Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes

Abstract

BackgroundGenetic variants within the fatty acid desaturase (FADS) gene cluster (human Chr11) are important regulators of long-chain (LC) polyunsaturated fatty acid (PUFA) biosynthesis in the liver and consequently have been associated with circulating LC-PUFA levels. More recently, epigenetic modifications such as DNA methylation, particularly within the FADS cluster, have been shown to affect LC-PUFA levels. Our lab previously demonstrated strong associations of allele-specific methylation (ASM) between a single nucleotide polymorphism (SNP) rs174537 and CpG sites across the FADS region in human liver tissues. Given that epigenetic signatures are tissue-specific, we aimed to evaluate the methylation status and ASM associations between rs174537 and DNA methylation obtained from human saliva, CD4+ cells and total leukocytes derived from whole blood. The goals were to (1) determine if DNA methylation from these peripheral samples would display similar ASM trends as previously observed in human liver tissues and (2) evaluate the associations between DNA methylation and circulating LC-PUFAs.ResultsDNA methylation at six CpG sites spanning FADS1 and FADS2 promoter regions and a putative FADS enhancer region were determined in two Caucasian cohorts of healthy volunteers: leukocytes in cohort 1 (n = 89, median age = 43, 35% male) and saliva and CD4+ cells in cohort 2 (n = 32, median age = 41, 41% male). Significant ASM between rs174537 and DNA methylation at three CpG sites located in the FADS2 promoter region (i.e., chr11:61594865, chr11:61594876, chr11:61594907) and one CpG site in the putative enhancer region (chr11:61587979) were observed with leukocytes. In CD4+ cells, significant ASM was observed at CpG sites chr11:61594876 and chr11:61584894. Genotype at rs174537 was significantly associated with DNA methylation from leukocytes. Similar trends were observed with CD4+ cells, but not with saliva. DNA methylation from leukocytes and CD4+ cells also significantly correlated with circulating omega-6 LC-PUFAs.ConclusionsWe observed significant ASM between rs174537 and DNA methylation at key regulatory regions in the FADS region from leukocyte and CD4+ cells. DNA methylation from leukocytes also correlated with circulating omega-6 LC-PUFAs. These results support the use of peripheral whole blood samples, with leukocytes showing the most promise for future nutrigenomic studies evaluating epigenetic modifications affecting LC-PUFA biosynthesis in humans.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0480-5) contains supplementary material, which is available to authorized users.

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

“…We identified several associations for CpG methylation in SCD, FADS1/2, SLC7A11, TXNIP, and PHGDH with PUFAs. However, in line with previous studies, those in the FADS region appear to have a complex (epi)genetic architecture [37,[67][68][69][70]. The only CpG site showing associations with PUFAs, and additionally with the respective gene transcript, metabolic measure ratios, and disease endpoints was cg16246545 in PHGDH.…”

Crosstalk of Genetic Variants, Allele-Specific DNA Methylation, and Environmental Factors for Complex Disease Risk

“…That is, methylation-dependent recruitment of c-Jun and/or ATF3 (resulted due to CpG-SNP on the G allele) may understand the higher PEAR1 expression and risk. More recent reports linking ASMs to disease or complex traits include the SNP rs174537-regulated ASM at the FADS gene locus for long-chain polyunsaturated fatty acid biosynthesis (Rahbar et al, 2018) and ASMs of susceptibility genes for inflammatory bowel disease (Chiba et al, 2018).…”

DNA methylation of tumour necrosis factor (TNF) alpha gene is associated with specific blood fatty acid levels in a gender‐specific manner

“…Interactions between fatty acids and DNA methylation have been the subject of limited research utilising both candidate gene and genome-wide DNA methylation association studies. These studies have identified relationships between dietary fatty acids and biologically significant pathways related to inflammation (Aslibekyan et al, 2014;Cui et al, 2016;Haghighi et al, 2015;Hermsdorff et al, 2013;Hussey et al, 2017;Ma et al, 2016;Rahbar et al, 2018;Voisin et al, 2015). In a genome-wide DNA methylation association study of an adolescent population, fatty acid ratios (including (MUFA+PUFA)/SFA and PUFA/SFA) in the diet showed significant enrichment of pathways linked to nuclear factor kappa B (NFκB), peroxisome proliferator-activated receptor (PPARα), leptin (LEP) and interleukin (IL)-6 (Voisin et al, 2015).…”