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

By Klementy Shchetynsky, Boel Brynedal, Daniel Ramskold, Lena Israelsson, Monica Hansson, Linda Mathsson-Alm, Johan Ronnelid, Sebastien Viatte, Rikard Holmdahl, Anca Catrina, Lars Alfredsson, Vivianne Malmstrom, Lars Klareskog, David Gomez-Cabrero, Leonid Padyukov

Posted 19 Jul 2021
medRxiv DOI: 10.1101/2021.07.15.21259135

Objectives: Production 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. Methods: We 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. Results: We 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. Conclusion: Our data identifies several new loci which associate with subsets of RA characterized by presence of specific ACPA and indicate unknown disease heterogeneity.

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