Evaluation of CTLA-4 (+ 49A/G) polymorphism association with rheumatoid arthritis in Egyptian patients

Abstract

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory molecule that has an essential role in T-cell homeostasis and self-tolerance because of its inhibitory signals. Genetic polymorphisms in the CTLA-4 gene have been associated with several autoimmune diseases. We aimed to assess the association between the CTLA-4 +49 A/G polymorphism (rs231775) and rheumatoid arthritis (RA) in Egyptian RA patients. The study included 104 RA patients and 81 apparently healthy control individuals. The polymorphism was assessed using restriction fragment-length polymorphism analysis. Genotype distribution was compared between patients and controls under different models of inheritance. Under the codominant model, RA patients showed a higher frequency of AG and GG genotypes compared to the control subjects (p=0.0092). Under the dominant model, RA patients showed a higher frequency of AG and GG genotypes grouped together compared to control subjects (p=0.0026). Under the over-dominant model, the AG genotype was more frequent in RA patients compared to control subjects (p= 0.0395). No association was observed between CTLA-4 polymorphism rs231775 and RA using the recessive model (p=0.1356). A significant association was observed between carrying the G allele and the presence of RA (p=0.0032). In conclusion, our findings showed a positive association between the CTLA-4 gene +49 A>G polymorphism and RA. However, discrepancies in literature reflect both ethnic variability in CTLA-4 gene polymorphisms as well as the complex pathogenesis of RA.

A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A

“…Under the GCAS-approach, we found that the presence of FEIs on study entry ( ) versus their absence ( ) was strongly associated with four CTLA4 -assigned SNPs ( Figure 2 ), with rs231780 yielding the strongest signal ( p =2.3E-5) (Table 2), and suggestively associated with rs7528265, a SNP assigned to the interleukin (IL)-10 gene ( IL10 ) ( p =3.7E-3), which is closely linked to the three other Chr1 genes of the IL10 -superfamily, i.e., IL19 , IL20 , and IL24 encoding IL-19, IL-20, and IL-24 (Table 2). Like NOS2A and B3GNT2 , both CTLA4 and IL10 had previously been implicated in multiple AADs—including, e.g., RA, IDDM, and SLE 58 , 59 , 60 , 61 , 62 , 63 —but both had also been confirmed genetically to play a role in the development of FEIs. 20 , 22 , 23 Located on the long-arm of Chr2, CTLA4 comprises a telomerically-oriented, four-exon-containing transcription unit which spans sense-strand nucleotides 203,867,771–203,873,965 (GRCh38/hg38) ( Figure 3C ) and encodes the T-cell receptor—cytotoxic T-lymphocyte-associated-protein-4 (CTLA4)—that transduces inhibitory signals to down-regulate immune responses.…”