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

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.

Epigenetic changes in blood leukocytes following an omega-3 fatty acid supplementation

“…As previously mentioned, only few studies were conducted on the impact of n-3 FAs on DNA methylation in humans [19–24, 30]. Our results are in agreement with these studies suggesting that EPA and DHA can modulate DNA methylation levels.…”

The integration of epigenetics and genetics in nutrition research for CVD risk factors

“…Based on the current knowledge, there is clear genetic contribution to DNA methylation as shown by significant SNP-CpG pair associations for genes, including APOE, IL6 and ABCA (169)(170)(171) . Moreover, there are significant interactions between methylation-related SNP and other environmental factors of interest, such as age and circulating FA.…”

“…(169) IL6 gene variants, methylation and dietary n-3 n-3 PUFA reduce IL6 gene expression, but their effects on transcription regulatory mechanisms are not totally elucidated. As in previous instances, we systematically explore the relationships among n-3 PUFA, DNA methylation, sequence variants, gene expression and protein concentration of IL6 by conducting an integrated analysis of data from population (GOLDN study) and in vitro studies (ENCODE consortium) (170) . As a result, methylation of IL6 promoter CpG site (cg01770232) was positively associated with IL-6 plasma concentration, IL6 gene expression and more dosage of the A allele of rs2961298, but negatively associated with circulating total n-3 PUFA.…”

“…Therefore, in GOLDN, the association between n-3 PUFA and IL6 promoter methylation was not only negative but also dependent on sequence variants. (170) Genetic variation at lipid-related genes, methylation and dietary fatty acids…”

SnoVault and encodeD: A novel object-based storage system and applications to ENCODE metadata

“…These assays include sequencing selected RNAs for promoter characterization, nextgeneration RNA sequencing and assembly methods for detecting alternative splicing and for quantizing the level of RNA in different cellular contexts [15] . To determine transcriptional regulatory regions ENCODE uses DNase I [15,16] and nucleosome positioning assays to locate regions of the chromosome accessible to regulatory elements, DNA methylation assays and ChIPseq of modified histones to define the overall chromatin architecture [17] [18] , and ChIPseq of transcription factors to determine the players involved in the regulatory interactions [19] . To determine which regulatory elements interact with each other, ENCODE uses ChIAPET [19,20] and HiC [21] .…”