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

• Published in: Arthritis research & therapy 2014-08, Vol.16 (4), p.414-414, Article 414
• Main Authors: Snir, Omri, Gomez-Cabrero, David, Montes, Ariana, Perez-Pampin, Eva, Gómez-Reino, Juan J, Seddighzadeh, Maria, Klich, Katharina U, Israelsson, Lena, Ding, Bo, Catrina, Anca I, Holmdahl, Rikard, Alfredsson, Lars, Klareskog, Lars, Tegnér, Jesper, Gonzalez, Antonio, Malmström, Vivianne, Padyukov, Leonid
• Format: Article
• Language: English
• Subjects: Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Autoantibodies - blood; Autoantibodies - immunology; Autoantigens - immunology; Care and treatment; Complications and side effects; Cyclin-Dependent Kinase 6 - genetics; Development and progression; Diagnosis; Disease susceptibility; Enzyme-Linked Immunosorbent Assay; Genetic aspects; Genetic Predisposition to Disease; Genotype; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - immunology; Humans; Hydrolases - genetics; Medical research; Medicine, Experimental; Patient outcomes; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics; Protein-Arginine Deiminases
• ISSN: 1478-6354; 1478-6362; 1478-6354
• DOI: 10.1186/s13075-014-0414-3

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. 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. 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, P corrected