Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway

Abstract

Background Palmitic acid(16:0), stearic acid(18:0), palmitoleic acid(16:1n-7), and oleic acid(18:1n-9) are major saturated and mono-unsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis (DNL) and are the main saturated and mono-unsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes and coronary heart disease. Methods and Results Genome-wide association studies were conducted in 5 population-based cohorts comprising 8,961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these four fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of one or more of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0(P=2.7×10-11) and lower 18:0(P=2.2×10-18). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6×10-13) and 18:1n-9(P=2.2×10-32), and lower 18:0(P =1.3×10-20). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8×10-9). GCKR(glucokinase regulator, P =9.8×10-10) and HIF1AN(factor inhibiting hypoxia-inducible factor-1, P=5.7×10-9) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1(polycystic kidney disease 2-like 1, P=5.7×10-15) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1×10-8). Conclusion Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of four fatty acids in the DNL pathway. These results expand our knowledge of genetic factors relevant to DNL and fatty acid biology.

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

“…Our analyses support the presence of these haplotypes in this sample, as well as the finding that the more common haplotype is associated with increased efficiency of long-chain fatty acid synthesis [47]. Furthermore, these genes have been shown to be associated with a number of phenotypes in SNP association studies, including certain plasma fatty acids [48,49], plasma lipoproteins [48,50], and response to lipid therapy [51] as well as DNA methylation levels [52]. …”

Circulating Biomarkers of Dairy Fat and Risk of Incident Diabetes Mellitus Among Men and Women in the United States in Two Large Prospective Cohorts

“…Adjustment for fatty acid biomarkers of de novo lipogenesis, 16:0 and 18:0, 25, 26 had the greatest effect on plasma 15:0, which was no longer significantly associated with diabetes when 16:0 and 18:0 were removed as covariates (continuous HR=1.10, 95%CI=0.85–1.42). Conversely, removal of these fatty acid covariates had smaller influence on associations with diabetes for plasma 17:0 (HR=0.67, 95%CI=0.51–0.89) or t-16:1n-7 (HR=0.68, 95%CI=0.51–0.92).…”

The n-3 long-chain PUFAs modulate the impact of the GCKR Pro446Leu polymorphism on triglycerides in adolescents

“…Hepatic GCK mRNA expression is positively associated with lipogenic gene expression [FAS, acetylCoA carboxylase (ACC)] and with the de novo lipogenesis index ( 29 ). A GWAS showed that the GCKR rs780093 SNP [of which the minor allele is in strong linkage disequilibrium with the minor allele of rs1260326 ( 30 )] is associated with increased de novo lipogenesis ( 31 ). LC-PUFAs [mainly DHA ( 32 )] may act by downregulating FAS activation both directly ( 33 ) and by inhibiting sterol regulatory element-binding protein ( 34,35 ) and carbohydrate responsive element-binding protein.…”