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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 4/2014

Open Access 01-08-2014 | Research article

Non-HLA genes PTPN22, CDK6 and PADI4 are associated with specific autoantibodies in HLA-defined subgroups of rheumatoid arthritis

Authors: Omri Snir, David Gomez-Cabrero, Ariana Montes, Eva Perez-Pampin, Juan J Gómez-Reino, Maria Seddighzadeh, Katharina U Klich, Lena Israelsson, Bo Ding, Anca I Catrina, Rikard Holmdahl, Lars Alfredsson, Lars Klareskog, Jesper Tegnér, Antonio Gonzalez, Vivianne Malmström, Leonid Padyukov

Published in: Arthritis Research & Therapy | Issue 4/2014

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Abstract

Introduction

Genetic susceptibility to complex diseases has been intensively studied during the last decade, yet only signals with small effect have been found leaving open the possibility that subgroups within complex traits show stronger association signals. In rheumatoid arthritis (RA), autoantibody production serves as a helpful discriminator in genetic studies and today anti-citrullinated cyclic peptide (anti-CCP) antibody positivity is employed for diagnosis of disease. The HLA-DRB1 locus is known as the most important genetic contributor for the risk of RA, but is not sufficient to drive autoimmunity and additional genetic and environmental factors are involved. Hence, we addressed the association of previously discovered RA loci with disease-specific autoantibody responses in RA patients stratified by HLA-DRB1*04.

Methods

We investigated 2178 patients from three RA cohorts from Sweden and Spain for 41 genetic variants and four autoantibodies, including the generic anti-CCP as well as specific responses towards citrullinated peptides from vimentin, alpha-enolase and type II collagen.

Results

Our data demonstrated different genetic associations of autoantibody-positive disease subgroups in relation to the presence of DRB1*04. Two specific subgroups of autoantibody-positive RA were identified. The SNP in PTPN22 was associated with presence of anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Cochran-Mantel-Haenszel test P = 0.0001, Pcorrected <0.05), whereas SNPs in CDK6 and PADI4 were associated with anti-CCP status in DRB1*04 negative patients (Cochran-Mantel-Haenszel test P = 0.0004, Pcorrected <0.05 for both markers). Additionally we see allelic correlation with autoantibody titers for PTPN22 SNP rs2476601 and anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02) and between CDK6 SNP rs42041 and anti-CCP in non-carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02).

Conclusion

These data point to alternative pathways for disease development in clinically similar RA subgroups and suggest an approach for study of genetic complexity of disease with strong contribution of HLA.
Appendix
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Metadata
Title
Non-HLA genes PTPN22, CDK6 and PADI4 are associated with specific autoantibodies in HLA-defined subgroups of rheumatoid arthritis
Authors
Omri Snir
David Gomez-Cabrero
Ariana Montes
Eva Perez-Pampin
Juan J Gómez-Reino
Maria Seddighzadeh
Katharina U Klich
Lena Israelsson
Bo Ding
Anca I Catrina
Rikard Holmdahl
Lars Alfredsson
Lars Klareskog
Jesper Tegnér
Antonio Gonzalez
Vivianne Malmström
Leonid Padyukov
Publication date
01-08-2014
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 4/2014
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-014-0414-3

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