The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter

Authors: MA, YI YI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Lai, Chao Qiang; IRVIN, MARGUERITE - University Of Alabama; Parnell, Laurence; LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PHAM, LUCIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ASLIBEKYAN, STELLA - University Of Alabama; CLAAS, STEVEN - University Of Alabama; TSAI, MICHAEL - University Of Minnesota; BORECKI, INGRID - Washington University; KAGAMBE, EDMOND - Vanderbilt University; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology; ARNETT, DONNA - University Of Alabama

Submitted to: Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/21/2015
Publication Date: 2/1/2016
Citation: Ma, Y., Smith, C.E., Lai, C., Irvin, M.R., Parnell, L.D., Lee, Y., Pham, L.D., Aslibekyan, S., Claas, S.A., Tsai, M.Y., Borecki, I.B., Kagambe, E.K., Ordovas, J.M., Absher, D., Arnett, D.K. 2016. The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter. Epigenetics. 60(2):410-419. doi: 10.1002/mnfr.201500436.

Interpretive Summary: Inflammation is at the cross road of all major age-related diseases, such as atherosclerosis, cancer, obesity, and diabetes. Interleukin 6 (IL6) is one of several proteins induced during inflammation, and previous research has shown that dietary factors, such as omega-3 polyunsaturated fatty acids (omega3 PUFAs,) ameliorate inflammation status by reducing the expression of the gene (IL6) that encodes this protein. However, the underlying mechanism is not known. Because of the knowledge connecting genes with a type of genetic modification, called DNA methylation, we postulated that the effects of omega3 PUFAs on the expression of IL6 gene may act through this mechanism. We tested our hypothesis in a cohort of about one thousand individuals. In this research, we identified a potentially functional methylation site within IL6 gene, called cg01770232. We found the methylation status of this site was associated with blood levels of omega3 PUFAs, plasma levels of IL6 protein, and status of gene expression of IL6 gene. We further found that the effects of omega3 PUFAs on the methylation status of cg01770232 were dependent on different genetic forms of the IL6 gene. Our findings provide mechanistic support for the beneficial effects of dietary omega3 on age-related diseases.

Technical Abstract: Scope: Omega-3 PUFAs (n-3 PUFAs) reduce IL-6 gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6. Methods and results: Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL-6 plasma concentration (p=0.03) and greater IL6 gene expression (p=0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (p=0.007) and lower IL-6 concentration (p=0.02). Moreover, an allele of IL6 rs2961298 was associated with higher cg01770232 methylation (p=2.55 x 10-7). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (p=0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (p=0.04) not in the homozygotes. Conclusion: Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs.