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

Vernerova L, Spoutil F, Vlcek M, Krskova K, Penesova A, Meskova M, Marko A, Raslova K, Vohnout B, Rovensky J, Killinger Z, Jochmanova I, Lazurova I, Steiner G, Smolen J, Imrich R - PLoS ONE (2016)

Bottom Line: 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 risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.

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.

No MeSH data available.


Related in: MedlinePlus

Factors associated with clinical severity in RA.Redundancy analysis plot showing that risk alleles in AFF3 gene, together with ACPA positivity are associated with higher clinical severity of RA. ACPA—anti-citrullinated peptides antibodies (□); AFF3 (TT, AT, AA)–genotypes in AFF3 gene (T risk allele) (▽). Diagram reading clue: Symbols are genetic and serologic factors. Large bold symbols represent genotypes and antibody presence significantly influencing the clinical parameters of disease severity (DAS28, CRP, ESR, TJC, SJC, HAQ-DI). Small empty symbols represent other factors and genotypes of selected genes. Direction of arrow indicates which of the clinical factors are associated with the genetic and serologic parameters and the length of the arrow indicates the magnitude of the association.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4836711&req=5

pone.0153316.g003: Factors associated with clinical severity in RA.Redundancy analysis plot showing that risk alleles in AFF3 gene, together with ACPA positivity are associated with higher clinical severity of RA. ACPA—anti-citrullinated peptides antibodies (□); AFF3 (TT, AT, AA)–genotypes in AFF3 gene (T risk allele) (▽). Diagram reading clue: Symbols are genetic and serologic factors. Large bold symbols represent genotypes and antibody presence significantly influencing the clinical parameters of disease severity (DAS28, CRP, ESR, TJC, SJC, HAQ-DI). Small empty symbols represent other factors and genotypes of selected genes. Direction of arrow indicates which of the clinical factors are associated with the genetic and serologic parameters and the length of the arrow indicates the magnitude of the association.

Mentions: In general, RDA analysis with forward selection performed in RA patients showed that ACPA positivity, AFF3 gene, in particular AFF3 TT genotype and smoking significantly associate with higher disease activity defined by clinical parameters DAS28, CRP, ESR, TJC, SJC and HAQ-DI. The explanatory variables explain 6.1% of variability among RA patients (Trace = 0.061; F = 3.482; P = 0.0020). In particular, higher CRP levels were associated with the presence of AFF3 TT genotype, whereas higher DAS28 and higher number of swollen and tender joints were correlated with ACPA positivity (Fig 3).


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

Vernerova L, Spoutil F, Vlcek M, Krskova K, Penesova A, Meskova M, Marko A, Raslova K, Vohnout B, Rovensky J, Killinger Z, Jochmanova I, Lazurova I, Steiner G, Smolen J, Imrich R - PLoS ONE (2016)

Factors associated with clinical severity in RA.Redundancy analysis plot showing that risk alleles in AFF3 gene, together with ACPA positivity are associated with higher clinical severity of RA. ACPA—anti-citrullinated peptides antibodies (□); AFF3 (TT, AT, AA)–genotypes in AFF3 gene (T risk allele) (▽). Diagram reading clue: Symbols are genetic and serologic factors. Large bold symbols represent genotypes and antibody presence significantly influencing the clinical parameters of disease severity (DAS28, CRP, ESR, TJC, SJC, HAQ-DI). Small empty symbols represent other factors and genotypes of selected genes. Direction of arrow indicates which of the clinical factors are associated with the genetic and serologic parameters and the length of the arrow indicates the magnitude of the association.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836711&req=5

pone.0153316.g003: Factors associated with clinical severity in RA.Redundancy analysis plot showing that risk alleles in AFF3 gene, together with ACPA positivity are associated with higher clinical severity of RA. ACPA—anti-citrullinated peptides antibodies (□); AFF3 (TT, AT, AA)–genotypes in AFF3 gene (T risk allele) (▽). Diagram reading clue: Symbols are genetic and serologic factors. Large bold symbols represent genotypes and antibody presence significantly influencing the clinical parameters of disease severity (DAS28, CRP, ESR, TJC, SJC, HAQ-DI). Small empty symbols represent other factors and genotypes of selected genes. Direction of arrow indicates which of the clinical factors are associated with the genetic and serologic parameters and the length of the arrow indicates the magnitude of the association.
Mentions: In general, RDA analysis with forward selection performed in RA patients showed that ACPA positivity, AFF3 gene, in particular AFF3 TT genotype and smoking significantly associate with higher disease activity defined by clinical parameters DAS28, CRP, ESR, TJC, SJC and HAQ-DI. The explanatory variables explain 6.1% of variability among RA patients (Trace = 0.061; F = 3.482; P = 0.0020). In particular, higher CRP levels were associated with the presence of AFF3 TT genotype, whereas higher DAS28 and higher number of swollen and tender joints were correlated with ACPA positivity (Fig 3).

Bottom Line: 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 risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical and Translational Research, Biomedical Centre, Slovak Academy of Sciences, Bratislava, Slovakia.

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.

No MeSH data available.


Related in: MedlinePlus