Non-HLA genes PTPN22, CDK6 and PADI4 are associated with specific autoantibodies in HLA-defined subgroups of rheumatoid arthritis
1 Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Solna, CMM L8:O4 Karolinska Hospital, Stockholm SE-171 76, Sweden
2 Computational Medicine Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Solna, CMM L8:O5 Karolinska Hospital, Stockholm SE-171 76, Sweden
3 Laboratorio de Investigacion 10, Instituto de Investigacion Sanitaria–Hospital Clinico Universitario de Santiago, Travesia de Choupana sn, Santiago de Compostela ES-157 06, Spain
4 Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, Stockholm SE-171 77, Sweden
5 Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, B2, Stockholm SE-171 77, Sweden
Arthritis Research & Therapy 2014, 16:414 doi:10.1186/s13075-014-0414-3Published: 20 August 2014
IntroductionGenetic 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.MethodsWe 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.ResultsOur 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 <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, P corrected <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).ConclusionThese 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.