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Open Access 01-12-2017 | Research article

DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis

Authors: Weida Meng, Zaihua Zhu, Xia Jiang, Chun Lai Too, Steffen Uebe, Maja Jagodic, Ingrid Kockum, Shahnaz Murad, Luigi Ferrucci, Lars Alfredsson, Hejian Zou, Lars Klareskog, Andrew P. Feinberg, Tomas J. Ekström, Leonid Padyukov, Yun Liu

Published in: Arthritis Research & Therapy | Issue 1/2017

Abstract

Background

Multiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA.

Methods

We investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA). Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA.

Results

We identified and replicated one significant gene-environment interaction between rs6933349 and smoking in DNA methylation of cg21325723. This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicative P value = 0.056; additive P value = 0.016) and Asian populations (multiplicative P value = 0.035; additive P value = 0.00027), and it is mediated through DNA methylation of cg21325723.

Conclusions

We showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors.

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Costenbader KH, Feskanich D, Mandl LA, Karlson EW. Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am J Med. 2006;119(6):503–e501–509.CrossRefPubMed

Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010;69(1):70–81.CrossRefPubMed

Yahya A, Bengtsson C, Lai TC, Larsson PT, Mustafa AN, Abdullah NA, Muhamad N, Hussein H, Klareskog L, Alfredsson L, et al. Smoking is associated with an increased risk of developing ACPA-positive but not ACPA-negative rheumatoid arthritis in Asian populations: evidence from the Malaysian MyEIRA case-control study. Mod Rheumatol. 2012;22(4):524–31.CrossRefPubMed

Stolt P, Yahya A, Bengtsson C, Kallberg H, Ronnelid J, Lundberg I, Klareskog L, Alfredsson L, Group ES. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann Rheum Dis. 2010;69(6):1072–6.CrossRefPubMed

Yahya A, Bengtsson C, Larsson P, Too CL, Mustafa AN, Abdullah NA, Muhamad NA, Klareskog L, Murad S, Alfredsson L. Silica exposure is associated with an increased risk of developing ACPA-positive rheumatoid arthritis in an Asian population: evidence from the Malaysian MyEIRA case-control study. Mod Rheumatol. 2014;24(2):271–4.CrossRefPubMed

Saevarsdottir S, Wedren S, Seddighzadeh M, Bengtsson C, Wesley A, Lindblad S, Askling J, Alfredsson L, Klareskog L. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. Arthritis Rheum. 2011;63(1):26–36.CrossRefPubMed

Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum. 1996;39(5):732–5.CrossRefPubMed

Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, Alfredsson L, group Es. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003;62(9):835–41.CrossRefPubMedPubMedCentral

Kallberg H, Ding B, Padyukov L, Bengtsson C, Ronnelid J, Klareskog L, Alfredsson L, Group ES. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011;70(3):508–11.CrossRefPubMed

10.

Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, Ronnelid J, Harris HE, Ulfgren AK, Rantapaa-Dahlqvist S, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38–46.CrossRefPubMed

11.

Breitling LP, Yang R, Korn B, Burwinkel B, Brenner H. Tobacco-smoking-related differential DNA methylation: 27 K discovery and replication. Am J Hum Genet. 2011;88(4):450–7.CrossRefPubMedPubMedCentral

12.

Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, Reinius L, Acevedo N, Taub M, Ronninger M, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31(2):142–7.CrossRefPubMedPubMedCentral

13.

Hong X, Hao K, Ladd-Acosta C, Hansen KD, Tsai HJ, Liu X, Xu X, Thornton TA, Caruso D, Keet CA, et al. Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nat Commun. 2015;6:6304.CrossRefPubMedPubMedCentral

14.

Padyukov L, Seielstad M, Ong RT, Ding B, Ronnelid J, Seddighzadeh M, Alfredsson L, Klareskog L. Epidemiological Investigation of Rheumatoid Arthritis study g. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis. 2011;70(2):259–65.CrossRefPubMed

15.

Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5(6):e1000529.CrossRefPubMedPubMedCentral

16.

Hedstrom AK, Baarnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology. 2009;73(9):696–701.CrossRefPubMed

17.

Too CL, Yahya A, Murad S, Dhaliwal JS, Larsson PT, Muhamad NA, Abdullah NA, Mustafa AN, Klareskog L, Alfredsson L, et al. Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA). Arthritis Res Ther. 2012;14(2):R89.CrossRefPubMedPubMedCentral

18.

