Whole blood DNA methylation signatures of diet are associated with cardiovascular disease risk factors and all-cause mortality

Authors: MA, JIANTAO - Friedman School At Tufts; REBHOLZ, CASEY - Johns Hopkins School Of Public Health; BRAUN, KIM - Erasmus Medical Center; REYNOLDS, LINDSAY - Wake Forest School Of Medicine; ASLIBEKYAN, STELLA - University Of Alabama At Birmingham; XIA, RUI - University Of Texas Health Science Center; BILIGOWDA, NIRANJAN - University Of Alabama At Birmingham; HUAN, TIANXIAO - National Heart, Lung And Blood Institute(NHLBI, NIH); LIU, CHUNYU - National Heart, Lung And Blood Institute(NHLBI, NIH); MENDELSON, MICHAEL - National Heart, Lung And Blood Institute(NHLBI, NIH); JOEHANES, ROBY - National Heart, Lung And Blood Institute(NHLBI, NIH); HU, EMILY - Johns Hopkins School Of Public Health; VITOLINS, MARA - Wake Forest School Of Medicine; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); LOHMAN, KURT - Wake Forest School Of Medicine; OCHOA-ROSALES, CAROLINA - Erasmus Medical Center; VAN MEURS, JOYCE - Erasmus Medical Center; UITTERLINDEN, ANDRE - Erasmus Medical Center; LIU, YONGMEI - Wake Forest School Of Medicine; ELHADAD, MOHAMED - German Research Center For Environmental Health; HEIER, MARGIT - German Research Center For Environmental Health; WALDENBERGER, MELANIE - German Research Center For Environmental Health; PETERS, ANNETTE - German Research Center For Environmental Health; COLCINO, ELENA - Columbia University - New York; WHITSEL, ERIC - University Of North Carolina; BALDASSARI, ANTOINE - University Of North Carolina; GHARIB, SINA - University Of Washington; SOTOODEHNIA, NONA - University Of Washington; BRODY, JENNIFER - University Of Washington; SITLANI, COLLEEN - University Of Washington; TANAKA, TOSHIKO - National Institute On Aging (NIA, NIH); HILL, W - University Of Edinburgh; CORLEY, JANE - University Of Edinburgh; DEARY, IAN - University Of Edinburgh; ZHANG, YAN - German Cancer Research Center (DKFZ)- Germany; SCHOTTKER, BEN - German Cancer Research Center (DKFZ)- Germany; BRENNER, HERMANN - German Cancer Research Center (DKFZ)- Germany; WALKER, MAURA - Boston University Medical School; YE, SHUMAO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; NGUYEN, STEVE - University Of Minnesota; PANKOW, JIM - University Of Minnesota; DEMERATH, ELLEN - University Of Minnesota; ZHENG, YINAN - Northwestern University; HOU, LIFANG - Harvard School Of Public Health; LIANG, LIMING - Harvard School Of Public Health; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HU, FRANK - Harvard School Of Public Health; FORNAGE, MYRIAM - University Of Texas Health Science Center; VOORTMAN, TRUDY - Erasmus Medical Center; LEVY, DANIEL - National Heart, Lung And Blood Institute(NHLBI, NIH)

Submitted to: Circulation: Genomic and Precision Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/15/2020
Publication Date: 6/11/2020
Citation: Ma, J., Rebholz, C.M., Braun, K.V., Reynolds, L.M., Aslibekyan, S., Xia, R., Biligowda, N.G., Huan, T., Liu, C., Mendelson, M.M., Joehanes, R., Hu, E.A., Vitolins, M.Z., Wood, A.C., Lohman, K., Ochoa-Rosales, C., Van Meurs, J., Uitterlinden, A., Liu, Y., Elhadad, M.A., Heier, M., Waldenberger, M., Peters, A., Colcino, E., Whitsel, E.A., Baldassari, A., Gharib, S.A., Sotoodehnia, N., Brody, J.A., Sitlani, C.M., Tanaka, T., Hill, W.D., Corley, J., Deary, I.J., Zhang, Y., Schottker, B., Brenner, H., Walker, M.E., Ye, S., Nguyen, S., Pankow, J., Demerath, E.W., Zheng, Y., Hou, L., Liang, L., Lichtenstein, A.H., Hu, F.B., Fornage, M., Voortman, T., Levy, D. 2020. Whole blood DNA methylation signatures of diet are associated with cardiovascular disease risk factors and all-cause mortality. Circulation: Genomic and Precision Medicine. https://doi.org/10.1161/CIRCGEN.119.002766.
DOI: https://doi.org/10.1161/CIRCGEN.119.002766

Interpretive Summary: A healthy diet is one of the major lifestyle factors that can reduce your risk of developing conditions like obesity, type 2 diabetes (T2D) and cardiovascular disease (CVD). We still don't know what changes in the body convey this protection. In the past few changes, it has been strongly suggested that one pathway by which diet alters disease risk is my changing your gene expression levels – that is, what you eat can "turn on" or "turn off" genes to differing degrees. The genes that respond in this way to diet have not been weel described. Therefore, we looked at the association between gene expression and two well-known diets: the Mediterranean-style diet, and the Alternative Healthy Eating Index (AHEI) score which reflects how well someone's diet adheres to the recommendations for dietary index released by the USDA every 5 years. These analyses identified 30 genes where their expression levels were associated with either diet score, or both. Of these 30 genes, the expression levels of 22 of them were implicated in the chance that someone died over a period of 12 years. Eight of these seemed to be causal – that is their expression levels directly contributed to the chance of dying, while 14 of these genes were not through to directly influence all-cause mortality – it might be that they are just correlated with another, causal factor. This research is important as it can help us understand why a healthy diet is important and implicates specific gene regions as future targets for disease prevention and treatment.

Technical Abstract: DNA methylation patterns associated with habitual diet have not been well studied. Diet quality was characterized using a Mediterranean-style diet score (MDS) and the Alternative Healthy Eating Index score (AHEI). We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400,000 cytosine-guanine dinucleotides (CpGs) in five population-based cohorts including 6,662 European ancestry (EA), 2,702 African ancestry (AA), and 360 Hispanic ancestry (HA) participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease (CVD) risk factors and examined their longitudinal associations with all-cause mortality. We identified 30 CpGs associated with either MDS or AHEI, or both, in EA participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected p-value<1.6x10**-3). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both MDS and AHEI and lower risk for all-cause mortality (p-value = 5.7x10**-15). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (p-value<0.05). MR analysis revealed eight putatively causal associations for six CpGs with four CVD risk factors (BMI, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes; Bonferroni corrected MR p-value<4.5x10**-4). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR p-value=1.5x10**-14) and hypermethylation of cg02079413 (SNORA54; NAP1L4) was associated with BMI (corrected MR p-value=1x10**-6). Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in EA individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.