Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Rheumatology International
Published in: Rheumatology International 8/2018

01-08-2018 | Expert Opinion

The role of genetics and epigenetics in rheumatic diseases: are they really a target to be aimed at?

Authors: Masaru Kato, Shinsuke Yasuda, Tatsuya Atsumi

Published in: Rheumatology International | Issue 8/2018

Login to get access

Abstract

To date, numerous genetic and epigenetic studies have been performed and provided a crucial step forward in our understanding of the pathogenesis of rheumatic diseases. However, most of the recent advances in the treatment of rheumatic diseases including biological therapies are not based on or even discrepant from these genetic and epigenetic findings. For example, tumor necrosis factor inhibitors are quite successful in the treatment of rheumatoid arthritis (RA), Behçet’s disease (BD), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) but not in that of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s syndrome (SS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV), conversely, RA shares genetic backgrounds more with SLE, SSc, SS and AAV than BD, AS and PsA. In this review, we briefly highlight the findings from recent genetic and epigenetic studies and discuss what needs to be studied to provide a novel, more efficacious management of rheumatic diseases.
Literature
1.
Generali E, Ceribelli A, Stazi MA, Selmi C (2017) Lessons learned from twins in autoimmune and chronic inflammatory diseases. J Autoimmun 83:51–61CrossRef
2.
Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K et al (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506(7488):376–381CrossRef
3.
Wen L, Zhu C, Zhu Z, Yang C, Zheng X, Liu L et al (2018) Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population. Ann Rheum Dis 77(3):417–422CrossRef
4.
Terao C, Kawaguchi T, Dieude P, Varga J, Kuwana M, Hudson M et al (2017) Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis. Ann Rheum Dis 76(6):1150–1158CrossRef
5.
Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM et al (2013) Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren’s syndrome. Nat Genet 45(11):1284–1292CrossRef
6.
Merkel PA, Xie G, Monach PA, Ji X, Ciavatta DJ, Byun J et al (2017) Identification of functional and expression polymorphisms associated with risk for antineutrophil cytoplasmic autoantibody-associated vasculitis. Arthritis Rheumatol 69(5):1054–1066CrossRef
7.
Takeuchi M, Mizuki N, Meguro A, Ombrello MJ, Kirino Y, Satorius C et al (2017) Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behcet’s disease susceptibility. Nat Genet 49(3):438–443CrossRef
8.
International Genetics of Ankylosing Spondylitis C, Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T et al (2013) Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45(7):730–738CrossRef
9.
Stuart PE, Nair RP, Tsoi LC, Tejasvi T, Das S, Kang HM et al (2015) Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am J Hum Genet 97(6):816–836CrossRef
10.
Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M et al (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34(4):395–402CrossRef
11.
Kirino Y, Zhou Q, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E et al (2013) Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behcet disease. Proc Natl Acad Sci USA 110(20):8134–8139CrossRef
12.
Adrianto I, Wen F, Templeton A, Wiley G, King JB, Lessard CJ et al (2011) Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet 43(3):253–258CrossRef
13.
Padyukov L, Seielstad M, Ong RT, Ding B, Ronnelid J, Seddighzadeh M et al (2011) A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis 70(2):259–265CrossRef
14.
Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J et al (2010) Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature 466(7303):243–247CrossRef
15.
Jeffries MA, Dozmorov M, Tang Y, Merrill JT, Wren JD, Sawalha AH (2011) Genome-wide DNA methylation patterns in CD4 + T cells from patients with systemic lupus erythematosus. Epigenetics 6(5):593–601CrossRef
16.
Quddus J, Johnson KJ, Gavalchin J, Amento EP, Chrisp CE, Yung RL et al (1993) Treating activated CD4 + T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Invest 92(1):38–53CrossRef
17.
Lu Q, Wu A, Richardson BC (2005) Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J Immunol 174(10):6212–6219CrossRef
18.
Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B (2007) Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 179(9):6352–6358CrossRef
19.
Deng C, Kaplan MJ, Yang J, Ray D, Zhang Z, McCune WJ et al (2001) Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum 44(2):397–407CrossRef
20.
Yasuda S, Stevens RL, Terada T, Takeda M, Hashimoto T, Fukae J et al (2007) Defective expression of Ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus. J Immunol 179(7):4890–4900CrossRef
21.
Pan W, Zhu S, Yuan M, Cui H, Wang L, Luo X et al (2010) MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4 + T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 184(12):6773–6781CrossRef
22.
Zhao S, Wang Y, Liang Y, Zhao M, Long H, Ding S et al (2011) MicroRNA-126 regulates DNA methylation in CD4 + T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum 63(5):1376–1386CrossRef
23.
Glossop JR, Emes RD, Nixon NB, Packham JC, Fryer AA, Mattey DL et al (2016) Genome-wide profiling in treatment-naive early rheumatoid arthritis reveals DNA methylome changes in T and B lymphocytes. Epigenomics 8(2):209–224CrossRef
24.
25.
Altorok N, Coit P, Hughes T, Koelsch KA, Stone DU, Rasmussen A et al (2014) Genome-wide DNA methylation patterns in naive CD4 + T cells from patients with primary Sjogren’s syndrome. Arthritis Rheumatol 66(3):731–739CrossRef
26.
Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M (2009) DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 60(12):3613–3622CrossRef
27.
Altorok N, Tsou PS, Coit P, Khanna D, Sawalha AH (2015) Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann Rheum Dis 74(8):1612–1620CrossRef
28.
Charras A, Konsta OD, Le Dantec C, Bagacean C, Kapsogeorgou EK, Tzioufas AG et al (2017) Cell-specific epigenome-wide DNA methylation profile in long-term cultured minor salivary gland epithelial cells from patients with Sjogren’s syndrome. Ann Rheum Dis 76(3):625–628CrossRef
29.
Huber LC, Brock M, Hemmatazad H, Giger OT, Moritz F, Trenkmann M et al (2007) Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum 56(4):1087–1093CrossRef
30.
Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, Garcia S et al (2017) Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann Rheum Dis 76(1):277–285CrossRef
31.
Joosten LA, Leoni F, Meghji S, Mascagni P (2011) Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol Med 17(5–6):391–396PubMedPubMedCentral
32.
Vojinovic J, Damjanov N, D’Urzo C, Furlan A, Susic G, Pasic S et al (2011) Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 63(5):1452–1458CrossRef
33.
Klein K, Kabala PA, Grabiec AM, Gay RE, Kolling C, Lin LL et al (2016) The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis 75(2):422–429CrossRef
34.
Mele DA, Salmeron A, Ghosh S, Huang HR, Bryant BM, Lora JM (2013) BET bromodomain inhibition suppresses TH17-mediated pathology. J Exp Med 210(11):2181–2190CrossRef
35.
de Andres MC, Perez-Pampin E, Calaza M, Santaclara FJ, Ortea I, Gomez-Reino JJ et al (2015) Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate. Arthritis Res Ther 17:233CrossRef
36.
Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A et al (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol 31(2):142–147CrossRef
37.
Gorelik GJ, Yarlagadda S, Patel DR, Richardson BC (2012) Protein kinase Cdelta oxidation contributes to ERK inactivation in lupus T cells. Arthritis Rheum 64(9):2964–2974CrossRef
38.
Sunahori K, Nagpal K, Hedrich CM, Mizui M, Fitzgerald LM, Tsokos GC (2013) The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients. J Biol Chem 288(30):21936–21944CrossRef
Metadata
Title
The role of genetics and epigenetics in rheumatic diseases: are they really a target to be aimed at?
Authors
Masaru Kato
Shinsuke Yasuda
Tatsuya Atsumi
Publication date
01-08-2018
Publisher
Springer Berlin Heidelberg
Published in
Rheumatology International / Issue 8/2018
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-018-4026-0

Other articles of this Issue 8/2018

Rheumatology International 8/2018 Go to the issue

Systematic Review

Efficacy and safety of interleukin-1 antagonists in rheumatoid arthritis: a systematic review and meta-analysis

Observational Research

Correlation of neurocognitive function and brain lesion load on magnetic resonance imaging in systemic lupus erythematosus

Validation Studies

A new biopsychosocial and clinical questionnaire to assess juvenile idiopathic arthritis: JAB-Q

Observational Research

Lupus retinopathy: a marker of active systemic lupus erythematosus

Review

Novel insights into the role of inflammasomes in autoimmune and metabolic rheumatic diseases

Observational Research

Pain, fatigue and functional disability are associated with higher educational needs in systemic sclerosis: a cross-sectional study
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits