Genetic and epigenetic predictors of responsiveness to treatment in RA

Methotrexate and TNF-blocking agents are the DMARDs most commonly prescribed for the treatment of rheumatoid arthritis (RA). However, not all patients treated with these nonbiologic and biologic DMARDs respond satisfactorily and few predictors of treatment efficacy have been identified, despite the fact that these therapies have now been available for many years. Many studies have investigated genetic factors that might predict patient responsiveness to therapies used to treat RA, and epigenetic studies regarding response to treatment are expected to accumulate in the literature in the near future. Herein, we review the advances in identifying genetic and epigenetic predictors of therapeutic responses to methotrexate and/or TNF inhibitors in RA that have been made to date, and highlight important considerations for future studies, such as the need for an improved, preferably biological, outcome measure reflecting response to treatment.

[1]  Fan Li,et al.  Protocadherin 10 is frequently downregulated by promoter methylation and functions as a tumor suppressor gene in non-small cell lung cancer. , 2012, Cancer biomarkers : section A of Disease markers.

[2]  Katie Smith,et al.  Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. , 2004, Arthritis and rheumatism.

[3]  M. Kennedy,et al.  Polymorphisms within the folate pathway predict folate concentrations but are not associated with disease activity in rheumatoid arthritis patients on methotrexate , 2010, Pharmacogenetics and genomics.

[4]  A. Murasawa,et al.  Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. , 2012, Journal of periodontology.

[5]  G. Watanabe,et al.  Long interspersed nuclear element‐1 hypomethylation is a potential biomarker for the prediction of response to oral fluoropyrimidines in microsatellite stable and CpG island methylator phenotype‐negative colorectal cancer , 2011, Cancer science.

[6]  I. Bruce,et al.  Reduction of Long-Term Disability in Inflammatory Polyarthritis by Early and Persistent Suppression of Joint Inflammation: Results From the Norfolk Arthritis Register , 2011, Arthritis care & research.

[7]  J. Carulli,et al.  Development of a Multi-Biomarker Disease Activity Test for Rheumatoid Arthritis , 2013, PloS one.

[8]  A. Barton,et al.  Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis , 2008 .

[9]  A. Taniguchi,et al.  Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. , 2002, Pharmacogenetics.

[10]  F. Breedveld,et al.  Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? , 1997, British journal of rheumatology.

[11]  Y L Lin,et al.  Clinical and Prognostic Significance of Protocadherin-10 (PCDH10) Promoter Methylation in Bladder Cancer , 2012, The Journal of international medical research.

[12]  B. Christensen,et al.  Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context , 2009, PLoS genetics.

[13]  S Hanash,et al.  Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. , 1990, Arthritis and rheumatism.

[14]  J. Kremer,et al.  Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[15]  D. Symmons,et al.  Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register , 2015, Annals of the rheumatic diseases.

[16]  Anne Barton,et al.  Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. , 2008, Human molecular genetics.

[17]  I. González-Álvaro,et al.  GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis. , 2013, Pharmacogenomics.

[18]  R K Gordon,et al.  S‐Adenosylmetliionine and methylation , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  P. van Riel,et al.  Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis. , 2002, Rheumatology.

[20]  M. Daly,et al.  Genetic variants at CD28, PRDM1, and CD2/CD58 are associated with rheumatoid arthritis risk , 2009, Nature Genetics.

[21]  G. Cavet,et al.  A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study , 2013, Rheumatology.

[22]  David Gillis,et al.  Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis. , 2008, The Journal of rheumatology.

[23]  A. Barton,et al.  MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms , 2011, The Pharmacogenomics Journal.

[24]  D. Tregouet,et al.  Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. , 2005, Blood.

[25]  S. Friend,et al.  Cancer Biomarkers—An Invitation to the Table , 2006, Science.

[26]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[27]  Gioacchino Natoli,et al.  Dynamic changes in histone H3 Lys 9 methylation occurring at tightly regulated inducible inflammatory genes. , 2002, Genes & development.

[28]  J. Kremer,et al.  Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study , 2005, Annals of the rheumatic diseases.

[29]  Eric S. Lander,et al.  Genomic Maps and Comparative Analysis of Histone Modifications in Human and Mouse , 2005, Cell.

[30]  T. Kouzarides Chromatin Modifications and Their Function , 2007, Cell.

[31]  G. Damante,et al.  Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis. , 2002, The Journal of rheumatology.

[32]  G. Lippi,et al.  Epigenetic alteration: new insights moving from tissue to plasma – the example of PCDH10 promoter methylation in colorectal cancer , 2013, British Journal of Cancer.

[33]  E. Kiss-Toth,et al.  Age-related loss of CpG methylation in the tumour necrosis factor promoter. , 2011, Cytokine.

[34]  A. Silman,et al.  Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? , 2008, Annals of the rheumatic diseases.

[35]  F. Schmidt Meta-Analysis , 2008 .

[36]  M. Lunt,et al.  Early remission is associated with improved survival in patients with inflammatory polyarthritis: results from the Norfolk Arthritis Register , 2013, Annals of the rheumatic diseases.

[37]  Bernhard Korn,et al.  Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. , 2011, American journal of human genetics.

[38]  Judith A M Wessels,et al.  Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. , 2006, Arthritis and rheumatism.

[39]  J. Kremer,et al.  Association of Rheumatoid Arthritis Risk Alleles with Response to Anti-TNF Biologics: Results from the CORRONA Registry and Meta-analysis , 2013, Inflammation.

[40]  M. Rieder,et al.  A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. , 2008, Blood.

[41]  S. Goodman,et al.  Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. , 2002, Journal of the National Cancer Institute.

[42]  G. Cavet,et al.  An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression , 2013, Rheumatology.

