (P < 10−12, MAF 5–45%). Other LC-PUFAs showed suggestive evidence of association with the same SNPs. Except for FADS2 SNPs, carriers of minor alleles of all other identified SNPs had lower levels of EPA and arachidonic acid with effect sizes ranging from 5–10%. The analysis of exome variants revealed significant association of EPA with two novel SNPs in syphingomyelin synthase 2 (SGMS2) (P = 1.6 × 10−8) and synaptotagmin 7 (SYT7) (<3 × 10−15, MAF 1.5–33%). The same two loci were associated with arachidonic acid (<6 × 10−9). No significant or suggestive associations were found for other LC-PUFAs. Conclusions In summary, our genome-wide and exome sequencing results replicated the association of EPA and arachidonic acid with FADS and TMEM258 genes and identified novel loci related to neuronal signaling mainly in MYRF, SGMS2 and SYT7. Funding Sources National Institutes of Health (NIH) [DK080457], and the USDA/ARS [Cooperative Agreement 6250-51000-053].