Association of CTLA4 c.49A > G (rs231775; p.Thr17Ala) gene variant with the risk of hepatocellular carcinoma and gastric cancer: A meta-analysis and meta-regression

Objective

Various reports have examined the contribution of the CTLA4 c.49A > G (rs231775; p.Thr17Ala) gene variant with different cancerous disorders. This meta-analysis was executed to further probe into the involvement of this missense variant with the susceptibility for hepatocellular carcinoma (HCC) and gastric cancer (GC).

Methodology

Following a wide-based scrutinized search of the internet done by three independent researchers for the contribution of the CTLA4 c.49A > G (rs231775; p.Thr17Ala) variant with the cancer risk up to February 2021, only 16 case-control studies were found relevant and usable to the analysis out of 575 total retrieved reports. Multiple genetic models were checked for the proposed association through the computation of the odds ratio (OR) in addition to their 95% confidence intervals (95%CIs). Stratification and regression analysis was also carried out for the analyzed reports based on their geographical distributions, genotyping techniques, source of cancer-free controls, genetic equilibrium within cancer-free controls, and quality score. In addition, trial sequential analysis (TSA) was applied to test for the adequacy of the total sample size.

Results

This meta-analysis has included 4320 HCC and GC patients in conjunction with 6601 cancer-free controls. This work disclosed a significant association for the CTLA4 c.49A > G (rs231775; p.Thr17Ala) variant with HCC among overall subjects tested by the recessive model [OR = 1.235, 95% CI = 1.050–1.453, P-value = 0.011]. Similarly, an elevated risk of GC was noticed associated with this variant within the overall subjects tested by the allelic model [OR = 1.225, 95% CI = 1.070–1.401, P-value = 0.003], and dominant model [OR = 1.352, 95% CI = 1.081–1.691, P-value = 0.008]. Furthermore, the stratification analysis showed a verification of correlation for this variant with HCC in Asian subjects under the recessive model, while the association was observed to be significant with GC in Asian and Caucasian patients under the dominant model. TSA confirmed that this work had significant findings noting that the collective Z-curve spanned the examining borderlines prior to attaining sample size confirming the acceptability of the study sample size.

Conclusion

The CTLA4 c.49A > G (rs231775; p.Thr17Ala) gene variant could be considered as an actual risk factor for the susceptibility of HCC and GC warranting efficient and adequate genetic counseling for this gene variant carriers.