A genome-wide association study of saturated, mono- and polyunsaturated red blood cell fatty acids in the Framingham Heart Offspring Study

Abstract

Most genome-wide association studies have explored relationships between genetic variants and plasma phospholipid fatty acid proportions, but few have examined apparent genetic influences on the membrane fatty acid profile of red blood cells (RBC). Using RBC fatty acid data from the Framingham Offspring Study, we analyzed over 2.5 million single nucleotide polymorphisms (SNPs) for association with 14 RBC fatty acids identifying 191 different SNPs associated with at least 1 fatty acid. Significant associations (p<1×10−8) were located within five distinct 1 MB regions. Of particular interest were novel associations between (1) arachidonic acid and PCOLCE2 (regulates apoA-I maturation and modulates apoA-I levels), and (2) oleic and linoleic acid and LPCAT3 (mediates the transfer of fatty acids between glycerol-lipids). We also replicated previously identified strong associations between SNPs in the FADS (chromosome 11) and ELOVL (chromosome 6) regions. Multiple SNPs explained 8–14% of the variation in 3 high abundance (>11%) fatty acids, but only 1–3% in 4 low abundance (<3%) fatty acids, with the notable exception of dihomo-gamma linolenic acid with 53% of variance explained by SNPs. Further studies are needed to determine the extent to which variations in these genes influence tissue fatty acid content and pathways modulated by fatty acids.

TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation

“…Using the Geuvadis dataset (Tintle et al, 2015), which is comprised of matched genome sequences and transcriptomes from immortalized lymphoblasts, we found a strong eQTL effect for rs174538 on TMEM258 , wherein the minor allele was associated with increased expression. Importantly, rs174538 is in LD with the IBD risk SNP rs174537 (r 2 0.86, D’ 0.98), and the minor alleles for both SNPs correspond to IBD risk and increased expression of TMEM258 (Figure 6A).…”

“…Data were derived from lymphoblasts in the Geuvadis study (Tintle et al, 2015). Data represent mean and SD.…”

Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study

“…The two major factors that determine n-3 and n-6 PUFA levels – dietary PUFA intake and variants in FA desaturase and elongase genes - were not explored here, in part because they were beyond the scope of this study, but also because of their own inherent limitations. Estimated PUFA intakes derived from food records are inferior to circulating PUFA levels as indicators of PUFA exposure 64, 65 , and the effects of genetic variants on PUFA levels, while substantial for ARA 66 , are minimal to non-existent for EPA and DHA 67 . Finally, the inability to rule out the possibility of residual or unmeasured confounding also precludes inferences about causality 68 .…”

Discovery and fine-mapping of loci associated with MUFAs through trans-ethnic meta-analysis in Chinese and European populations

“…Reported association of FADS1/2 with oleic acid in European populations (17, 18) reached genome-wide significance in the Chinese-specific GWAS meta-analysis ( P = 2.92 × 10 −10 ; Table 2) and in the trans-ethnic meta-analysis (BF = 38.0, P = 1.44 × 10 −39 ; Table 2). These loci exhibited no evidence of heterogeneity between Chinese and European populations (Phet ≤ 0.061; Table 2).…”