MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies

Background

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent.

Methods and Findings

Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (P _{heterogeneity} = 0.000) and publication bias (P _egger = 0.039), but it turned into null after the trim-and-fill method was implemented (OR = 1.12, 95% CI = 0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (P _{heterogeneity} = 0.150, OR = 1.16, 95% CI = 1.05–1.29) and publication bias (P _egger = 0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size.

Conclusions

Both infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs.     

Association between Methylenetetrahydrofolate Reductase C677T Polymorphism and Susceptibility to Cervical Cancer: A Meta-Analysis

Background

To assess the association between MTHFR polymorphism and cervical cancer risk, a meta-analysis was performed.

Methods

Based on comprehensive searches of the PubMed, Embase, and Web of Science databases, we identified outcome data from all articles estimating the association between MTHFR polymorphism and cervical cancer risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.

Results

A total of 12 studies with 2,924 cases (331 cervical intraepithelial neoplasia (CIN) I, 742 CIN II/III, 1851 invasive cervical cancer) and 2,581 controls were identified. There was no significant association between MTHFR C677T polymorphism and CIN I risk (T vs. C, OR = 1.10, 95% CI = 0.92–1.31; TT vs. CC, OR = 1.14, 95% CI = 0.78–1.68; TT+CT vs. CC, OR = 1.22, 95% CI = 0.94–1.58; TT vs. CT+CC, OR = 0.99, 95% CI = 0.70–1.40). For the CIN II/III, lack of an association was also found (T vs. C, OR = 1.08, 95% CI = 0.95–1.23; TT vs. CC, OR = 1.15, 95% CI = 0.87–1.52; TT+CT vs. CC, OR = 1.13, 95% CI = 0.94–1.35; TT vs. CT+CC, OR = 1.07, 95% CI = 0.83–1.38). The T allele had significant association to susceptibility of invasive cervical cancer in recessive model (TT vs. CT+CC, OR = 1.23, 95% CI = 1.02–1.49). On subgroup analysis by ethnicity, similarly significant differences in T vs. C, TT vs. CC, and recessive model were found in Asians.

Conclusion

The present meta-analysis suggested that MTHFR C677T polymorphism were to substantially contribute to invasive cervical cancer in recessive model.     

Association between 1p11-rs11249433 Polymorphism and Breast Cancer Susceptibility: Evidence from 15 Case-Control Studies

Genome-wide association studies have identified SNP rs11249433 at chromosome 1p11 as a new breast cancer (BC) susceptibility locus in populations of European descent. Since then, the relationship between 1p11- rs11249433 and breast cancer has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 15 studies involving a total of 90,154 cases and 137,238 controls for 1p11-rs11249433 polymorphism to evaluate its effect on genetic susceptibility for breast cancer. An overall random effects odds ratio of 1.09 (95% CI: 1.06-1.12, P<10^-5) was found for rs11249433-G variant. Significant results were also observed for heterozygous (OR=1.09, 95% CI: 1.05-1.12, P<10^-5) and homozygote (OR=1.14, 95% CI: 1.08-1.21, P<10^-5). There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. After stratified by ethnicity, significant associations were found among Caucasians. However, no significant associations were detected among East Asian and African populations. In addition, we found that rs11249433 polymorphism on 1p11 confer risk, exclusively for ER-positive tumors with per-allele OR of 1.13 (95% CI: 1.08-1.18; P <10^-5) compared to ER-negative tumors of 1.01 (95% CI: 0.98-1.04; P=0.49). Similar results were also observed when stratified by PR status. Our findings demonstrated that rs11249433-G allele is a risk-conferring factor for the development of breast cancer, especially in Caucasians.     

Maternal Methylenetetrahydrofolate Reductase C677T Polymorphism and Down Syndrome Risk: A Meta-Analysis from 34 Studies

Background

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate metabolic pathway which catalyzes the irreversible conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-methyltetrahydrofolate donates methyl group for the methylation of homocysteine to methionine. Several studies have investigated maternal MTHFR C677T polymorphism as a risk factor for DS, but the results were controversial and inconclusive. To come into a conclusive estimate, authors performed a meta-analysis.

