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- Title
Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.
- Authors
Liu, Yun; Aryee, Martin J; Padyukov, Leonid; Fallin, M Daniele; Hesselberg, Espen; Runarsson, Arni; Reinius, Lovisa; Acevedo, Nathalie; Taub, Margaret; Ronninger, Marcus; Shchetynsky, Klementy; Scheynius, Annika; Kere, Juha; Alfredsson, Lars; Klareskog, Lars; Ekström, Tomas J; Feinberg, Andrew P
- 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.
- Subjects
GENETICS of rheumatoid arthritis; DNA methylation; EPIGENETICS; ENVIRONMENTALLY induced diseases; RHEUMATOID arthritis risk factors; MAJOR histocompatibility complex; IMMUNOGLOBULINS
- Publication
Nature Biotechnology, 2013, Vol 31, Issue 2, p142
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt.2487