Decoding the genetic influence of CT60 non-coding polymorphism in CTLA-4 gene and sCTLA-4 biomarker with rheumatoid arthritis in the Indian population.

Background: Cytoplasmic T Lymphocyte Antigen - 4 (CTLA-4) gene encodes an immunoregulatory receptor expressed on surface of activated T-cells to mediate peripheral tolerance against self-antigen. It suppresses auto-reactive T-cell proliferation either by inactivation or apoptosis of T-cells. The CTLA-4 mRNA undergoes alternative splicing to synthesize a native soluble form of CTLA-4 (sCTLA-4) protein, which lacks exon 3 that encodes for transmembrane region. As a result, sCTLA-4 circulates as a soluble serum protein and acts as an immunoregulator molecule to maintain homeostasis in the blood.

Materials and results: Techniques coupled with quantitative Polymerase Chain Reaction (qPCR) and High-Resolution Melting Analysis (HRMA) were used to screen CTLA-4 3'Untranslated Region (UTR) CT60 (A/G) rs3087243 Single Nucleotide Polymorphism (SNP) and their association with Rheumatoid Arthritis (RA) in the Indian population. In addition, we also evaluated the concentration of sCTLA-4 serum protein in RA patients carrying rs3087243 SNP with different genotypes (A/A, G/A, and G/G). Statistical analysis of Odds Ratio (OR), Confidence Interval (C.I), and Relative Risk (RR) have shown that frequency of CTLA-4 rs3087243 SNP G/G genotype was significantly associated with RA in the Indian population (OR 1.7140; CI = 1.0765 to 2.7290; RR = 1.5434; p = 0.0232). The sCTLA-4 concentration was also significantly lower in RA patients carrying rs3087243 SNP G/G genotype than control group (p < 0.001).

Conclusion: Co-inheritance of CTLA-4 signal peptide and 3'UTR SNPs may activate RAPP pathway. Downregulation of CTLA-4 and sCTLA-4 serum protein by rs3087243 SNP can increase the hyperactivation of T-cells, which causes RA.