Evidence of Association between CTLA-4 Gene Polymorphisms and Colorectal Cancers in Saudi Patients

Abstract

Cytotoxic T lymphocyte antigen-4 (CTLA-4) has been identified as an immunosuppressive molecule involved in the negative regulation of T cells. It is highly expressed in several types of autoimmune diseases and cancers including colorectal cancer (CRC). (1) Objective: To explore the association between CTLA-4 single nucleotide polymorphisms (SNP) and risk to (CRC) in the Saudi population. (2) Methods: In this case-control study, 100 patients with CRC and 100 matched healthy controls were genotyped for three CTLA-4 SNPs: rs11571317 (−658C > T), rs231775 (+49A > G) and rs3087243 (CT60 G > A), using TaqMan assay method. Associations were evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs) for five inheritance models (co-dominant, dominant, recessive, over-dominant and log-additive). Furthermore, CTLA-4 expression levels were evaluated using quantitative real-time PCR (Q-RT-PCR) in colon cancer and adjacent colon tissues. (3) Results: Our result showed a significant association of the G allele (OR = 2.337, p < 0.0001) and GG genotype of the missense SNP +49A > G with increased risk of developing CRC in codominant (OR = 8.93, p < 0.0001) and recessive (OR = 16.32, p < 0.0001) models. Inversely, the AG genotype was significantly associated with decreased risk to CRC in the codominant model (OR = 0.23, p < 0.0001). In addition, the CT60 G > A polymorphism exhibited a strong association with a high risk of developing CRC for the AA genotype in codominant (OR = 3.323, p = 0.0053) and in allele models (OR = 1.816, p = 0.005). No significant association was found between −658C > T and CRC. The haplotype analysis showed that the G-A-G haplotype of the rs11571317, rs231775 and rs3087243 was associated with high risk for CRC (OR = 57.66; p < 0.001). The CTLA-4 mRNA gene expression was found significantly higher in tumors compared to normal adjacent colon samples (p < 0.001). (4) Conclusions: Our findings support an association between the CTLA-4 rs231775 (+49A > G) and rs3087243 (CT60 G > A) polymorphisms and CRC risk in the Saudi population. Further validation in a larger cohort size is needed prior to utilizing these SNPs as a potential screening marker in the Saudi population.

The Variant Allele Frequency of CTLA-4 rs11571317 (−658 C/T) Polymorphism With Colorectal Cancer Susceptibility in the Saudi Population and Other Ethnic Groups

“…This is an association-based study; however, the association studies compare the frequency of a genetic variant in disease-affected patients and healthy controls. The SNP rs11571317 was observed as significantly associated with the populations of Saudi Arabia [18], confirming an early finding by Goske et al (2017) [21], Welsh et al (2009) [22], and Wang et al ( 2007) [15].…”

“…In this study, the prevalence rate of CTLA-4 rs11571317 −658 C>T polymorphisms was extracted from six studies [15,[18][19][20][21][22] (as shown in Table 1) and it was compared with the population of Saudi Arabia (as shown in Table 2) [18].…”

“…Several epidemiological studies were conducted for the investigation of the correlation of the CTLA-4 rs11571317 −658 C>T polymorphism and their chances of cancer progression [18]. Although CTLA-4 is localized in the promoter region for the risk of cancers, their presence, and functional effects of CTLA-4 rs11571317 −658 C>T polymorphisms in the population of Saudi Arabia in any types of cancers have not yet been elucidated.…”