Aim

A meta-analysis of published case control studies was performed to investigate the association between maternal MTHFR C677T polymorphism and Down syndrome.

Methods

PubMed, Google Scholar, Elsevier, Springer Link databases were searched to select the eligible case control studies using appropriate keywords. The pooled odds ratio (OR) with 95%confidence interval were calculated for risk assessment.

Results

Thirty four studies with 3,098 DS case mothers and 4,852 control mothers were included in the present meta-analysis. The pooled OR was estimated under five genetic models and significant association was found between maternal MTHFR 677C>T polymorphism and Down syndrome under four genetic models except recessive model (for T vs. C, OR = 1.26, 95% CI = 1.09–1.46, p = 0.001; for TT vs. CC, OR = 1.49, 95% CI = 1.13–1.97, p = 0.008; for CT vs. CC, OR = 1.29, 95% CI = 1.10–1.51, p = 0.001; for TT+CT vs. CC, OR = 1.35, 95% CI = 1.13–1.60, p = 0.0008; for TT vs. CT+CC, OR = 0.76, 95% CI = 0.60–0.94, p = 0.01).

Conclusion

The results of the present meta-analysis support that maternal MTHFR C677T polymorphism is a risk factor for DS- affected pregnancy.     

DNMT1错义突变与神经管畸形易感性的相关性研究

DNMT1(DNA(cytosine-5)-methyltransferase 1)在神经管的闭合过程中发挥重要作用,已有研究表明,DNMT1敲除的小鼠会出现神经管畸形(neural tube defects,NTDs)的表型.为了进一步探索DNMT1基因错义突变与神经管畸形发生的相关性,本研究对来自中国汉族人群的10...     

Investigation of MTHFR C677T Gene Polymorphism, Biochemical and Clinical Parameters in Turkish Migraine Patients: Association with Allodynia and Fatigue

We investigated whether there is any relationship between biochemical and clinical parameters of migraine and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism, associated with the migraine subtypes, symptoms, and gender. A total of 150 migraine patients with and without aura (MA and MO) and 107 non-sufferers were included in the study. Biochemical and clinical parameters were measured and genetic analysis was performed. The MTFHR C677T genotype was significantly higher in the migraine group (p = 0.000). The CT genotype frequency of individuals with a family history of migraine was significantly higher (p = 0.025). This genotype frequency was higher in patients who suffer from compression, allodynia, fatigue, and sleeplessness (p = 0.027, 0.023, 0.006, and 0.05, respectively). Homocysteine and total cholesterol levels were significantly higher in the migraine group than the control group (p = 0.007 and 0.010, respectively). However, the other biochemical and clinical parameters did not differ from each other (p > 0.05), with only attack frequency being significantly higher in the MO group (p = 0.005). While the folate and HDL levels were significantly higher in females (p = 0.001 and 0.000, respectively), the homocysteine and triglyceride levels were significantly higher in males (p = 0.000 for each one). BMIs were significantly lower in the control than the migraine group (p = 0.021); however, an association between the C677T variant and BMI was not found (p = 0.787) in the migraine group. An association between the MTHFR C667T polymorphism and migraine susceptibility was found. Additional studies including genetic, clinic, and biochemical parameters should be conducted to better understand the disease.     

Prevalence of MTHFR C677T Single Nucleotide Polymorphism in Genetically Isolated Populations in Jordan

Methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism is a major inherited risk factor of venous thromboembolism. We sought to determine its prevalence in genetically isolated populations of Chechens and Circassians in Jordan. The MTHFR C677T mutation was analyzed from blood samples taken from 120 random unrelated Chechens and 72 Circassians. The prevalence of the MTHFR mutation in the Chechen population was 27.5% (allele frequency 15%); the prevalence among the Circassians was 50% (allele frequency 29.2%). The prevalence in the Chechen population is similar to that in Jordan and other world populations, but it is higher in the Circassian population. This study will contribute to understanding the interaction between genetic and environmental risk factors underlying thrombosis and will be useful in deciding which genetic variants should be tested in a clinical genetic testing service.     

