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Title: Genetic variant modifies the effect of N3 PUFAs on DNA methylation of IL6 in the Genetics of Lipid Lowering Drugs and Diet Network study

Author
item MA, YI YI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Lai, Chao Qiang
item INVIN, RYAN - University Of Alabama
item Parnell, Laurence
item LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item PHAM, LUCIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ASLIBEKYAN, STELLA - University Of Alabama
item CLAAS, STEVEN - University Of Alabama
item TSAI, MICHAEL - University Of Minnesota
item BORECKI, INTRID - Washington University
item KABAGAMBE, EDMOND - Vanderbilt University
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ABSHER, DEVIN - Hudsonalpha Institute For Biotechnology
item DONNA, ARNETT - University Of Alabama

Submitted to: Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/21/2015
Publication Date: 2/11/2016
Citation: Ma, Y., Smith, C.E., Lai, C., Invin, R.M., Parnell, L.D., Lee, Y., Pham, L., Aslibekyan, S., Claas, S.A., Tsai, M.Y., Borecki, I.B., Kabagambe, E.K., Ordovas, J.M., Absher, D., Donna, A.K. 2016. Genetic variant modifies the effect of N3 PUFAs on DNA methylation of IL6 in the Genetics of Lipid Lowering Drugs and Diet Network study. Epigenetics. doi: 10.1002/mnfr.201500436.

Interpretive Summary: Chronic 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) improve inflammation status by reducing the levels of this protein circulating in the blood. We suspect that omega3 PUFAs affects the expression of IL6 gene, however, the underlying mechanism is not known. We tested our theory on about thousand individuals and found that the DNA methylation of the IL6 gene affected blood levels of omega3 PUFAs, and that this methylation was dependent on the presence of different genetic forms of the IL6 gene. Our findings support the idea that dietary omega3 is effective on age related diseases and provides the molecular mechanisms of action.

Technical Abstract: N3 polyunsaturated fatty acids (N3 PUFAs) ameliorate inflammation status with specific regulation on interleukin-6 (IL6) expression. However, the molecular mechanism for this regulation is unclear. Using both cell lines data from Encyclopedia of DNA Elements (ENCODE) consortium and population data from the Genetics of Lipid Lowering Drugs and Diet Network study (GOLDN), we identified potential functional methylation sites within the IL6 locus. Using the GOLDN dataset, we studied the association between N3 PUFAs and the methylation of the functional CpG site, and whether this association can be further modified by IL6 sequence variants. Our findings suggest a CpG site (cg01770232) within IL6 may be a potential functional methylation site because it is significantly correlated with both IL6 gene expression based on ENCODE (R = 0.8, P = 0.0003), and plasma IL6 concentration based on GOLDN (P = 0.03). Red blood cell membrane level of total N3 PUFAs were shown to be associated with both the methylation status of cg01770232 (P = 0.007), and plasma concentration of IL6 (P = 0.02). SNP rs2961298 was shown to have significant association with the methylation of cg01770232 (P = 2.5510**-7), as well as to modify the association between N3 PUFAs and methylation of cg01770232 (P for interaction = 0.02). Total N3 PUFAs decrease the methylation of cg01770232 in the heterozygotes (P for interaction = 0.04) but not the homozygotes of SNP rs2961298 (P > 0.05). To conclude, N3 PUFAs may affect IL6 through methylation of its potential functional site cg01770232 in the promoter region, and this effect may be further modified by IL6 SNP rs2961298. These findings may increase mechanistic understanding of the link between N3 PUFAs and IL6.