A Combination of CD28 (rs1980422) and IRF5 (rs10488631) Polymorphisms Is Associated with Seropositivity in Rheumatoid Arthritis: A Case Control Study.
BACKGROUND
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.
Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Lucia
http://orcid.org/0000-0001-6087-2175
L
Vernerova
Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.|Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czech Republic.
Frantisek
F
Spoutil
Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Miroslav
M
Vlcek
Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Katarina
K
Krskova
Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Adela
A
Penesova
Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Milada
M
Meskova
Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Andrea
A
Marko
Slovak Medical University, Bratislava, Slovakia.
Katarina
K
Raslova
Slovak Medical University, Bratislava, Slovakia.
Branislav
B
Vohnout
National Institute of Rheumatic Diseases, Piešťany, Slovakia.
Jozef
J
Rovensky
5th Department of Internal Medicine, Medical Faculty of Comenius University, Bratislava, Slovakia.
Zdenko
Z
Killinger
1st Department of Internal Medicine, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovakia.
Ivana
I
Jochmanova
1st Department of Internal Medicine, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovakia.
Ivica
I
Lazurova
Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria.
Guenter
G
Steiner
Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria.
Josef
J
Smolen
Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
Richard
R
Imrich
D000328:Adult; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001323:Autoantibodies / Q000235:genetics; D018106:CD28 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012217:Rheumatoid Factor / Q000235:genetics; D012307:Risk Factors
D001323:Autoantibodies; D018106:CD28 Antigens; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D012217:Rheumatoid Factor