Methylenetetrahydrofolate Reductase C677T Polymorphism and Type 2 Diabetes Mellitus in Chinese Population: A Meta-Analysis of 29 Case-Control Studies

Background

Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, had significant effects on the homocysteine levels. The common functional MTHFR C677T polymorphism had been extensively researched. Several studies had evaluated the relationship between MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM), but the results were still controversial in the Chinese Han population. This meta-analysis was conducted to evaluate the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population.

Methods

We searched the relevant studies in multiple electronic databases, which published up to December 2013. We reviewed and extracted data from all the included studies on the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) were used to evaluate the relationship. Fixed-effects and random-effects meta-analysis were used to pool ORs by the heterogeneity. Publication bias and sensitivity analysis were also examined.

Results

29 studies were finally included in our meta-analysis, which contained 4656 individuals with T2DM and 2127 healthy controls. There was a significant relationship between MTHFR C677T polymorphism and T2DM under dominant (OR: 1.70, 95% CI: 1.42–2.02), recessive (OR: 1.48, 95% CI: 1.21–1.80), homozygous (OR: 1.89, 95% CI: 1.47–2.42), heterozygous (OR: 1.58, 95% CI: 1.33–1.87), and additive (OR: 1.46, 95% CI: 1.28–1.68) genetic model in a random-effects model. Subgroup analysis also reached similar results. Sensitivity analysis indicated that the overall result were dependable.

Conclusions

There was a significant relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The results of our meta-analysis suggested that MTHFR 677T allele might be a risk genetic factor of T2DM in the Chinese Han population.     

Association between MTHFR C677T polymorphism and primary open-angle glaucoma: A meta-analysis

Epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and primary open-angle glaucoma (POAG) risk. However, the results remain conflicting. The aim of this study was to investigate the association between MTHFRC677T polymorphism and POAG risk. All genetic association studies on MTHFR C677T polymorphism and POAG were systematically searched by the electronic databases PubMed, Embase and Web of Science. Study selection, data abstraction and study quality evaluation were conducted in duplicate independently. The strength of association between MTHFR C677T polymorphism and POAG was measured by odds ratios (ORs) and 95% confidence intervals (CIs). Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 10 studies including 1224 cases and 1105 controls were included in our final meta-analysis. There was no evidence of significant association of the overall population (for allelic model: OR = 1.17, 95% CI = 0.94–1.46; for additive model: OR = 1.15, 95% CI = 0.85–1.57; for dominant model: OR = 1.19, 95% CI = 0.92–1.55 and for recessive model: OR = 1.11, 95% CI = 0.83–1.49). Significant associations were found between MTHFR C677T polymorphisms and POAG in allelic model (OR = 1.39, 95% CI = 1.05–1.83) and additive model (OR = 1.88, 95% CI = 1.04–3.43) for population-based (PB) subgroup. This meta-analysis suggested that there were significant associations between MTHFR C677T polymorphism and POAG in allelic model and additive model for PB subgroup which indicated that the T allele or TT genotype might increase the risk of POAG, whereas no evidence of significant association was shown of the overall studied population. However, this conclusion should be interpreted cautiously. More large sample-size and multi-ethnicity studies with well-defined POAG patients and well-study design are needed in the future study.     

