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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) consortiu

TitleGenome-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) consortiu
Publication TypeJournal Article
Year of Publication2013
AuthorsH Y Wu J, Lemaitre RN, Manichaikul A, Guan W, Tanaka T, Foy M, Kabagambe EK, Djoussé L, Siscovick D, Fretts AM, Johnson C, King IB, Psaty BM, McKnight B, Rich SS, Chen Y-DI, Nettleton JA, Tang W, Bandinelli S, Jacobs DR, Browning BL, Laurie CC, Gu X, Tsai MY, Steffen LM, Ferrucci L, Fornage M
Secondary AuthorsMozaffarian D
JournalCirc Cardiovasc Genet
Volume6
Issue2
Pagination171-83
Date Published2013 Apr
ISSN1942-3268
KeywordsAdult, Aged, Chromosomes, Human, Pair 2, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 2, Fatty Acids, Monounsaturated, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Lipogenesis, Male, Middle Aged, Oleic Acid, Palmitic Acid, Polymorphism, Single Nucleotide, Stearic Acids
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 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)). 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 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.

DOI10.1161/CIRCGENETICS.112.964619
Alternate JournalCirc Cardiovasc Genet
PubMed ID23362303
PubMed Central IDPMC3891054
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
U01-HG-004446 / HG / NHGRI NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
R01 HG004960 / HG / NHGRI NIH HHS / United States
R01 HL071251 / HL / NHLBI NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
HSN268200625226C / / PHS HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
R01 HL071259 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
R01 HL085710 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
R01 HL071252 / HL / NHLBI NIH HHS / United States
N01HC48049 / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
N01HC45205 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
R01 MD009164 / MD / NIMHD NIH HHS / United States
RR-024156 / RR / NCRR NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
263 MD 821336 / MD / NIMHD NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
N01-HC-45204 / HC / NHLBI NIH HHS / United States
R01 HL071250 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
UL1 RR024156 / RR / NCRR NIH HHS / United States
N01-HC-95159 / HC / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
U01 HG004424 / HG / NHGRI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
R01-HL-084099 / HL / NHLBI NIH HHS / United States
R01HL071252 / HL / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
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P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 HL071051 / HL / NHLBI NIH HHS / United States
HL075366 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
/ / Intramural NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
N01HC95095 / HL / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
U01-HG-004424 / HG / NHGRI NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
N01-HC-55222 / HC / NHLBI NIH HHS / United States
N01-HC-48049 / HC / NHLBI NIH HHS / United States
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R01 HL084099 / HL / NHLBI NIH HHS / United States
N01 HC045134 / HC / NHLBI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
U01-HG-004729 / HG / NHGRI NIH HHS / United States
N01HC48050 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
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5K01DK082729-02 / DK / NIDDK NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
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HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01 HL071205 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01HC45204 / HL / NHLBI NIH HHS / United States
K01 DK082729 / DK / NIDDK NIH HHS / United States
R01HL071259 / HL / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
N01-HC-48048 / HC / NHLBI NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
R01HL071251 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01HL071258 / HL / NHLBI NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
263 MD 9164 / MD / NIMHD NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
R01HL071051 / HL / NHLBI NIH HHS / United States
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N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
R01HL071250 / HL / NHLBI NIH HHS / United States
UL 1RR033176 / RR / NCRR NIH HHS / United States
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R01HL086694 / HL / NHLBI NIH HHS / United States