Cytotoxic T lymphocyte antigen 4 (CTLA4) gene polymorphism with bladder cancer risk in North Indian population

Area of Science:

• Immunogenetics
• Oncology
• Molecular Biology

Background:

• Cytotoxic T Lymphocyte antigen 4 (CTLA4) is a key regulator of T cell activation, crucial in suppressing antitumor immune responses.
• Genetic variations within the CTLA4 gene are implicated in various autoimmune and malignant diseases.
• Understanding CTLA4's role in bladder cancer (BC) susceptibility is vital for early detection and targeted therapies.

Purpose of the Study:

• To investigate the association between specific single nucleotide polymorphisms (SNPs) in the CTLA4 gene (+49A/G, CT60A/G, -318C/T) and the risk of developing bladder cancer (BC).
• To evaluate the influence of these CTLA4 gene polymorphisms on BC risk, particularly in the North Indian population.
• To explore potential correlations between CTLA4 gene variations, smoking, tumor characteristics, and response to BCG immunotherapy in BC patients.

Main Methods:

• Genotyping of 200 histopathologically confirmed BC patients and 200 healthy controls from North India using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and Amplification Refractory Mutation Specific (PCR-ARMS) methods.
• Analysis of candidate disease-susceptibility SNPs: CTLA4 +49A/G, CT60A/G, and -318C/T.
• In silico analysis and haplotype analysis (GAC, AGT) to further support SNP associations and identify combined genetic effects.

Main Results:

• The CTLA4 +49A/G variant genotype was associated with a 3.74-fold increased risk of BC. The G allele also showed a significant risk (OR=1.54).
• The CTLA4 CT60A/G variant genotype showed a 1.36-fold risk for BC, with the G allele carrier and variant G allele showing reduced risk.
• The CTLA4 +49A/G genotype increased BC risk by 1.57-fold in smokers with homozygous mutant genotype. Haplotype GAC showed high risk, while AGT showed reduced risk for BC.
• No significant association was found between CTLA4 SNPs and tumor stage/grade, nor with BCG immunotherapy response.

Conclusions:

• Genetic variations in CTLA4, specifically at +49A/G and CT60A/G, contribute to bladder cancer susceptibility in the North Indian population.
• The GAC haplotype is identified as a high-risk haplotype for BC, whereas the AGT haplotype is associated with reduced risk.
• Further large-scale association studies with diverse ethnicities and advanced techniques are warranted to validate these findings and elucidate the precise mechanisms of CTLA4 in BC pathogenesis.