Association between MTHFR C677T polymorphism and osteonecrosis of the femoral head: a meta-analysis

The results of studies on association between the C677T polymorphism of the 5,10-methylene-tetrahydrofolate reductase (MTHFR) gene and osteonecrosis of the femoral head (ONFH) are controversial. To derive a more precise estimation of the relationship between the MTHFR C677T polymorphism and ONFH, a meta-analysis was performed. Eight studies on MTHFR C677T association with ONFH were searched up to April 2011, and the genotype frequencies in control group were consistent with Hardy–Weinberg equilibrium. The effect summary odds ratio (OR) and 95% confidence intervals were obtained. Publication bias was tested by funnel plot, Egger’s regression test, and heterogeneity was assessed. Eight studies containing 778 cases and 1,162 controls were included. Heterogeneity was observed (χ ² = 18.58, P = 0.01). Under the random effects model, the common OR was 1.38 (95% CI: 0.92–2.08; P = 0.12). In the subgroup meta-analysis, there was an association between MTHFR C677T polymorphism and ONFH in non-Asian population for CT + TT vs. CC (OR = 1.72; 95% CI: 1.21–2.43; P = 0.002; I ²  = 37.9%, P = 0.17), but not for Asian population (OR = 0.88; 95% CI: 0.66–1.66; P = 0.35; I ²  = 45.4%, P = 0.16). There was heterogeneity between studies and no clear evidence of an association on a worldwide population. When stratifying for the race, this meta-analysis did not provide an evidence of confirming association between MTHFR C677T polymorphism and ONFH. The large sample and well-designed study based on different ethnic groups should be considered in future associated studies to clarify the association of MTHFR C677T polymorphism with ONFH susceptibility.     

Methylenetetrahydrofolate Reductase C677T Polymorphism and Susceptibility to Cervical Cancer and Cervical Intraepithelial Neoplasia: A Meta-Analysis

Background

A number of studies have explored the association between methyl enetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia (CIN). However, results remained controversial. To address this gap, we decided to conduct a meta-analysis of all available published studies.

Methods

Electronic literature searches of the PubMed, EmBase and Medline databases were performed up to April 30, 2012. Fixed-effects or random-effects model was used to calculate the pooled ORs for different genetic models.

Results

A total of 12 case-control studies were ultimately identified. No statistical correlation was found between C677T variants and cervical cancer for the overall population. However, subgroup analyses on the White women pointed to a significant protective effect for individuals heterozygous or homozygous for the T-allele (for CT vs. CC: OR = 0.72, 95% CI 0.59–0.88; for TT vs. CC: OR = 0.69, 95% CI = 0.49–0.97; for CT+TT vs. CC: OR = 0.71, 95% CI 0.59–0.86). C677T variants were associated with neither combined nor stratified CIN among the overall population.

Conclusions

This meta-analysis suggests that White women with mutant C677T genotypes might have a lower risk of cervical cancer, yet lacking enough statistical robustness. Further investigations are needed to get more insight into the role of this polymorphism in cervical carcinogenesis.     

rs3746444 Polymorphism and Susceptibility to Hepatocellular Carcinoma: Evidence from Published Studies

The present study was undertaken to quantitatively evaluate the association between rs3746444 polymorphism and HCC risk. In this analysis with 667 cancer cases and 1,006 control subjects, we summarized 4 eligible case–control studies by searching databases of PubMed, EMBASE, and CNKI. The strength of the association was assessed by calculating odds ratios (ORs) with 95 % confidence intervals (CIs) with the fixed-effects model. We found that neither the allele frequency nor genotype distribution of this polymorphism was associated with risk of HCC in any genetic model. Similarly, no associations were suggested either in subgroup analyses by ethnicity or by source of control. Our research suggested that rs3746444 polymorphism may not be a risk factor for HCC. However, well-designed studies with a larger sample size are needed to confirm these findings.     

MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies

Background and Objectives

Methylenetetrahydrofolate reductase (MTHFR) polymorphism may be a risk factor for male infertility. However, the epidemiologic studies showed inconsistent results regarding MTHFR polymorphism and the risk of male infertility. Therefore, we performed a meta-analysis of published case-control studies to re-examine the controversy.

