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 journalArticle

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
Externally publishedYes

Fingerprint

Lipogenesis
Genome-Wide Association Study
Phospholipids
Epidemiology
Fatty Acids
Research
Monounsaturated Fatty Acids
Glucokinase
Autosomal Dominant Polycystic Kidney
Acyltransferases
Chromosomes, Human, Pair 2
Palmitic Acid
Asparagine
Oleic Acid
Metabolic Networks and Pathways
Unsaturated Fatty Acids
Glycosylation
Type 2 Diabetes Mellitus
Genes
Coronary Disease

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

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

In: Circulation: Cardiovascular Genetics, Vol. 6, No. 2, 04.2013, p. 171-183.

Research output: Contribution to journalArticle

Wu, JHY, Lemaitre, RN, Manichaikul, A, Guan, W, Tanaka, T, Foy, M, Kabagambe, EK, Djousse, L, Siscovick, D, Fretts, AM, Johnson, C, King, IB, Psaty, BM, McKnight, B, Rich, SS, Chen, YDI, Nettleton, JA, Tang, W, Bandinelli, S, Jacobs, DR, Browning, BL, Laurie, CC, Gu, X, Tsai, MY, Steffen, LM, Ferrucci, L, Fornage, M & Mozaffarian, D 2013, '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', Circulation: Cardiovascular Genetics, vol. 6, no. 2, pp. 171-183. https://doi.org/10.1161/CIRCGENETICS.112.964619
Wu, Jason H Y ; Lemaitre, Rozenn N. ; Manichaikul, Ani ; Guan, Weihua ; Tanaka, Toshiko ; Foy, Millennia ; Kabagambe, Edmond K. ; Djousse, Luc ; Siscovick, David ; Fretts, Amanda M. ; Johnson, Catherine ; King, Irena B. ; Psaty, Bruce M. ; McKnight, Barbara ; Rich, Stephen S. ; Chen, Yii Der I ; Nettleton, Jennifer A. ; Tang, Weihong ; Bandinelli, Stefania ; Jacobs, David R. ; Browning, Brian L. ; Laurie, Cathy C. ; Gu, Xiangjun ; Tsai, Michael Y. ; Steffen, Lyn M. ; Ferrucci, Luigi ; Fornage, Myriam ; Mozaffarian, Dariush. / 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. In: Circulation: Cardiovascular Genetics. 2013 ; Vol. 6, No. 2. pp. 171-183.
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title = "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",
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.",
keywords = "Epidemiology, Fatty acids, Genome-wide association study, Lipogenesis",
author = "Wu, {Jason H Y} and Lemaitre, {Rozenn N.} and Ani Manichaikul and Weihua Guan and Toshiko Tanaka and Millennia Foy and Kabagambe, {Edmond K.} and Luc Djousse and David Siscovick and Fretts, {Amanda M.} and Catherine Johnson and King, {Irena B.} and Psaty, {Bruce M.} and Barbara McKnight and Rich, {Stephen S.} and Chen, {Yii Der I} and Nettleton, {Jennifer A.} and Weihong Tang and Stefania Bandinelli and Jacobs, {David R.} and Browning, {Brian L.} and Laurie, {Cathy C.} and Xiangjun Gu and Tsai, {Michael Y.} and Steffen, {Lyn M.} and Luigi Ferrucci and Myriam Fornage and Dariush Mozaffarian",
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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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