DNA methylation in an enhancer region of the FADS cluster is associated with FADS activity in human liver.
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.
Center for Genomics & Personalized Medicine Research, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Timothy D
TD
Howard
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
Rasika A
RA
Mathias
Department of Internal Medicine Section on Molecular Medicine and Section on Pulmonary, Critical Care, and Allergic and Immunologic Disease, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
Michael C
MC
Seeds
Department of Cardiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
David M
DM
Herrington
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
James E
JE
Hixson
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
Lawrence C
LC
Shimmin
Center for Genomics & Personalized Medicine Research, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Greg A
GA
Hawkins
Department of Cardiology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Matthew
M
Sellers
Program in Molecular Genetics and Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Hannah C
HC
Ainsworth
Department of Biochemistry, Wake Forest Health Sciences, Winston-Salem, North Carolina, United States of America; Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
Susan
S
Sergeant
Department of Physiology/Pharmacology, Wake Forest Health Sciences, Winston-Salem, North Carolina, United States of America.
Leslie R
LR
Miller
Department of Physiology/Pharmacology, Wake Forest Health Sciences, Winston-Salem, North Carolina, United States of America; Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
Floyd H
FH
Chilton
D000483:Alleles; D019175:DNA Methylation / Q000235:genetics*; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000235:genetics*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017962:alpha-Linolenic Acid / Q000378:metabolism
D000090943:Delta-5 Fatty Acid Desaturase; D043371:Fatty Acids, Omega-6; D017962:alpha-Linolenic Acid; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human