The −319C/+49G/CT60G Haplotype of CTLA-4 Gene Confers Susceptibility to Rheumatoid Arthritis in Mexican Population

Abstract

Several single nucleotide polymorphisms (SNPs) within the CTLA-4 gene and elevated serum levels of soluble CTLA-4 (sCTLA-4) have been associated with autoimmunity including rheumatoid arthritis (RA). In this case-control study, we evaluated the relationship between the -319C/T (rs5742909) and CT60 G/A (rs3087243) SNPs and sCTLA-4 levels in 200 RA patients and 200 control subjects (CS) from Western Mexico. Both SNPs were genotyped with the polymerase chain reaction-restriction fragment length polymorphism technique and the sCTLA-4 levels were quantified using an enzyme-linked immunosorbent assay kit. In addition, we performed a haplotype analysis, including our previous data of the +49A/G (rs231775) SNP. The G/A genotype of the rs3087243 SNP was associated with a decreased risk of RA [odd ratio (OR) 0.61, 95% confidence interval (CI) 0.38-0.96, p = 0.024]. This protection was also observed in the negative anti-cyclic citrullinated peptide group of RA carriers of the A allele (OR 0.48, 95% CI 0.22-1.05, p = 0.042). On the contrary, we identified the -319C/+49G/CT60G haplotype of CTLA-4 gene as a risk factor for RA (OR 1.69, 95% CI 1.13-2.52, p = 0.01). The sCTLA-4 levels were not associated with RA (p = 0.377), but were correlated with the functional disability of these patients (r = 0.282, p = 0.012). However, in CS the C/T genotype of the rs5742909 SNP, as well as the G/G and G/A genotypes of the rs3087243 SNP were associated with higher sCTLA-4 levels (p < 0.001). In conclusion, our results suggest that the -319C/+49G/CT60G haplotype of CTLA-4 gene is a genetic marker of susceptibility to RA in Western Mexico, whereas the rs3087243 SNP confers protection against this disease. Moreover, both SNPs showed an effect on the sCTLA-4 production in our control population. However, further studies are required to evaluate the role of sCTLA-4 in RA, as well as the molecular and functional basis of the association between both CTLA-4 gene SNPs and soluble levels of CTLA-4 in CS.

Association of the HLA‐B27 antigen and the CTLA4 gene CT60/rs3087243 polymorphism with ankylosing spondylitis in Algerian population: A case–control study

“…The CT60 *G allele has been extensively studied, but its frequency changes with ethnicity. In our population, the minor allele frequency (MAF) of this variant in controls group (MAF ≤50%) was found similar to those reported in European (Farago et al., ) Tunisian (Benmansour et al., ) and Chinese Han (Wang et al., ) populations, whereas it was different (MAF >50%) in Asian (Lei et al., ; Tsukahara et al., ) and American populations (Pincerati et al., ; Torres‐Carrillo et al., ).…”

Investigation of CTLA‐4 and CD86 gene polymorphisms in Iranian patients with brucellosis infection

“…This finding is in accordance with several studies, which have shown associations between this variation and risk of COPD , Graves disease , autoimmune type 1 diabetes , acute anterior uveitis and multi‐factorial autoimmune diseases . However, this association was not found for Behcet disease , RA , and systemic lupus erythematosus . The TT genotype at −318 C/T has been shown to be associated with upregulation of CTLA4 transcription .…”

Association between the CTLA-4, CD226, FAS polymorphisms and rheumatoid arthritis susceptibility: A meta-analysis

“…Four articles were excluded because 2 were review articles, 1 contained duplicate data, and 1 had no data concerning the polymorphisms. Thus, 19 studies met our inclusion criteria [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. They consisted of 8 studies on the CTLA-4 polymorphism with 2093 patients and 2480 controls, 5 on the CD226 polymorphism with 2278 patients and 1940 controls, 6 on the FAS polymorphism with 546 patients and 618 controls, and 3 on the FASL polymorphism with 321 patients and 307 controls (Fig.…”

“…While some studies have found that CTLA-4 rs5742909, CD226 rs763361, FAS-670 rs1800682, and FASL rs763110 polymorphisms are associated with RA, other studies have reported no such association [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. To overcome the limitations of individual studies, resolve inconsistencies, and reduce the likelihood that random errors are responsible for false positive or false negative associations [32][33][34], we performed a meta-analysis to determine whether these polymorphisms are associated with RA susceptibility.…”