Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: results from the CHARGE Consortium

Authors: DE OLIVEIRA OTTO, MARCIA - UNIVERSITY OF TEXAS; LEMAITRE, ROZENN - UNIVERSITY OF WASHINGTON; SUN, QI - HARVARD UNIVERSITY; KING, IRENA - UNIVERSITY OF NEW MEXICO; WU, JASON - THE GEORGE INSTITUTE FOR GLOBAL HEALTH; MANICHAIKUL, ANI - UNIVERSITY OF VIRGINIA; RICH, STEPHEN - UNIVERSITY OF VIRGINIA; TSAI, MICHAEL - UNIVERSITY OF MINNESOTA; CHEN, YII-DER - UCLA MEDICAL CENTER; FORNAGE, MYRIAM - UNIVERSITY OF TEXAS; WEIHUA, GUAN - UNIVERSITY OF MINNESOTA; ASLIBEKYAN, STELLA - UNIVERSITY OF KENTUCKY; IRVIN, MARGUERITE - UNIVERSITY OF KENTUCKY; KABAGAMBE, EDMOND - VANDERBILT UNIVERSITY; ARNETT, DONNA - UNIVERSITY OF KENTUCKY; JENSEN, MAJKEN - BRIGHAM & WOMEN'S HOSPITAL; MCKNIGHT, BARBARA - UNIVERSITY OF WASHINGTON; PSATY, BRUCE - UNIVERSITY OF WASHINGTON; STEFFEN, LYN - UNIVERSITY OF MINNESOTA; SMITH, CAREN - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; RISERUS, ULF - UPPSALA UNIVERSITY; LIND, LARS - UPPSALA UNIVERSITY; HU, FRANK - HARVARD UNIVERSITY; RIMM, ERIC - HARVARD UNIVERSITY; SISCOVICK, DAVID - NEW YORK ACADEMY OF MEDICINE; MOZAFFARIAN, DARIUSH - TUFTS UNIVERSITY

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2018
Publication Date: 5/8/2018
Citation: De Oliveira Otto, M.C., Lemaitre, R.N., Sun, Q., King, I., Wu, J.H., Manichaikul, A., Rich, S., Tsai, M.Y., Chen, Y., Fornage, M., Weihua, G., Aslibekyan, S., Irvin, M.R., Kabagambe, E.K., Arnett, D.K., Jensen, M.K., McKnight, B., Psaty, B.M., Steffen, L.M., Smith, C.E., Riserus, U., Lind, L., Hu, F., Rimm, E., Siscovick, D.S., Mozaffarian, D. 2018. Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids results from the CHARGE Consortium. PLoS One. 13(5):e0196951. https://doi.org/10.1371/journal.pone.0196951.
DOI: https://doi.org/10.1371/journal.pone.0196951

Interpretive Summary: Fatty acids in the bloodstream (circulating fatty acids) can indicate health status in that some fatty acids are associated with protection against disease and some are linked to greater disease risk. The composition of circulating fatty acids is influenced by the diet and also by the metabolism of foods, which in turn is influenced by genetics. The current study investigated a specific type of fatty acids, called odd-numbered chain saturated fatty acids, to determine whether genetic mutations influenced levels of these fatty acids in the blood. Importantly, dairy products are one of the sources of odd-chain saturated fatty acids in the diet. Using standard statistical methods, study investigators reported that genetics did not play a major role in determining the levels of this type of fatty acids. The overall conclusion of the study is that for some types of fatty acids, genetics does not play a major role in determining circulating concentrations. To investigate further, the investigators looked more closely at a gene that is involved with the metabolism of dairy products and found that a few mutations in that gene were related to odd-numbered chain saturated fatty acids concentrations. These results imply that consumption of dairy products, or mutations in the genes that metabolize dairy products, determine the concentrations of odd-numbered chain saturated fatty acids.

Technical Abstract: Objective: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA. Design: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels. Results: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37x10^-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07x10^-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4x10^-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5x10^-2). Conclusions: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.