title: Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.
abstract: Epigenetic mechanisms integrate genetic and environmental causes of disease, but comprehensive genome-wide analyses of epigenetic modifications have not yet demonstrated robust association with common diseases. Using Illumina HumanMethylation450 arrays on 354 anti-citrullinated protein antibody-associated rheumatoid arthritis cases and 337 controls, we identified two clusters within the major histocompatibility complex (MHC) region whose differential methylation potentially mediates genetic risk for rheumatoid arthritis. To reduce confounding factors that have hampered previous epigenome-wide studies, we corrected for cellular heterogeneity by estimating and adjusting for cell-type proportions in our blood-derived DNA samples and used mediation analysis to filter out associations likely to be a consequence of disease. Four CpGs also showed an association between genotype and variance of methylation. The associations for both clusters replicated at least one CpG (P < 0.01), with the rest showing suggestive association, in monocyte cell fractions in an independent cohort of 12 cases and 12 controls. Thus, DNA methylation is a potential mediator of genetic risk.
authors: Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Yun
authors: Y
authors: Liu
authors: Martin J
authors: MJ
authors: Aryee
authors: Leonid
authors: L
authors: Padyukov
authors: M Daniele
authors: MD
authors: Fallin
authors: Espen
authors: E
authors: Hesselberg
authors: Arni
authors: A
authors: Runarsson
authors: Lovisa
authors: L
authors: Reinius
authors: Nathalie
authors: N
authors: Acevedo
authors: Margaret
authors: M
authors: Taub
authors: Marcus
authors: M
authors: Ronninger
authors: Klementy
authors: K
authors: Shchetynsky
authors: Annika
authors: A
authors: Scheynius
authors: Juha
authors: J
authors: Kere
authors: Lars
authors: L
authors: Alfredsson
authors: Lars
authors: L
authors: Klareskog
authors: Tomas J
authors: TJ
authors: Ekström
authors: Andrew P
authors: AP
authors: Feinberg
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors