Skip to main content
Top
Published in: Arthritis Research & Therapy 1/2015

Open Access 01-12-2015 | Research article

Variation at interleukin-6 receptor gene is associated to joint damage in rheumatoid arthritis

Authors: Maria Lopez-Lasanta, Antonio Julià, Joan Maymó, Benjamín Fernández-Gutierrez, Inmaculada Ureña-Garnica, Francisco J. Blanco, Juan D. Cañete, Mercedes Alperi-López, Alex Olivè, Héctor Corominas, Jesus Tornero, Alba Erra, Miriam Almirall, Nuria Palau, Ana Ortiz, Gabriela Avila, Luis Rodriguez-Rodriguez, Arnald Alonso, Raül Tortosa, Isidoro Gonzalez-Alvaro, Sara Marsal

Published in: Arthritis Research & Therapy | Issue 1/2015

Login to get access

Abstract

Introduction

Interleukin-6 (IL-6) cytokine signaling is key in Rheumatoid Arthritis (RA) pathophysiology. Blocking IL-6 receptor (IL6R) has proven to be a highly effective treatment to prevent joint damage. This study was performed to investigate the association between the genetic variation at IL6R gene and the severity of joint damage in RA.

Methods

IL6R gene tagging SNPs (n = 5) were genotyped in a discovery group of 527 RA patients from 5 different university hospitals from Spain. For each marker, a linear regression analysis was performed using an additive model and adjusting for the years of evolution of the disease, autoantibody status, gender and age. Haplotypes combining the SNPs were also estimated and tested for association with the level of joint destruction. Using an independent cohort of 705 RA patients from 6 university hospitals we performed a validation study of the SNPs associated in the discovery phase.

Results

In the discovery group we found a highly significant association between IL6R SNP rs4845618 and the level of joint destruction in RA (P = 0.0058, P corrected = 0.026), and a moderate association with SNP rs4453032 (P = 0.02, P corrected = 0.05). The resulting haplotype from both SNPs was more significantly associated with joint damage (P = 0.0037, P corrected = 0.011). Using the validation cohort, we replicated the association between the two IL-6R SNPs with the degree of joint destruction in RA (P = 0.007 and P = 0.04, meta-analysis P = 0.00011 and P = 0.0021, respectively), and the haplotype association (P = 0.0058, meta-analysis P = 6.64 e-5).

Conclusions

Genetic variation at IL6R gene is associated with joint damage in RA.
Appendix
Available only for authorised users
Literature
2.
go back to reference Knevel R, Grondal G, Huizinga TWJ, Visser AW, Jonsson H, Vikingsson A, et al. Genetic predisposition of the severity of joint destruction in rheumatoid arthritis: a population-based study. Ann Rheum Dis. 2012;71:707–9.CrossRefPubMed Knevel R, Grondal G, Huizinga TWJ, Visser AW, Jonsson H, Vikingsson A, et al. Genetic predisposition of the severity of joint destruction in rheumatoid arthritis: a population-based study. Ann Rheum Dis. 2012;71:707–9.CrossRefPubMed
3.
go back to reference McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.CrossRefPubMed McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.CrossRefPubMed
4.
go back to reference Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987–97.CrossRefPubMed Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987–97.CrossRefPubMed
5.
go back to reference Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10:720–7.CrossRefPubMed Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10:720–7.CrossRefPubMed
6.
go back to reference Arnett FC. Revised criteria for the classification of rheumatoid arthritis. Bull Rheum Dis. 1989;38:1–6.PubMed Arnett FC. Revised criteria for the classification of rheumatoid arthritis. Bull Rheum Dis. 1989;38:1–6.PubMed
7.
go back to reference Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn. 1977;18:481–91.CrossRef Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn. 1977;18:481–91.CrossRef
8.
go back to reference Van der Heijde D, Van Leeuven M, Van Riel P, Koster A, Van’t Hof M, Van Rijswijk M. Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum. 1992;35:26–34.CrossRefPubMed Van der Heijde D, Van Leeuven M, Van Riel P, Koster A, Van’t Hof M, Van Rijswijk M. Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum. 1992;35:26–34.CrossRefPubMed
9.
go back to reference Van der Heijde D. Radiographic imaging: the “gold standard” for assessment of disease progression in rheumatoid arthritis. Rheumatology. 2000;39:9–16.CrossRefPubMed Van der Heijde D. Radiographic imaging: the “gold standard” for assessment of disease progression in rheumatoid arthritis. Rheumatology. 2000;39:9–16.CrossRefPubMed
10.
go back to reference Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.CrossRefPubMed Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.CrossRefPubMed
13.
go back to reference Gabriel S, Schaffner S, Nguyen H, Moore J, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296: 2225–9.CrossRefPubMed Gabriel S, Schaffner S, Nguyen H, Moore J, Roy J, Blumenstiel B, et al. The structure of haplotype blocks in the human genome. Science. 2002;296: 2225–9.CrossRefPubMed
14.
go back to reference Ferreira RC, Freitag DF, Cutler AJ, Howson JM, Rainbow DB, Smyth DJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet. 2013;9, e1003444.PubMedCentralCrossRefPubMed Ferreira RC, Freitag DF, Cutler AJ, Howson JM, Rainbow DB, Smyth DJ, et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet. 2013;9, e1003444.PubMedCentralCrossRefPubMed
15.
go back to reference Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506:376–81.PubMedCentralCrossRefPubMed Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506:376–81.PubMedCentralCrossRefPubMed
16.
go back to reference Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–53.PubMedCentralCrossRefPubMed Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–53.PubMedCentralCrossRefPubMed
17.
go back to reference Westra H-J, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45:1238–43.PubMedCentralCrossRefPubMed Westra H-J, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45:1238–43.PubMedCentralCrossRefPubMed
18.
go back to reference Romanoski CE, Glass CK, Stunnenberg HG, Wilson L, Almouzni G. Epigenomics: Roadmap for regulation. Nature. 2015;518:314–6.CrossRefPubMed Romanoski CE, Glass CK, Stunnenberg HG, Wilson L, Almouzni G. Epigenomics: Roadmap for regulation. Nature. 2015;518:314–6.CrossRefPubMed
19.
go back to reference Kremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon E, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63:609–21.CrossRefPubMed Kremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon E, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63:609–21.CrossRefPubMed
20.
go back to reference Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 2009;60:2747–56.CrossRefPubMed Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 2009;60:2747–56.CrossRefPubMed
21.
go back to reference Enevold C, Baslund B, Linde L, Josephsen NL, Tarp U, Lindegaard H, et al. Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis. Pharmacogenet Genomics. 2014;24:401–5.PubMed Enevold C, Baslund B, Linde L, Josephsen NL, Tarp U, Lindegaard H, et al. Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis. Pharmacogenet Genomics. 2014;24:401–5.PubMed
22.
go back to reference Lamas JR, Rodriguez-Rodriguez L, Varade J, Lopez-Romero P, Tornero-Esteban P, Abasolo L, et al. Influence of IL6R rs8192284 polymorphism status in disease activity in rheumatoid arthritis. J Rheumatol. 2010;37:1579–81.CrossRefPubMed Lamas JR, Rodriguez-Rodriguez L, Varade J, Lopez-Romero P, Tornero-Esteban P, Abasolo L, et al. Influence of IL6R rs8192284 polymorphism status in disease activity in rheumatoid arthritis. J Rheumatol. 2010;37:1579–81.CrossRefPubMed
Metadata
Title
Variation at interleukin-6 receptor gene is associated to joint damage in rheumatoid arthritis
Authors
Maria Lopez-Lasanta
Antonio Julià
Joan Maymó
Benjamín Fernández-Gutierrez
Inmaculada Ureña-Garnica
Francisco J. Blanco
Juan D. Cañete
Mercedes Alperi-López
Alex Olivè
Héctor Corominas
Jesus Tornero
Alba Erra
Miriam Almirall
Nuria Palau
Ana Ortiz
Gabriela Avila
Luis Rodriguez-Rodriguez
Arnald Alonso
Raül Tortosa
Isidoro Gonzalez-Alvaro
Sara Marsal
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2015
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-015-0737-8

Other articles of this Issue 1/2015

Arthritis Research & Therapy 1/2015 Go to the issue
Obesity Clinical Trial Summary

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.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

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

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

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

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