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 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium

Jason H Y Wu, Rozenn N. Lemaitre, Ani Manichaikul, Weihua Guan, Toshiko Tanaka, Millennia Foy, Edmond K. Kabagambe, Luc Djousse, David Siscovick, Amanda M. Fretts, Catherine Johnson, Irena B. King, Bruce M. Psaty, Barbara McKnight, Stephen S. Rich, Yii Der I Chen, Jennifer A. Nettleton, Weihong Tang, Stefania Bandinelli, David R. JacobsBrian L. Browning, Cathy C. Laurie, Xiangjun Gu, Michael Y. Tsai, Lyn M. Steffen, Luigi Ferrucci, Myriam Fornage, Dariush Mozaffarian

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)171-183
Number of pages13
JournalCirculation: Cardiovascular Genetics
Volume6
Issue number2
DOIs
StatePublished - Apr 2013

Keywords

  • Epidemiology
  • Fatty acids
  • Genome-wide association study
  • Lipogenesis

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