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Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association
Dariush Mozaffarian1, Edmond K Kabagambe1, Catherine O Johnson1
1From the Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (DM); the Divisions of Cardiovascular Medicine (DM and PMR), Genetics (DIC), Preventive Medicine (LW, DIC, AYC, and PMR), and Aging (LD) and the Channing Division of Network Medicine (DM, QS, EBR, FBH), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; the Departments of Epidemiology (DM, EBR, and FBH) and Nutrition (DM, QS, H Wu, MKJ, EBR, and FBH), Harvard School of Public Health, Boston, MA; the Department of Medicine (COJ, RNL, BMP, and DSS), School of Medicine, and the Departments of Biostatistics (BM), Epidemiology (DSS and BMP), and Health Services (BMP), School of Public Health, University of Washington, Seattle, WA; the Group Health Collaborative Research Institute, Seattle, WA (BMP); Center for Public Health Genomics (AM and SSR) and the Division of Biostatistics (AM), Department of Public Health Sciences, University of Virginia, Charlottesville, VA; the Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (EKK); the Division of Epidemiology & Community Health, School of Public Health (LS) and Department of Laboratory Medicine & Pathology (MYT), University of Minnesota, Minneapolis, MN; Institute of Molecular Medicine (M Foy and M Fornage) and Division of Epidemiology (M Fornage), Human Genetics, and Environmental Science, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX; Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, CA (IY-DC); The George Institute for Global Health, University of Sydney, Australia (JHYW); and the Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL (H Wiener, MRI, and DKA).
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 (β = 0.0035, P = 4.90 × 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 (β = 0.0053, P = 1.05 × 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 × 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 cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-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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