Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: meta-analysis of nine studies in the CHARGE consortium

Authors: SMITH, CAREN - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; FOLLIS, JACK - UNIVERSITY OF ST. THOMAS; NETTLETON, JENIFER - UNIVERSITY OF TEXAS; FOY, MILLENNIA - UNIVERSITY OF TEXAS; WU, JASON - UNIVERSITY OF SYDNEY; MA, YIYI - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; TANAKA, TOSHIKO - NATIONAL INSTITUTE ON AGING (NIA, NIH); MANICHAKUL, ANI - UNIVERSITY OF VIRGINIA; WU, HONGYU - HARVARD INSTITUTE; CHU, AUDREY - BRIGHAM & WOMEN'S HOSPITAL; STEFFEN, LYN - UNIVERSITY OF MINNESOTA; FORNAGE, MYRIAM - UNIVERSITY OF TEXAS; MOZAFFARIAN, DARIUSH - HARVARD UNIVERSITY; KABAGAMBE, EDMOND - VANDERBILT UNIVERSITY; FERRUCI, LUIGI - NATIONAL INSTITUTE ON AGING (NIA, NIH); CHEN, YII-DER IDA - UCLA MEDICAL CENTER; RICH, STEPHEN - UNIVERSITY OF VIRGINIA; DJOUSSE, LUC - BRIGHAM & WOMEN'S HOSPITAL; RIDKER, PAUL - HARVARD UNIVERSITY; TANG, WEIHONG - UNIVERSITY OF MINNESOTA; MCKNIGHT, BARBARA - UNIVERSITY OF WASHINGTON; TSAI, MICHAEL - UNIVERSITY OF MINNESOTA; BANDINELLI, STEFANIA - AZIENDA SANITARIA DI FIRENZE; ROTTER, JEROME - UCLA MEDICAL CENTER; HU, FRANK - HARVARD UNIVERSITY; CHASMAN, DANIEL - HARVARD UNIVERSITY; PSATY, BRUCE - GROUP HEALTH COOPERATIVE; ARNETT, DONNA - UNIVERSITY OF ALABAMA; KING, IRENA - UNIVERSITY OF NEW MEXICO; SUN, QI - HARVARD UNIVERSITY; WANG, LU - BRIGHAM & WOMEN'S HOSPITAL; LUMLEY, THOMAS - UNIVERSITY OF AUCKLAND; CHIUVE, STEPHANIE - HARVARD UNIVERSITY; SISCOVICK, DAVID - GROUP HEALTH COOPERATIVE; ORDOVAS, JOSE - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; LEMAITRE, ROZENN - GROUP HEALTH COOPERATIVE

Submitted to: Molecular Nutrition and Food Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/20/2015
Publication Date: 7/1/2015
Citation: Smith, C.E., Follis, J.L., Nettleton, J.A., Foy, M., Wu, J.H., Ma, Y., Tanaka, T., Manichakul, A.W., Wu, H., Chu, A.Y., Steffen, L.M., Fornage, M., Mozaffarian, D., Kabagambe, E.K., Ferruci, L., Chen, Y., Rich, S.S., Djousse, L., Ridker, P.M., Tang, W., Mcknight, B., Tsai, M.Y., Bandinelli, S., Rotter, J.I., Hu, F.B., Chasman, D.I., Psaty, B.M., Arnett, D.K., King, I.B., Sun, Q., Wang, L., Lumley, T., Chiuve, S.E., Siscovick, D.S., Ordovas, J.M., Lemaitre, R.N. 2015. Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: meta-analysis of nine studies in the CHARGE consortium. Molecular Nutrition and Food Research. 59(7):1373-1383. https://doi.org/10.1002/mnfr.201400734.

Interpretive Summary: Omega-3 fatty acids in the blood appear to be protective against cardiovascular disease, and the evidence is most consistent for the omega-3 fatty acids that are referred to as "long-chain" fatty acids. While blood concentrations are determined in part by dietary intakes of these fatty acids, genetic factors that affect fatty acids' conversion and synthesis also play a role in determining their blood concentrations. Examining the relationships between dietary and genetic factors in combination may be more informative than limiting study to either diet or genetics alone. Previous genetic studies identified a set of genes that are important contributors to omega-3 concentrations. In the current study, we selected a small number of genetic variants from a previous large-scale study, and we explored the impact of diet and genotype using data from nine populations. Of the genetic factors we explored, the variant FADS1 (fatty acid desaturase 1,) which encodes an enzyme in the pathway that converts shorter-chain fatty acids to longer-chain fatty acids, emerged as a potential modulator of omega-3 fatty acids in the blood. Accumulating evidence suggests that carriers of FADS1 variants have reduced capacity to synthesize longer chain omega-3 fatty acids, which may be relevant to dietary recommendations. The long-term objective of gene-diet interaction studies such as this one is to more effectively prevent disease through the development of tailored dietary recommendations that are based on the genetic background of the individual.

Technical Abstract: Scope: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid. Methods and results: We conducted meta-analyses (N=11,668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid. Conclusion: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.