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.
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.
Department of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. jasonwu@hsph.harvard.edu
Jason H Y
JH
Wu
Rozenn N
RN
Lemaitre
Ani
A
Manichaikul
Weihua
W
Guan
Toshiko
T
Tanaka
Millennia
M
Foy
Edmond K
EK
Kabagambe
Luc
L
Djousse
David
D
Siscovick
Amanda M
AM
Fretts
Catherine
C
Johnson
Irena B
IB
King
Bruce M
BM
Psaty
Barbara
B
McKnight
Stephen S
SS
Rich
Yii-Der I
YD
Chen
Jennifer A
JA
Nettleton
Weihong
W
Tang
Stefania
S
Bandinelli
David R
DR
Jacobs
Brian L
BL
Browning
Cathy C
CC
Laurie
Xiangjun
X
Gu
Michael Y
MY
Tsai
Lyn M
LM
Steffen
Luigi
L
Ferrucci
Myriam
M
Fornage
Dariush
D
Mozaffarian
D000328:Adult; D000368:Aged; D002889:Chromosomes, Human, Pair 2; D015331:Cohort Studies; D003327:Coronary Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000097:blood*; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D050155:Lipogenesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019301:Oleic Acid / Q000097:blood; D019308:Palmitic Acid / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D013229:Stearic Acids / Q000097:blood
D000090943:Delta-5 Fatty Acid Desaturase; D005229:Fatty Acids, Monounsaturated; D013229:Stearic Acids; C008757:palmitoleic acid; D019301:Oleic Acid; D019308:Palmitic Acid; C031183:stearic acid; C000716847:FADS1 protein, human