Abstract
Omega‐6 (n‐6) and omega‐3 (n‐3), long chain polyunsaturated fatty acids (LcPUFAs) impact a wide range of biological activities ranging from immune signaling to brain function. Two desaturase steps (Δ6, encoded by FADS2 and Δ5, encoded by FADS1) are rate‐limiting in the conversion of dietary essential 18 carbon PUFAs such as linoleic acid (n‐6) to arachidonic acid and α‐linolenic acid (n‐3) to eicosapentaenoic and docosahexaenoic acids. Genetic variants in and around FADS1 and FADS2 are highly associated with levels of LcPUFAs as well as cardiovascular disease risk factors. Particularly, rs174537 is associated with both FADS activity and circulating AA levels (p = 5.95 x 10‐46). FADS1 and FADS2 sit adjacent (5’ to 5’) on chromosome 11 (11q12.2). We hypothesized that SNPs such as rs174537 were associated with DNA methylation variation that impacted LcPUFA levels and FADS activities. To test this hypothesis, we performed a genome‐wide allele‐specific methylation study with rs174537 in 144 human liver samples. This approach identified a strong association of rs174537 with CpG sites in an enhancer region between FADS1 and FADS2 (p=2.69x10‐29). These data suggested that rs174537 was serving as a genetic proxy for methylation variability in a critical enhancer region sitting between two proximal promoters for FADS1 and FADS2. Importantly, methylation levels of the significant probes were shown to be strongly associated with FADS1 and FADS2 activities within the liver.Grant Funding Source: NIH ‐ P50 AT002782
Highlights
Association studies have identified hundreds of relationships between single nucleotide polymorphisms (SNPs) and phenotypic traits [1]
Given recent evidence that variation in DNA methylation can be associated with cis genetic variation [19,20], we performed a genome-wide, allele-specific methylation (ASM) analysis with rs174537
As liver is known to be a primary organ involved in long chain polyunsaturated fatty acids (LcPUFAs) biosynthesis, DNA was extracted from 144 liver samples obtained from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study [21]
Summary
Association studies have identified hundreds of relationships between single nucleotide polymorphisms (SNPs) and phenotypic traits [1]. Numerous studies have identified associations between genetic variants in FADS1 and FADS2 and LcPUFA levels, as well as precursor-product desaturase activities, with little evidence for genetic loci outside of 11q12.2 (reviewed in Lattka et al, 2009 [7]).
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