Methods

Electronic searches of PubMed, EMBASE, Google Scholar and China National Knowledge Infrastructure (CNKI) were conducted to select eligible literatures for this meta-analysis (updated to June 19, 2014). According to our inclusion criteria and the Newcastle-Ottawa Scale (NOS), only high quality studies that observed the association between MTHFR polymorphism and male infertility risk were included. Crude odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of association between the MTHFR polymorphism and male infertility risk.

Results

Twenty-six studies involving 5,575 cases and 5,447 controls were recruited. Overall, MTHFR 677C>T polymorphism showed significant associations with male infertility risk in both fixed effects (CT+TT vs. CC: OR = 1.34, 95% CI: 1.23–1.46) and random effects models (CT+TT vs. CC: OR = 1.39, 95% CI: 1.19–1.62). Further, when stratified by ethnicity, sperm concentration and control sources, the similar results were observed in Asians, Caucasians, Azoo or OAT subgroup and both in population-based and hospital-based controls. Nevertheless, no significant association was only observed in oligo subgroup.

Conclusions

Our results indicated that the MTHFR polymorphism is associated with an increased risk of male infertility. Further well-designed analytical studies are necessary to confirm our conclusions and evaluate gene-environment interactions with male infertility risk.     

Association between MCP-1 -2518A/G Polymorphism and Cancer Risk: Evidence from 19 Case-Control Studies

Background

Single nucleotide polymorphisms (SNPs) may affect the development of diseases. The -2518A/G polymorphism in the regulatory region of the monocyte chemo-attractant protein-1 (MCP-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to obtain a more precise estimation of the relationship between the -2518A/G polymorphism and cancer risk.

Methodology/Principal Findings

We performed a meta-analysis, including 4,162 cases and 5,173 controls, to evaluate the strength of the association between the −2518A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Overall, the results indicated that the −2518A/G polymorphism was not statistically associated with cancer risk. However, sub-group analysis revealed that individuals with GG genotypes showed an increased risk of cancer in digestive system compared with carriers of the A allele (GG vs. AA: OR = 1.43, 95%CI = 1.05–1.96, P_{heterogeneity} = 0.08; GG vs. AG/AA: OR = 1.29, 95%CI = 1.02–1.64, P_{heterogeneity} = 0.14). In addition, the increased risk of GG genotype was also observed in Caucasians (GG vs. AG/AA: OR = 1.81, 95%CI = 1.10–2.96, P_{heterogeneity} = 0.02).

Conclusion

This meta-analysis suggests that the MCP-1 −2518A/G polymorphism may have some relation to digestive system cancer susceptibility or cancer development in Caucasian. Large-scale and well-designed case-control studies are needed to validate the findings.     

Association of PDE4B Polymorphisms with Susceptibility to Schizophrenia: A Meta-Analysis of Case-Control Studies

Background

The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis.

Methods

A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I² > 50%) existed, otherwise the fixed effects model was used.

Results

Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76–0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72–0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64–0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75–1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76–1.00, P = 0.055).

Conclusion

This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia.     

不明原因复发性自然流产夫妇MTHFR C677T位点多态性分析

目的：分析不明原因复发性自然流产（URSA）夫妇与亚甲基四氢叶酸还原酶基因C677T（MTHFR C677T）位点多态性的关 联性研究。方法：采用聚合酶链式反应- 限制性片段长度多态性( PCR-RFLP)对URSA 组和对照组各50 对夫妇的外周血进行 MTHFR C677T 的位点多态性进行检测分析。结果：URSA 组MTHFR 基因677 位点的T/T、C/T+T/T 基因型的发生频率显著高于 对照组,差异具有统计学意义(P<0.05),而对照组MTHFR 基因677 位点的C/C 基因型发生频率显著高于URSA 组（P<0.05）,两 组MTHFR 基因677 位点的C/T 基因型比较无明显差异（P>0.05)。另外URSA 组等位基因T 明显高于C 的频率,且URSA 组等 位基因T 发生频率显著高于对照组,对照组等位基因C 发生频率显著高于USRA 组,差异均具有统计学意义（P<0.05）。结论： MTHFR C677T 位点的多态性与URSA 的发生密切相关,是该病的重要遗传风险因素。     

