Identification of genetic loci associated with antibodies to specific sets of citrullinated peptides in rheumatoid arthritis patients

ObjectivesProduction of anti-citrullinated peptide/protein antibodies (ACPA) is characteristic for rheumatoid arthritis (RA) and may inform about biological pathways involved in disease development in specific subgroups. Since multiple loci in genome wide association screens have been implicated in RA risk, we investigated the association between genetic variations and the development of multiple types of ACPA in three big cohorts of RA patients from Sweden, USA and UK (EIRA, NARAC and WTCCC) with overall 6,127 individuals with RA. MethodsWe combined genotyping data from Illumina Immunochip with serological data for 16 ACPA specificities from a custom-made multiplex microarray (Thermo Fisher Scientific, ImmunoDiagnostic division). A logistic regression-based association test in each cohort was followed by meta-analysis. ResultsWe report several loci, harbouring three or more variants associated with ACPA, reaching study-wide significance (FDR<0.1) - PTPN22, LINC02341_TNFSF11, THADA and TMEM174. Most of these loci are not known to be associated with RA. Stratification by "shared epitope" (SE) alleles indicated an association between the PTPN22 locus and levels of antibodies binding to the vimentin peptide, Cit-Vim60-75, in SE positive cases, but not in SE negative cases. ConclusionOur data identifies several new loci which associate with subsets of RA characterized by presence of specific ACPA and indicate unknown disease heterogeneity. Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIACPA define two subgroups within RA, and has been an important biomarker included in diagnostic criteria C_LIO_LICommonly used ACPA test, anti-CCP, accumulate signals from autoantibodies to several peptides and does not discriminate between multiple autoantibody specificities. C_LI What does this study add?O_LIOur study demonstrates that different sets of ACPAs in RA have distinct genetic associations. Associated variants from our study localize in known regulatory regions and have transcriptomic effects beyond the associated locus C_LIO_LIWe find that PTPN22 locus can drive positivity for multiple APCAs, while other found loci associate with specific autoantibody positivities C_LI How might this impact on clinical practice?O_LIOur study will extend personalized approach in handling of rheumatoid arthritis with focus on serologically defined subgroups of the disease. C_LI