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

被引：707

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：

美国国家卫生研究院; 瑞典研究理事会; 欧洲研究理事会;

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

共 41 条

[1] Intra-individual change over time in DNA methylation with familial clustering [J].

Bjornsson, Hans T. ;

Sigurdsson, Martin I. ;

Fallin, M. Daniele ;

Irizarry, Rafael A. ;

Aspelund, Thor ;

Cui, Hengmi ;

Yu, Wenqiang ;

Rongione, Michael A. ;

Ekstrom, Tomas J. ;

Harris, Tamara B. ;

Launer, Lenore J. ;

Eiriksdottir, Gudny ;

Leppert, Mark F. ;

Sapienza, Carmen ;

Gudnason, Vilmundur ;

Feinberg, Andrew P. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2008, 299 (24) :2877-2883

[2] An integrated epigenetic and genetic approach to common human disease [J].

Bjornsson, HT ;

Fallin, MD ;

Feinberg, AP .

TRENDS IN GENETICS, 2004, 20 (08) :350-358

[3] Harnessing naturally randomized transcription to infer regulatory relationships among genes [J].

Chen, Lin S. ;

Emmert-Streib, Frank ;

Storey, John D. .

GENOME BIOLOGY, 2007, 8 (10)

[4] Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease [J].

Feinberg, Andrew P. ;

Irizarry, Rafael A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 :1757-1764

[5] Personalized Epigenomic Signatures That Are Stable Over Time and Covary with Body Mass Index [J].

Feinberg, Andrew P. ;

Irizarry, Rafael A. ;

Fradin, Delphine ;

Aryee, Martin J. ;

Murakami, Peter ;

Aspelund, Thor ;

Eiriksdottir, Gudny ;

Harris, Tamara B. ;

Launer, Lenore ;

Gudnason, Vilmundur ;

Fallin, M. Daniele .

SCIENCE TRANSLATIONAL MEDICINE, 2010, 2 (49)

[6] Timeline - The history of cancer epigenetics [J].

Feinberg, AP ;

Tycko, B .

NATURE REVIEWS CANCER, 2004, 4 (02) :143-153

[7]

Grabar PB, 2009, CLIN EXP RHEUMATOL, V27, P229

[8] Magnitude of Stratification in Human Populations and Impacts on Genome Wide Association Studies [J].

Hao, Ke ;

Chudin, Eugene ;

Greenawalt, Danielle ;

Schadt, Eric E. .

PLOS ONE, 2010, 5 (01)

[9] Glutathione S-transferase polymorphisms and their biological consequences [J].

Hayes, JD ;

Strange, RC .

PHARMACOLOGY, 2000, 61 (03) :154-166

[10] DNA methylation arrays as surrogate measures of cell mixture distribution [J].

Houseman, Eugene Andres ;

Accomando, William P. ;

Koestler, Devin C. ;

Christensen, Brock C. ;

Marsit, Carmen J. ;

Nelson, Heather H. ;

Wiencke, John K. ;

Kelsey, Karl T. .

BMC BIOINFORMATICS, 2012, 13

← 1 2 3 4 5 →