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PMID: 23334450 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.

Nature biotechnology ·Vol. 31 ·No. 2 ·2013-02-00 ·Pages 142-7

Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, Reinius L, Acevedo N, Taub M, Ronninger M, Shchetynsky K, Scheynius A, Kere J, Alfredsson L, Klareskog L, Ekström TJ, Feinberg AP

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.

MeSH Terms
Arthritis, Rheumatoid/genetics Case-Control Studies DNA Methylation/genetics Epigenesis, Genetic/genetics Genetic Predisposition to Disease Genome-Wide Association Study Humans Major Histocompatibility Complex/genetics Polymorphism, Single Nucleotide Risk Factors
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Liu Yun
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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
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Article Info
Journal
Nature biotechnology
Abbr.
Nat Biotechnol
ISSN
1546-1696
DOI
10.1038/nbt.2487
Published
2013-02-00
Epub
2013-00-20
Pages
142-7
Language
English
Region
United States
NLM ID
9604648
PMCID
PMC3598632
Subset
IM
Grants
NHGRI NIH HHS · P50 HG003233 · United States
NHGRI NIH HHS · 5P50HG003233 · United States
Databases
GEO
GSE42861
Corrections
CommentIn
PMID: 23381560
External Links
PubMed source DOI: 10.1038/nbt.2487 PMC Full Text View journal details
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