Ferrucci L, Bandinelli S, Benvenuti E, Di Iorio A, Macchi C, Harris TB, Guralnik JM. Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study. J Am Geriatr Soc. 2000;48(12):1618–25.CrossRefPubMed

19.

Moore AZ, Hernandez DG, Tanaka T, Pilling LC, Nalls MA, Bandinelli S, Singleton AB, Ferrucci L. Change in epigenome-wide DNA Methylation over 9 years and subsequent mortality: results from the InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2016;71(8):1029–35.CrossRefPubMed

20.

Gao X. Multiple testing corrections for imputed SNPs. Genet Epidemiol. 2011;35(3):154–8.CrossRefPubMedPubMedCentral

21.

Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, Wiencke JK, Kelsey KT. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinforma. 2012;13:86.CrossRef

22.

Andersson T, Alfredsson L, Kallberg H, Zdravkovic S, Ahlbom A. Calculating measures of biological interaction. Eur J Epidemiol. 2005;20(7):575–9.CrossRefPubMed

23.

Mahdi H, Fisher BA, Kallberg H, Plant D, Malmstrom V, Ronnelid J, Charles P, Ding B, Alfredsson L, Padyukov L, et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet. 2009;41(12):1319–24.CrossRefPubMed

24.

Kallberg H, Ahlbom A, Alfredsson L. Calculating measures of biological interaction using R. Eur J Epidemiol. 2006;21(8):571–3.CrossRefPubMed

25.

Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekstrom TJ, Harris TB, et al. Intra-individual change over time in DNA methylation with familial clustering. JAMA. 2008;299(24):2877–83.CrossRefPubMedPubMedCentral

26.

Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiology. 1992;3(5):452–6.CrossRefPubMed

27.

Rothman KJ, Greenland S, Walker AM. Concepts of interaction. Am J Epidemiol. 1980;112(4):467–70.CrossRefPubMed

28.

Lundstrom E, Kallberg H, Alfredsson L, Klareskog L, Padyukov L. Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important. Arthritis Rheum. 2009;60(6):1597–603.CrossRefPubMed

29.

Valeri L, Vanderweele TJ. Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18(2):137–50.CrossRefPubMedPubMedCentral

30.

Maher B. Personal genomes: The case of the missing heritability. Nature. 2008;456(7218):18–21.CrossRefPubMed

31.

Murcray CE, Lewinger JP, Gauderman WJ. Gene-environment interaction in genome-wide association studies. Am J Epidemiol. 2009;169(2):219–26.CrossRefPubMed

32.

Kim K, Jiang X, Cui J, Lu B, Costenbader KH, Sparks JA, Bang SY, Lee HS, Okada Y, Raychaudhuri S, et al. Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis. Arthritis Rheumatol. 2015;67(10):2611–23.CrossRefPubMedPubMedCentral

33.

Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, Alfredsson L, Padyukov L, Klareskog L, Worthington J, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44(3):291–6.CrossRefPubMedPubMedCentral

34.

James EA, Moustakas AK, Bui J, Papadopoulos GK, Bondinas G, Buckner JH, Kwok WW. HLA-DR1001 presents "altered-self" peptides derived from joint-associated proteins by accepting citrulline in three of its binding pockets. Arthritis Rheum. 2010;62(10):2909–18.CrossRefPubMedPubMedCentral

35.

Klareskog L, Malmstrom V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol. 2011;23(2):92–8.CrossRefPubMed

36.

Snir O, Rieck M, Gebe JA, Yue BB, Rawlings CA, Nepom G, Malmstrom V, Buckner JH. Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients. Arthritis Rheum. 2011;63(10):2873–83.CrossRefPubMedPubMedCentral

37.

Hedstrom AK, Sundqvist E, Baarnhielm M, Nordin N, Hillert J, Kockum I, Olsson T, Alfredsson L. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain. 2011;134(Pt 3):653–64.CrossRefPubMed

Title: DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis
Authors: Weida Meng
Zaihua Zhu
Xia Jiang
Chun Lai Too
Steffen Uebe
Maja Jagodic
Ingrid Kockum
Shahnaz Murad
Luigi Ferrucci
Lars Alfredsson
Hejian Zou
Lars Klareskog
Andrew P. Feinberg
Tomas J. Ekström
Leonid Padyukov
Yun Liu
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2017
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-017-1276-2

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DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis

Abstract

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Results

Conclusions

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