Methylenetetrahydrofolate Reductase Gene rs1801133 and rs1801131 Polymorphisms and Essential Hypertension Risk: A Comprehensive Analysis

Abstract

Background: Essential hypertension (EH) is a common and multifactorial disorder that is likely to be influenced by multiple genes. The methylenetetrahydrofolate reductase (MTHFR) gene rs1801133 and rs1801131 polymorphisms influence MTHFR enzyme activity and plasma homocysteine concentration. In addition, variations in MTHFR functions likely play roles in the etiology of EH. Thus far, a large number of studies investigating the associations between the MTHFR polymorphisms and EH have provided controversial or inconclusive results. To better assess the purported relationship, we performed a comprehensive analysis of 52 published studies. Objective and Methods. Eligible studies were identified by searching the PubMed, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the potential association between the MTHFR rs1801133 polymorphism and EH.

Results: Overall, 10712 patients and 11916 controls were involved; we observed significantly increased association between the MTHFR rs1801133 polymorphism and EH risk (such as T vs. C: OR = 1.38, 95% CI = 1.25 - 1.54, P ≤ 0.001), with similar results evident within race subgroups (such as Asian: T vs. C: OR = 1.47, 95% CI = 1.30 - 1.67, P ≤ 0.001; compared to Chinese: T vs. C: OR = 1.54, 95% CI = 1.33 - 1.79, P ≤ 0.001). Similar associations were also found in subgroups defined by the source of controls and genotype methods. To our regret, based on the limited studies, no association was detected for rs1801131 polymorphism.

Conclusions: Our study provides evidence that the MTHFR rs1801133 null genotype may increase EH risk. Future studies with larger sample sizes are warranted to evaluate this association in more detail.

Figure 1

Flowchart illustrating the search strategy used to identify association studies for MTHFR gene rs1801133 polymorphisms and EH risk.

Figure 2

(a) The MAF of minor allele (mutant allele) for MTHFR gene rs1801133 polymorphism from the 1000 Genomes online database. (b) The frequency about T-allele or C-allele both in the case and control groups. (c) The distribution of each genotype from online GTEx Portal (https://www.gtexportal.org/home/). (d) The risk frequency of rs1801133 polymorphism to several diseases from TCGA database.

Figure 3

(a) The MAF of minor allele (mutant allele) for MTHFR gene rs1801131 polymorphism from the 1000 Genomes online database. (b) The frequency about T-allele or C-allele both in the case and control groups. (c) The distribution of each genotype from online GTEx Portal (https://www.gtexportal.org/home/). (d) The risk frequency of rs1801131 polymorphism to several diseases from TCGA database.

Figure 4

T-allele frequencies for the MTHFR gene rs1801133 polymorphism among cases/controls stratified by subgroups in T-allele vs. C-allele model in regular ethnic subgroup.

Figure 5

T-allele frequencies for the MTHFR gene rs1801133 polymorphism among cases/controls stratified by subgroups in T-allele vs. C-allele model in Chinese/non-Chinese subgroup.

Figure 6

T-allele frequencies for the MTHFR gene rs1801133 polymorphism among cases/controls stratified by subgroups in T-allele vs. C-allele model in source of control subgroup.

Figure 7

T-allele frequencies for the MTHFR gene rs1801133 polymorphism among cases/controls stratified by subgroups in T-allele vs. C-allele model in genotype method subgroup by random-effect model.

Figure 8

T-allele frequencies for the MTHFR gene rs1801133 polymorphism among cases/controls stratified by subgroups in T-allele vs. C-allele model in genotype method subgroup by fixed effect model.

Figure 9

(a) Begg's funnel plot for publication bias test (T-allele vs. C-allele). (b) Egger's publication bias plot (T-allele vs. C-allele). (c) Sensitivity analysis (T-allele vs. C-allele).

Figure 10

Random-effect metaregression of log odds ratio versus publication year (a), regular ethnicity (b), Chinese/non-Chinese (c), source of control (d), and genotype methods (e), respectively, in EH.

Figure 11

Human MTHFR interaction network with other genes obtained from STRING server. At least 10 genes have been indicated to correlate with MTHFR gene. (a) The gene-gene interaction. (b) The detail of relative ten core genes.