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Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk : An update meta-analysis and trial sequential analysis

ABSTRACT: Abstract

Aim:

To evaluate the associations between the methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and hepatocellular carcinoma (HCC) with meta-analysis and trial sequential analysis.

Methods:

PubMed, Embase, the Google Scholar, Wan fang database, VIP database, and China National Knowledge Infrastructure were extensively searched before April 2021. Odds ratios (ORs) and 95% confidence interval (95% CI) were calculated. Review Manager Version 5.3, STATA version 12.0 and TSA 0.9.5.10 Beta software were used.

Results:

Nineteen studies with 6941 HCC patients and 9436 controls were finally included. The MTHFR rs1801133 (C677T) SNP was associated with increased HCC risk under heterozygote genetic model (OR = 1.10, 95% CI = [1.01, 1.20]). For Subgroup analysis, increased risks of HCC were detected in Mongoloid, Chinese. For MTHFR rs1801131 (A1298C) SNP, increased risk of HCC was only observed in Caucasians (allelic: OR = 1.86, 95% CI = [1.49, 2.31]; homozygote: OR = 3.39, 95% CI = [2.18, 5.27]), interesting decreased risk was detected in Mongoloid (recessive: OR = 0.30, 95% CI = [0.15, 0.58]; homozygote: OR = 0.41, 95% CI = [0.24, 0.72]). Sensitivity analysis indicated stability in our results. Publication bias was not detected based on Begg test and Egger test. Trial sequential analysis indicated further studies to confirm the associations in MTHFR C677T polymorphism.

Conclusion:

The MTHFR rs1801133 SNP was associated with an increased risk of HCC in Mongoloid population especially in Chinese. Increased HCC risk is also observed in Caucasian population for the MTHFR rs1801131 SNP, and decreased risk of HCC is remarkably discovered in Mongoloid and Chinese subgroups, which need further validation.

SUBMITTER: Wang B

PROVIDER: S-EPMC8519208 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMethylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate. The non-synonymous single nucleotide polymorphism (nsSNP), C677T (Ala>Val, rs1801133), has been verified to impair enzyme activity. The association with cancer susceptibility, including hepatocellular carcinoma (HCC), has also been widely studied. The results, however, were inconsistent. To shed light on the influence of MTHFR C677T polymorphism on HCC, a meta-analysis was conducted.MethodsThe meta-analysis of C677T consisted of 10 studies (1814 cases/2862 controls). The association was measured by using random-effect (RE) or fixed-effect (FE) odds ratio (OR) combined with 95% confidence intervals (CIs) according to the studies' heterogeneity.ResultsUsing genetic model analysis, C677T polymorphism was found to increase the risk of HCC in a complete overdominant model, which indicates that heterozygotes CT are at a lesser risk of HCC than either homozygotes CC or TT. Meta-analyses of the 10 studies showed that the TT genotype increased the risk of HCC as compared to the CT genotype: FE OR was 1.20 (95%CI: 1.00-1.45, p for heterogeneity = 0.21). When subgroup analysis was done between the HCC cases and the chronic liver disease (CLD) patients of four studies, meta-analysis showed that individuals with the TT genotype had increased HCC risk compared with those with the CT genotype: FE OR (TT vs. CT) reached 1.81 (1.22-2.71, p for heterogeneity = 0.25). Meanwhile, the C677T polymorphism also increased HCC risk in a recessive model when cases were compared to CLD patients of four studies: RE OR reached 1.85 (95%CI: 1.00-3.42, p for heterogeneity = 0.06). Overall, there was some extent heterogeneity when analyses were performed in various models. There was no publication bias.ConclusionMTHFR C677T polymorphism increased the risk of HCC in an overdominant model, and might be a risk factor for HCC occurrence, especially in CLD patients. The association warranted further studies.

Project description:BackgroundThe association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis.MethodsThe previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping.ResultsNeither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P = 0.006, OR = 0.83, 95% CI = 0.72-0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69-1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53-1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P = 0.06, OR = 1.21, 95% CI = 0.99-1.49) and AC vs. AA (P = 0.09, OR = 1.21, 95% CI = 0.97-1.51).ConclusionsThe MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study.

Project description:Background18 previous meta-analyses have been published on the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with male infertility risk. However, results of the previous meta-analyses were still inconsistent. Moreover, their meta-analyses did not assess false-positive report probabilities except one study. Furthermore, many new studies have been published, and therefore an updated meta-analysis and re-analysis of systematic previous meta-analyses were performed to further explore these issues.ObjectivesTo determine the association between MTHFR C677T and A1298C polymorphisms and male infertility risk.MethodsCrude odds ratios and their 95% confidence intervals were used to assess the association between MTHFR C677T and A1298C polymorphisms and male infertility risk. We used the Bayesian false discovery probability (BFDP) to assess the credibility of statistically significant associations.ResultsFifty-nine studies were included concerning the MTHFR C677T and 28 studies were found on the MTHFR A1298C with male infertility risk. Overall, the MTHFR C677T was associated with increased male infertility risk in overall populations, Africans, East Asians, West Asians, South Asians, azoospermia, and Oligoasthenoteratozoospermia (OAT). In further sensitivity analysis and BFDP test, the positive results were only considered as "noteworthy" in the overall population (TT vs CC: BFDP = 0.294, CT + TT vs CC: BFDP = 0.300, T vs C: BFDP = 0.336), East Asians (TT vs CC: BFDP = 0.089, TT vs CT + CC: BFDP = 0.020, T vs C: BFDP < 0.001), West Asians (TT vs CC: BFDP = 0.584), hospital-based studies (TT vs CC: BFDP = 0.726, TT vs CT + CC: BFDP = 0.126), and OAT (TT vs CT + CC: BFDP = 0.494) for MTHFR C677T. In addition, a significantly increased male infertility risk was found in East Asians and population-based studies for MTHFR A1298C. However, we did not find that the positive results were considered as "noteworthy" in the overall and all subgroup analyses for MTHFR A1298C.ConclusionsIn summary, this study indicates that the MTHFR C677T is associated with increased male infertility risk in East Asians, West Asians, and OAT. No significant association was observed on the MTHFR A1298C with male infertility risk.