[43]  K. Reedquist,et al.  The ascent of acetylation in the epigenetics of rheumatoid arthritis , 2013, Nature Reviews Rheumatology.

[44]  J. Beyene,et al.  TNF-α −308 G/A polymorphism and responsiveness to TNF-α blockade therapy in moderate to severe rheumatoid arthritis: a systematic review and meta-analysis , 2009, The Pharmacogenomics Journal.

[45]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[46]  A S Rigby,et al.  Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. , 2000, Arthritis and rheumatism.

[47]  J. Kremer,et al.  Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[48]  J. Mason,et al.  DNA hypomethylation in inflammatory arthritis: reversal with methotrexate. , 1996, The Journal of laboratory and clinical medicine.

[49]  P. Emery,et al.  Should imaging be a component of rheumatoid arthritis remission criteria? A comparison between traditional and modified composite remission scores and imaging assessments , 2011, Annals of the rheumatic diseases.

[50]  P. Guldberg,et al.  Methylation-dependent Silencing of the Reduced Folate Carrier Gene in Inherently Methotrexate-resistant Human Breast Cancer Cells* , 2001, The Journal of Biological Chemistry.

[51]  Scott M Langevin,et al.  The influence of aging, environmental exposures and local sequence features on the variation of DNA methylation in blood , 2011, Epigenetics.

[52]  A. Silman,et al.  Predictors of Response to Anti-tnf-therapy among Patients with Rheumatoid Arthritis: Results from the British Society for Rheumatology Biologics Register , 2022 .

[53]  J. Kremer,et al.  Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis , 2012, Pharmacogenetics and genomics.

[54]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[55]  Vita Dolžan,et al.  Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism , 2008, European Journal of Clinical Pharmacology.

[56]  Jing Cui,et al.  Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis , 2013, PLoS genetics.

[57]  Mark Lunt,et al.  Extended Report , 2022 .

[58]  Jing Cui,et al.  Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate. , 2009, Rheumatology.

[59]  R. Gay,et al.  DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. , 2009, Arthritis and rheumatism.

[60]  P. Park ChIP–seq: advantages and challenges of a maturing technology , 2009, Nature Reviews Genetics.

[61]  R. Read,et al.  Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. , 2008, Arthritis and rheumatism.

[62]  N. Bottini,et al.  Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors , 2013, Nature Reviews Rheumatology.

[63]  P. Reinach,et al.  Epigenetic Regulation of Tumor Necrosis Factor α (TNFα) Release in Human Macrophages by HIV-1 Single-stranded RNA (ssRNA) Is Dependent on TLR8 Signaling* , 2012, The Journal of Biological Chemistry.

[64]  P. Laird Principles and challenges of genome-wide DNA methylation analysis , 2010, Nature Reviews Genetics.

[65]  Zheng-Kai He,et al.  Downregulation of protocadherin-10 expression correlates with malignant behaviour and poor prognosis in human bladder cancer , 2013, The Journal of international medical research.

[66]  W. Dixon,et al.  The risk of serious infections in patients receiving anakinra for rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. , 2011, Rheumatology.

[67]  I. Georgiou,et al.  Transcription regulatory polymorphism −43T>C in the 5′-flanking region of SLC19A1 gene could affect rheumatoid arthritis patient response to methotrexate therapy , 2007, Rheumatology International.

[68]  Hugo Y. K. Lam,et al.  Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes , 2012, Cell.

[69]  M. Liang,et al.  Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. , 2006, Arthritis and rheumatism.

[70]  Barbara Burwinkel,et al.  Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease. , 2012, European heart journal.

[71]  G. Bhagat,et al.  Promoter methylation‐mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance , 2011, Genes, chromosomes & cancer.

[72]  A. Barton,et al.  Replication of Association of the PTPRC Gene With Response to Anti–Tumor Necrosis Factor Therapy in a Large UK Cohort , 2012, Arthritis and rheumatism.

[73]  W. Hörl,et al.  Molecular biology of 5,10-methylenetetrahydrofolate reductase. , 2000, Journal of nephrology.

[74]  Wei Wang,et al.  DNA methylome signature in rheumatoid arthritis , 2012, Annals of the rheumatic diseases.

[75]  J. Tegnér,et al.  Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. , 2013, Journal of autoimmunity.

[76]  A. Barton,et al.  The potential use of expression profiling: implications for predicting treatment response in rheumatoid arthritis , 2013, Annals of the rheumatic diseases.

[77]  A. Ponsonby,et al.  Genome-scale case-control analysis of CD4+ T-cell DNA methylation in juvenile idiopathic arthritis reveals potential targets involved in disease , 2012, Clinical Epigenetics.

[78]  J. D. de Vries-Bouwstra,et al.  Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[79]  P. Gregersen,et al.  Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. , 2010, Arthritis and rheumatism.

[80]  D. Banerjee,et al.  Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier , 2008, BMC Cancer.

[81]  G. Haegeman,et al.  Keeping up NF-kappaB appearances: epigenetic control of immunity or inflammation-triggered epigenetics. , 2006, Biochemical pharmacology.

[82]  M. Droździk,et al.  Reduced folate carrier-1 80G>A polymorphism affects methotrexate treatment outcome in rheumatoid arthritis , 2007, The Pharmacogenomics Journal.

[83]  A. Gnirke,et al.  Charting a dynamic DNA methylation landscape of the human genome , 2013, Nature.

[84]  Martin J. Aryee,et al.  Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in Rheumatoid Arthritis , 2013, Nature Biotechnology.

[85]  J. Mathers,et al.  Nutritional factors and gender influence age-related DNA methylation in the human rectal mucosa , 2012, Aging cell.