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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,  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).    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.    Electronic supplementary material  The online version of this article (doi:10.1186/s13075-014-0414-3) contains supplementary material, which is available to authorized users.

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