Correlations of MTHFR 677C>T Polymorphism with Cardiovascular Disease in Patients with End-Stage Renal Disease: A Meta-Analysis

ObjectiveThis meta-analysis was conducted to evaluate the correlations of a common polymorphism (677C>T) in the methylenetetrahydrofolate reductase (MTHFR) gene with risk of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD).MethodThe following electronic databases were searched without language restrictions: Web of Science (1945∼2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966∼2013), EMBASE (1980∼2013), CINAHL (1982∼2013) and the Chinese Biomedical Database (CBM) (1982∼2013). Meta-analysis was performed using STATA statistical software. Odds ratios (ORs) with their 95% confidence intervals (95%CIs) were calculated.ResultsEight cohort studies met all inclusion criteria and were included in this meta-analysis. A total of 2,292 ESRD patients with CVD were involved in this meta-analysis. Our meta-analysis results revealed that the MTHFR 677C>T polymorphism might increase the risk of CVD in ESRD patients (TT vs. CC: OR = 2.75, 95%CI = 1.35∼5.59, P = 0.005; CT+TT vs. CC: OR = 1.39, 95%CI = 1.09∼1.78, P = 0.008; TT vs. CC+CT: OR = 2.52, 95%CI = 1.25∼5.09, P = 0.010; respectively). Further subgroup analysis by ethnicity suggested that the MTHFR 677C>T polymorphism was associated with an elevated risk for CVD in ESRD patients among Asians (TT vs. CC: OR = 3.38, 95%CI = 1.11∼10.28, P = 0.032; CT+TT vs. CC: OR = 1.44, 95%CI = 1.05∼1.97, P = 0.022; TT vs. CC+CT: OR = 3.15, 95%CI = 1.02∼9.72, P = 0.046; respectively), but not among Africans or Caucasians (all P>0.05).ConclusionOur findings indicate that the MTHFR 677C>T polymorphism may be associated with an elevated risk for CVD in ESRD patients, especially among Asians.     

Prenatal Exposure to Maternal Depressed Mood and the MTHFR C677T Variant Affect SLC6A4 Methylation in Infants at Birth

Background

Prenatal and early postnatal exposure to maternal depression may “program” childhood behavior via epigenetic processes such as DNA methylation. Methylenetetrahydro-folate reductase (MTHFR) is an important enzyme in the generation of methyl groups for DNA methylation. The common MTHFR C677T variant is associated with depression in men and non-pregnant women, and with global changes in DNA methylation. This study investigated the effect of maternal MTHFR C677T genotype on antenatal maternal mood, and their impact on the gene-specific methylation in pregnant women and their newborn infants. The methylation status of SLC6A4, which encodes the transmembrane serotonin transporter, and BDNF, which encodes brain derived neurotrophic factor, were assessed because of their potential role in behaviour.

Methods/Principal Findings

Depressed mood was assessed by the Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale for Depression (HAM-D) in women (n = 82, all taking folate) during the 2^nd and 3^rd trimesters of pregnancy. The methylation status of SLC6A4 and BDNF were assessed in 3rd trimester maternal peripheral leukocytes and in umbilical cord leukocytes collected from their infants at birth. Women with the MTHFR 677TT genotype had greater 2^nd trimester depressed mood (p<0.05). Increased 2^nd trimester maternal depressed mood (EPDS scores) was associated with decreased maternal and infant SLC6A4 promoter methylation (p<0.05), but had no effect on BDNF promoter methylation.

Conclusions

These findings show that the MTHFR C677T variant is associated with greater depressed mood during pregnancy. We further showed that prenatal exposure to maternal depressed mood affects gene-specific DNA methylation patterns. These findings support the concept that alterations in epigenetic processes may contribute to developmental programming of behaviour by maternal depression.