Association Between Polymorphisms Of MTHFR And The Genetic Susceptibility To Esophageal Cancer In Henan Han Population

BackgroundMethylenetetrahydrofolate reductase gene (MTHFR), an important metabolic enzyme gene, is a key rate-limiting enzyme in the metabolism cycle of folic acid, and plays a role in DNA methylation and DNA synthesis, thus it is likely related to the formation of esophageal cancer. Polymorphisms 677 and 1298 of MTHFR gene are the common loci which are focused on by many studies. The two loci could result in missense mutations, and are closely related with the activity of the enzyme, so it is particularly necessary to study deeply on the relationship between polymorphisms of MTHFR gene and esophageal cancer. It will provide scientific basis for the etiology of esophageal cancer and has important significance in screening susceptible and high-risk populations and taking the effective intervention measures for these populations.Currently, there are some researches concerning of the polymorphisms of MTHFR and the risk of esophageal cancer. But the conclusions of these research are considerably different, even opposite. Therefore, in this study, a case-control study was carried out by using PCR-RFLP, PCR-CTPP genotyping methods to further investigate the relationship between MTHFR 677 and 1298 loci and susceptibility to esophageal cancer in Henan Han population.ObjectiveThe relationship between SNPs of metabolic gene MTHFR and susceptibility to esophageal cancer will be discussed on gene-gene and gene-environment interactions. It will provide a theoretical basis to reveal the development of esophageal cancer etiology and prevention interventions.MethodsIn Henan Han population,381 patients with esophageal cancer and 432 healthy controls matched on age and sex were selected to this case-control study. PCR-RFLP and PCR-CTPP methods were used to identify genotypes of 677 and 1298 polymorphisms of MTHFR gene;χ2 test was used to compare the distribution differences between case-control groups in the two points of various state, non-conditional Logistic regression method was carried out to get the OR value and its 95% confidence interval (95% CI) by adjusting for age, sex, smoking, alcohol consumption, and family history of cancer. Haplotypes were evaluated by using SNPHAP software.χ2 test was also used to compare the distribution differences between case-control groups in Joint genotype frequence, trends in the number of mutations and allele frequence and the interactions between the two points and smoking or drinking were investigated in this study.ResultsAssociated with esophageal cancer susceptibility analysis677 point:Compared with the CC genotype, the risk of esophageal cancer was reduced in individuals carrying TT and dominance effects model (CT+TT) genotype, the adjusted OR(95% CI) were 0.44(0.28～0.71),0.57(0.37～0.88). And compared with the wild allele C, the mutant T allele also can reduce the susceptibility of esophageal cancer(adjusted OR=0.66,95% CI:0.53-0.82).1298 point:Compared with the genotype AA, the susceptibility of esophageal cancer was not changed for individuals carrying AC, CC, and (AC+CC) genotype; their adjusted OR(95% CI) were 1.05(0.74～1.48),0.90(0.37～2.23) and 1.03 (0.74-1.44). Compared with the A allele, C allele was unrelated to esophageal cancer. MTHFR 1298 may be is not associated with susceptibility to esophageal cancer as a single locus.Haplotype analysisComparing to haplotype CA consisted by the wild-type allele of 677 point and 1298 point, there are differences between the distribution in case-control groups of TA, TC haplotypes in the other 3 haplotypes, which can reduce susceptibility to esophageal cancer. The adjusted OR(95% CI) were 0.61(0.47～0.79),0.06(0.01～0.43).Combined genotype analysisThe combined wild genotype GG/AA as the reference, there are distribution differences in CT/AA, CT/AC, CT/CC, and TT/AA between case and control groups in the other seven combined genotypes, the adjusted OR(95% CI) were 0.48(0.24～0.98),0.46(0.22～0.98),0.11(0.01～0.97),0.31(0.15～0.62), suggesting that they can reduce the risk of esophageal cancer.Interaction between genes and environmentThe results showed that the interactions had statistically significant between smoking and 677 point; and there was no statistically significant interaction between smoking and 1298 point; and also no interaction between alcohol consumption and the two points.ConclusionPolymorphism 677 of MTHFR may be associated with the occurrence of esophageal cancer in Henan Han population, because the TT, (CT+TT) genotype, T allele could reduce the susceptibility of esophageal cancer; polymorphism 1298 of MTHFR may be not related to the incidence of esophageal cancer in Henan Han population; There were interactions between 677 and 1298 point of MTHFR, the haplotype:TA, TC, combined genotypes:CT/AA, CT/AC, CT/CC, TT/AA could reduce the risk of esophageal cancer; There were statistically significant interactions between the 677 point and smoking, and no interaction between the 1298 point and smoking; and also no interaction between alcohol consumption and the two points.