Association Between MTHFR Polymorphisms and the Risk of Essential Hypertension: An Updated Meta-analysis

Abstract

Background: Since the 1990s, there have been a lot of research on single-nucleotide polymorphism (SNP) and different diseases, including many studies on 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism and essential hypertension (EH). Nevertheless, their conclusions were controversial. So far, six previous meta-analyses discussed the internal relationship between the MTHFR polymorphism and EH, respectively. However, they did not evaluate the credibility of the positive associations. To build on previous meta-analyses, we updated the literature by including previously included papers as well as nine new articles, improved the inclusion criteria by also considering the quality of the papers, and applied new statistical techniques to assess the observed associations. Objectives: This study aims to explore the degree of risk correlation between two MTHFR polymorphisms and EH. Methods: PubMed, EMBASE, the Cochrane Library, CNKI, and Wan Fang electronic databases were searched to identify relevant studies. We evaluated the relation between the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and EH by calculating the odds ratios (OR) as well as 95% confidence intervals (CI). Here we used subgroup analysis, sensitivity analysis, cumulative meta-analysis, assessment of publication bias, meta-regression meta, False-positive report probability (FPRP), Bayesian false discovery probability (BFDP), and Venice criterion. Results: Overall, harboring the variant of MTHFR C677T was associated with an increased risk of EH in the overall populations, East Asians, Southeast Asians, South Asians, Caucasians/Europeans, and Africans. After the sensitivity analysis, positive results were found only in the overall population (TT vs. CC: OR = 1.14, 95% CI: 1.00–1.30, Ph = 0.032, I2 = 39.8%; TT + TC vs. CC: OR = 1.15, 95% CI: 1.01–1.29, Ph = 0.040, I2 = 38.1%; T vs. C: OR = 1.14, 95% CI: 1.04–1.25, Ph = 0.005, I2 = 50.2%) and Asian population (TC vs. CC: OR = 1.14, 95% CI: 1.01–1.28, Ph = 0.265, I2 = 16.8%; TT + TC vs. CC: OR = 1.17, 95% CI: 1.04–1.30, Ph = 0.105, I2 = 32.9%; T vs. C: OR = 1.10, 95% CI: 1.02–1.19, Ph = 0.018, I2 = 48.6%). However, after further statistical assessment by FPRP, BFDP, and Venice criteria, the positive associations reported here could be deemed to be false-positives and present only weak evidence for a causal relationship. In addition, when we performed pooled analysis and sensitivity analysis on MTHFR A1298C; all the results were negative. Conclusion: The positive relationships between MTHFR C677T and A1298C polymorphisms with the susceptibility to present with hypertension were not robust enough to withstand statistical interrogation by FPRP, BFDP, and Venice criteria. Therefore, these SNPs are probably not important in EH etiology.

The association of MTHFR (rs1801133) with hypertension in an indigenous south African population

“…Several studies performed in non-African countries also demonstrated that genotype TT or T allele of rs1801133 may increase the risk of HTN (Fan et al, 2016;Bouzidi et al, 2020;Wu et al, 2022). The discrepancies observed between these studies may be due to geographical location, ethnicity, and epigenetic mechanisms that are involved in the regulation of MTHFR gene expression (Fu et al, 2019;Meng et al, 2021). Suggesting that data linking HTN to rs1801133 remains controversial.…”

Association of MTHFR Polymorphisms with H-Type Hypertension: A Systemic Review and Network Meta-Analysis of Diagnostic Test Accuracy

“…The above association became less reliable after FPRP, BFDP, and Venice criteria tests. False positives may exist and should be further verified [ 42 ]. Both studies showed no significant association between MTHFR A1298C polymorphism and hypertension [ 41 , 42 ].…”

“…False positives may exist and should be further verified [ 42 ]. Both studies showed no significant association between MTHFR A1298C polymorphism and hypertension [ 41 , 42 ]. However, those meta-analyses only studied essential hypertension and did not focus on the association between MTHFR polymorphisms and the susceptibility to H- type hypertension.…”

Association of the methylenetetrahydrofolate reductase (MTHFR) gene variant C677T with serum homocysteine levels and the severity of ischaemic stroke: a case–control study in the southwest of China

“…11 The alteration of MTHFR activity is caused by several mutations in the MTHFR gene. 12 The MTHFR gene, which is found on chromosome 1 (1p36.3), encodes a 77 kDa dimeric protein that is the rate-limiting enzyme in the methyl cycle. 13 MTHFR catalyses only one biochemical reaction: the formation of 5-methylenetetrahydrofolate, a cosubstrate for the remethylation of Hcy to methionine.…”

“…13 MTHFR catalyses only one biochemical reaction: the formation of 5-methylenetetrahydrofolate, a cosubstrate for the remethylation of Hcy to methionine. 12 MTHFR C677T (C substitution at base pair 677) is a common MTHFR gene mutation that causes alanine to be replaced by valine at position 222 of the encoded protein product. 14 Previous research has linked TT variants of the MTHFR C677T polymorphism to elevated serum Hcy concentrations and the severity of ischaemic stroke, implying an important role as a marker of ischaemic stroke.…”