IL-10 polymorphism genotypes, haplotypes, and diplotypes are associated with colorectal cancer predisposition and outcome in Tunisian population

Abstract

Background and aim: As the presence of single nucleotide polymorphisms (SNPs) in the interleukin (IL)-10 gene continues to be a major challenge in the development of effective therapies for digestive cancers, this case-control study was conducted to assess the possible influence of genotype, haplotype and diplotype for two SNPs (-1082A/G (rs1800896) and -592A/C (rs1800872)) located in the promoter region of IL-10 gene on the incidence, severity and prognosis of colorectal cancer (CRC) in Tunisians.

Methods: IL-10 gene SNPs were analyzed in 130 CRC cases and 165 healthy subjects (HS) using PCR-SSP.

Results: For the IL-10 -1082A/G SNP, the comparison of genotype frequencies between cases and HS groups showed that the G allele significantly reduced CRC risk under the recessive model (GG vs. AA + AG: OR [95%CI] = 0.44 [0.21-0.93], p = 0.03). Conversely, a positive association was observed between the codominant model (AG vs. AA + GG) and high susceptibility (OR [95%CI] = 1.65 [1.02-2.63], p = 0.04). After stratification by disease site, the recessive model was also found to reduce susceptibility to colon cancer (OR [95%CI] = 0.18 [0.04-0.72], p = 0 0.01), while the homozygote model (AA vs. GG) was suggested as a risk factor (OR [95%CI] = 5.16 [1.31-23.26], p = 0.02). Furthermore, the codominant model (AG vs. AA + GG) doubled the risk of rectum cancer (OR [95%CI] = 1.98 [1.07-3.70], p = 0.03). For the IL-10 -592A/C SNP, the codominant model (AC vs. AA + CC) has a protective effect against the development of CRC (OR [95%CI] = 0.59 [0.36-0.94], p = 0.03). The IL-10 gene haplotype was not associated with CRC risk. A stratified analysis by disease site demonstrated that the presence of Hap3 (-1082G and -592C alleles) specifically reduced the risk of developing colon cancer (OR [95%CI] = 0.51 [0.32-0.80], p = 0.003). Moreover, homozygous Hap3/Hap3 diplotype significantly reduced susceptibility to CRC (OR [95%CI] = 0.35 [0.14-0.85], p = 0.02). Interestingly, this diplotype has not been identified in colon cancer patients. Kaplan-Meier analysis showed that the homozygous Hap2/Hap2 diplotype was significantly associated with decreased overall survival (Log-rank: p = 0.01). This association was also observed in the colon cancer subgroup (Log-rank: p = 0.001).

Conclusion: Our findings provide preliminary indications that the -1082A/G and -592/AC SNPs within the IL-10 gene may exhibit significant associations with the pathogenesis and prognostic outcomes of CRC. However, further investigations are still warranted to validate and establish the veracity of our findings.

Keywords: Colorectal cancer; Diplotype; Genotype; Haplotype; IL-10; Risk; SNP; Survival.

Fig. 1

HaploView linkage disequilibrium (LD) plots of -1082A/G (rs1800896) and -592A/C (rs1800872) SNPs in the promoter region of IL-10 gene. The LD pattern was derived from the combined study population (both cases and healthy subjects). Values in the LD blocks indicated the D’ (a.) and the r² (b.) in percentages.

Fig. 2

Effect of IL-10 gene SNPs on the overall survival in CRC cases Kaplan-Meier estimates showed no association between the genotypes of SNPs −1082A/G (Log-rank p = 0.53) (a.) and −592AC (Log-rank p = 0.066) (b.) in the promoter region of the IL-10 gene and the overall survival of CRC cases. Kaplan-Meier estimates showed an association between the IL-10 -592 AA genotype versus other genotypes (CC + AC) (Log-rank p = 0.021) (c.).

Fig. 3

Effect of IL-10 gene haplotypes on the overall survival in CRC cases Kaplan-Meier estimates showed no association between all the combinations of haplotypes derived from the −1082A/G and −592A/C SNPs in the promoter region of the IL-10 gene and the overall survival in CRC cases (Log-rank p value > 0.05) (a. b. and c.).

Fig. 4

Effect of IL-10 gene haplotypes on the overall survival in cases with colon cancer. In cases with colon cancer subgroup, Kaplan-Meier estimates showed that Hap1 carriers (consisting of the 1082A and 592C alleles) had a better overall survival (OS) compared with non-carriers (Log-rank p = 0.002) (a.). No significant results were observed for other haplotype combinations (Log-rank p values > 0.05) (b. and c.).

Fig. 5

Effect of IL-10 gene diplotypes on the overall survival in CRC cases Kaplan-Meier estimates showed that carriers of the homozygous Hap2/Hap2 diplotype had a lower overall survival (OS) compared with Hap2/Others + Others/Others carriers (Log-rank p = 0.01) (b.). No significant association was observed between all the other combinations of diplotype and OS in CRC cases (Log-rank p values > 0.05) (a. and c.).

Fig. 6

Effect of IL-10 gene diplotypes on the overall survival in cases with colon cancer. In cases with colon cancer subgroup, Kaplan-Meier estimates showed that carriers of homozygous Hap2/Hap2 diplotype had a significantly shorter OS compared to Hap2/Others + Others/Others carriers (Log-rank p = 0.001) (b.). No association was observed between homozygous Hap1/Hap1 diplotype and patients' outcome (Log-rank p = 0.21) (a.). None of cases with colon cancer had the homozygous Hap3/Hap3 diplotype.