DNA methylation in an enhancer region of the FADS cluster is associated with FADS activity in human liver
Autor: | Michael C. Seeds, Susan Sergeant, Timothy D. Howard, Lawrence C. Shimmin, G.A. Hawkins, Leslie R. Miller, David M. Herrington, Hannah C. Ainsworth, Floyd H. Chilton, Matthew B. Sellers, Rasika A. Mathias, James E. Hixson |
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Jazyk: | angličtina |
Rok vydání: | 2014 |
Předmět: |
Fatty Acid Desaturases
FADS1 FADS2 Gene Expression lcsh:Medicine Biology Biochemistry Polymorphism Single Nucleotide Linkage Disequilibrium Molecular Genetics chemistry.chemical_compound Delta-5 Fatty Acid Desaturase Nucleic Acids Fatty Acids Omega-6 Genetics Humans Gene Regulation lcsh:Science Genetic Association Studies Alleles Multidisciplinary Biology and life sciences alpha-Linolenic acid Fatty Acids lcsh:R alpha-Linolenic Acid Human Genetics Methylation DNA DNA Methylation Eicosapentaenoic acid Lipids 3. Good health Metabolism chemistry Liver Docosahexaenoic acid DNA methylation Genetics of Disease Arachidonic acid Epigenetics lcsh:Q DNA modification Research Article |
Zdroj: | PLoS ONE, Vol 9, Iss 5, p e97510 (2014) PLoS ONE |
ISSN: | 1932-6203 |
Popis: | Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20:4, n-6), eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and 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 (18C-PUFAs) such as LA (18:2, n-6) to AA and α-linolenic acid (ALA, 18:3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (5' to 5') in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ∼ 15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95 × 10(-46)) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities. |
Databáze: | OpenAIRE |
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