期刊
AMERICAN JOURNAL OF CLINICAL NUTRITION
卷 101, 期 2, 页码 398-406出版社
AMER SOC NUTRITION-ASN
DOI: 10.3945/ajcn.114.094557
关键词
arachidonic acid; genome-wide association; meta-analysis; phospholipid; trans fatty acids
资金
- National Heart, Lung, and Blood Institute (NHLBI) [HL105756]
- NHLBI in collaboration with the University of Alabama at Birmingham [HEISN268201300025C, HHSN268201300026C]
- Northwestern University [HHSN268201300027C]
- University of Minnesota [HHSN268201300028C]
- Kaiser Foundation Research Institute [HHSN268201300029C]
- Johns Hopkins University School of Medicine [HHSN268200900041C]
- Intramural Research Program of the National Institute on Aging
- National Human Genome Research Institute (NHGRI) [U01-HG004729, U01-H0004446, U01-H0004424]
- NHLBI [HL105756, HL084099, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL103612, HL120393, HL085251, HL085710, U01-HL072524, R01-HL091357, HL034594]
- National Institute on Aging [AG023629]
- National Center for Advancing Translational Sciences, CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetes Research Center [DK063491]
- Nurses' Health Study (NHS)
- National Cancer Institute [CA40356, CA087969, CA49449, CA055075, CA98233, CA167552, CA137088, CA059045, CA137178, CA047988]
- NIDDK [DK058845, DK070756, K01-DK082729]
- NHGRI [HG004399, HG004728]
- National Institute of Environmental Health Sciences [ES014433]
- Merck/Rosetta Research Laboratories, North Wales, PA
- Donald W. Reynolds Foundation
- Foundation Leducq
- American Heart Association [0735390N]
Background: Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health. Objective: The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers. Design: We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts. Results: Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (beta = 0.0035, P = 4.90 x 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (beta = 0.0053, P = 1.05 x 10(-6)) and Chinese Americans (beta = 0.0028, P = 0.002) but not African Americans (beta = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: beta = 0.0118, P = 4.05 X 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cisltrans-18:2 was nearly eliminated in European-ancestry participants (p-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans. Conclusions: Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.
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