Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway: Results from the CHARGE Consortium.

Publication Type:

Journal Article

Source:

Circulation. Cardiovascular genetics (2013)

Keywords:

February 2013, Public Health Sciences Division

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=2.7x10(-11)) and lower 18:0(P=2.2x10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7(P=6.6x10(-13)) and 18:1n-9(P=2.2x10(-32)), and lower 18:0(P =1.3x10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0(P=2.8x10(-9)). GCKR (glucokinase regulator, P=9.8x10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1, P=5.7x10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1, P=5.7x10(-15)) and a locus on chromosome 2(not near known genes) were associated with lower 16:1n-7(P=4.1x10(-8)). CONCLUSIONS: -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.