In this study we have demonstrated that specificity of autoantibody responses in seropositive RA is regulated not only by HLA-DRB1*04, but also by at least three additional non-HLA genetic variants: PADI4, PTPN22 and CDK6. Our data suggest that PTPN22 involvement is restricted to HLA-DRB1*04 carriers, while associations of PADI4 and CDK6 are restricted to the non-carriers, and they also differ in autoantibody specificity. Here, CDK6 is linked to rheumatoid arthritis.