TY - JOUR
T1 - Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway
T2 - Results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium
AU - Wu, Jason H Y
AU - Lemaitre, Rozenn N.
AU - Manichaikul, Ani
AU - Guan, Weihua
AU - Tanaka, Toshiko
AU - Foy, Millennia
AU - Kabagambe, Edmond K.
AU - Djousse, Luc
AU - Siscovick, David
AU - Fretts, Amanda M.
AU - Johnson, Catherine
AU - King, Irena B.
AU - Psaty, Bruce M.
AU - McKnight, Barbara
AU - Rich, Stephen S.
AU - Chen, Yii Der I
AU - Nettleton, Jennifer A.
AU - Tang, Weihong
AU - Bandinelli, Stefania
AU - Jacobs, David R.
AU - Browning, Brian L.
AU - Laurie, Cathy C.
AU - Gu, Xiangjun
AU - Tsai, Michael Y.
AU - Steffen, Lyn M.
AU - Ferrucci, Luigi
AU - Fornage, Myriam
AU - Mozaffarian, Dariush
PY - 2013/4
Y1 - 2013/4
N2 - Background-Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. Methods and Results-Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 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 hypoxiainducible 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). Conclusions-Our findings provide novel evidence that common variations in genes with diverse functions, including proteinglycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.
AB - Background-Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. Methods and Results-Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 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 hypoxiainducible 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). Conclusions-Our findings provide novel evidence that common variations in genes with diverse functions, including proteinglycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.
KW - Epidemiology
KW - Fatty acids
KW - Genome-wide association study
KW - Lipogenesis
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U2 - 10.1161/CIRCGENETICS.112.964619
DO - 10.1161/CIRCGENETICS.112.964619
M3 - Article
C2 - 23362303
AN - SCOPUS:84878092875
SN - 1942-325X
VL - 6
SP - 171
EP - 183
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 2
ER -