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

被引：704

作者：

Liu, Yun ^{[1
,2
]}

Aryee, Martin J. ^{[1
,3
]}

Padyukov, Leonid ^{[4
,5
]}

Fallin, M. Daniele ^{[1
,6
,7
]}

Hesselberg, Espen ^{[4
,5
]}

Runarsson, Arni ^{[1
,2
]}

Reinius, Lovisa ^{[8
]}

Acevedo, Nathalie ^{[9
]}

Taub, Margaret ^{[1
,6
]}

Ronninger, Marcus ^{[4
,5
]}

Shchetynsky, Klementy ^{[4
,5
]}

Scheynius, Annika ^{[9
]}

Kere, Juha ^{[8
]}

Alfredsson, Lars ^{[10
]}

Klareskog, Lars ^{[4
,5
]}

Ekstrom, Tomas J. ^{[5
,11
]}

Feinberg, Andrew P. ^{[1
,2
,6
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA

[2] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[4] Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden

[5] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden

[6] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

[7] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[8] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden

[9] Karolinska Inst, Dept Med Solna, Stockholm, Sweden

[10] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden

[11] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden

来源：

NATURE BIOTECHNOLOGY | 2013年 / 31卷 / 02期

基金：

欧洲研究理事会; 瑞典研究理事会; 美国国家卫生研究院;

关键词：

GLUTATHIONE-S-TRANSFERASE; POLYMORPHISMS; EXPRESSION; SMOKING; PROTEINS; ETIOLOGY; MHC; M1; T1; P1;

D O I：

10.1038/nbt.2487

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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 II lumina 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.

引用

页码：142 / 147

页数：6

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