Yiyi Ma1,2, Caren E Smith1, Chao-Qiang Lai1, Marguerite R Irvin3, Laurence D Parnell1, Yu-Chi Lee1, Lucia D Pham1, Stella Aslibekyan3, Steven A Claas3, Michael Y Tsai4, Ingrid B Borecki5, Edmond K Kabagambe6, José M Ordovás1,7,8, Devin M Absher9, Donna K Arnett3. 1. Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. 2. Biomedical Genetics, Department of Medicine, Boston University, Boston, MA, USA. 3. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA. 4. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. 5. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. 6. Department of Medicine, Vanderbilt University, Nashville, TN, USA. 7. Department of Epidemiology, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain. 8. Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA-FOOD), Madrid, Spain. 9. Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA.
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 × 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.
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 IL6rs2961298 was associated with higher cg01770232 methylation (p = 2.55 × 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.
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