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

Nat Biotechnol 2013 Feb 20;31(2):142-7. Epub 2013 Jan 20.

Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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.

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http://www.nature.com/articles/nbt.2487
Publisher Site
http://dx.doi.org/10.1038/nbt.2487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598632PMC
February 2013
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References

(Supplied by CrossRef)

AP Feinberg et al.
Nat. Rev. Cancer 2004

ZA Kaminsky et al.
Nat. Genet. 2009

AP Feinberg et al.
Sci. Transl. Med. 2010

BM Javierre et al.
Genome Res. 2010

VK Rakyan et al.
PLoS Genet. 2011

HT Bjornsson et al.
Trends Genet. 2004

HT Bjornsson et al.
J. Am. Med. Assoc. 2008

VK Rakyan et al.
Nat. Rev. Genet. 2011

L Klareskog et al.
Lancet 2009

DL Scott et al.
Lancet 2010

L Padyukov et al.
Ann. Rheum. Dis. 2011

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