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A Combination of CD28 (rs1980422) and IRF5 (rs10488631) Polymorphisms Is Associated with Seropositivity in Rheumatoid Arthritis: A Case Control Study

Author

Listed:
  • Lucia Vernerova
  • Frantisek Spoutil
  • Miroslav Vlcek
  • Katarina Krskova
  • Adela Penesova
  • Milada Meskova
  • Andrea Marko
  • Katarina Raslova
  • Branislav Vohnout
  • Jozef Rovensky
  • Zdenko Killinger
  • Ivana Jochmanova
  • Ivica Lazurova
  • Guenter Steiner
  • Josef Smolen
  • Richard Imrich

Abstract

Introduction: The aim of the study was to analyse genetic architecture of RA by utilizing multiparametric statistical methods such as linear discriminant analysis (LDA) and redundancy analysis (RDA). Methods: A total of 1393 volunteers, 499 patients with RA and 894 healthy controls were included in the study. The presence of shared epitope (SE) in HLA-DRB1 and 11 SNPs (PTPN22 C/T (rs2476601), STAT4 G/T (rs7574865), CTLA4 A/G (rs3087243), TRAF1/C5 A/G (rs3761847), IRF5 T/C (rs10488631), TNFAIP3 C/T (rs5029937), AFF3 A/T (rs11676922), PADI4 C/T (rs2240340), CD28 T/C (rs1980422), CSK G/A (rs34933034) and FCGR3A A/C (rs396991), rheumatoid factor (RF), anti–citrullinated protein antibodies (ACPA) and clinical status was analysed using the LDA and RDA. Results: HLA-DRB1, PTPN22, STAT4, IRF5 and PADI4 significantly discriminated between RA patients and healthy controls in LDA. The correlation between RA diagnosis and the explanatory variables in the model was 0.328 (Trace = 0.107; F = 13.715; P = 0.0002). The risk variants of IRF5 and CD28 genes were found to be common determinants for seropositivity in RDA, while positivity of RF alone was associated with the CTLA4 risk variant in heterozygous form. The correlation between serologic status and genetic determinants on the 1st ordinal axis was 0.468, and 0.145 on the 2nd one (Trace = 0.179; F = 6.135; P = 0.001). The risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA. Conclusions: The association among multiple risk variants related to T cell receptor signalling with seropositivity may play an important role in distinct clinical phenotypes of RA. Our study demonstrates that multiparametric analyses represent a powerful tool for investigation of mutual relationships of potential risk factors in complex diseases such as RA.

Suggested Citation

  • Lucia Vernerova & Frantisek Spoutil & Miroslav Vlcek & Katarina Krskova & Adela Penesova & Milada Meskova & Andrea Marko & Katarina Raslova & Branislav Vohnout & Jozef Rovensky & Zdenko Killinger & Iv, 2016. "A Combination of CD28 (rs1980422) and IRF5 (rs10488631) Polymorphisms Is Associated with Seropositivity in Rheumatoid Arthritis: A Case Control Study," PLOS ONE, Public Library of Science, vol. 11(4), pages 1-15, April.
    • Handle: RePEc:plo:pone00:0153316
    DOI: 10.1371/journal.pone.0153316
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    1. Ian C Scott & Seth D Seegobin & Sophia Steer & Rachael Tan & Paola Forabosco & Anne Hinks & Stephen Eyre & Ann W Morgan & Anthony G Wilson & Lynne J Hocking & Paul Wordsworth & Anne Barton & Jane Wort, 2013. "Predicting the Risk of Rheumatoid Arthritis and Its Age of Onset through Modelling Genetic Risk Variants with Smoking," PLOS Genetics, Public Library of Science, vol. 9(9), pages 1-13, September.
    2. Nick Patterson & Alkes L Price & David Reich, 2006. "Population Structure and Eigenanalysis," PLOS Genetics, Public Library of Science, vol. 2(12), pages 1-20, December.
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