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Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke.
Qin, X, Spence, JD, Li, J, Zhang, Y, Li, Y, Sun, N, Liang, M, Song, Y, Zhang, Y, Wang, B, et al
Neurology. 2020;(11):e1126-e1136
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Abstract
OBJECTIVE We evaluated the interaction of serum folate and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on the risk of first ischemic stroke and on the efficacy of folic acid treatment in prevention of first ischemic stroke. METHODS A total of 20,702 hypertensive adults were randomized to a double-blind treatment of daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months. RESULTS Median values of folate and B12 concentrations at baseline were 8.1 ng/mL and 280.2 pmol/L, respectively. Over a median of 4.5 years, among those not receiving folic acid, participants with baseline serum B12 or serum folate above the median had a significantly lower risk of first ischemic stroke (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57-0.96), especially in those with MTHFR 677 CC genotype (wild-type) (HR, 0.49; 95% CI, 0.31-0.78). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B12 below the median (2.3% in enalapril-folic acid group vs 3.6% in enalapril-only group; HR, 0.62; 95% CI, 0.46-0.86), particularly in MTHFR 677 CC carriers (1.6% vs 4.9%; HR, 0.24; 95% CI, 0.11-0.55). However, TT homozygotes responded better with both folate and B12 levels above the median (HR, 0.28; 95% CI, 0.10-0.75). CONCLUSIONS The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B12. Effect of folic acid treatment was greatest in patients with low folate and B12 with the CC genotype, and with high folate and B12 with the TT genotype.
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MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment.
Huang, X, Qin, X, Yang, W, Liu, L, Jiang, C, Zhang, X, Jiang, S, Bao, H, Su, H, Li, P, et al
Arteriosclerosis, thrombosis, and vascular biology. 2018;(3):679-685
Abstract
OBJECTIVE This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.
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Homocysteine and all-cause mortality in hypertensive adults without pre-existing cardiovascular conditions: Effect modification by MTHFR C677T polymorphism.
Xu, B, Kong, X, Xu, R, Song, Y, Liu, L, Zhou, Z, Gu, R, Shi, X, Zhao, M, Huang, X, et al
Medicine. 2017;(8):e5862
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Abstract
BACKGROUND Previous studies support an association between elevated total homocysteine (tHcy) levels and increased all-cause mortality. However, few prospective studies have examined this association in hypertensive patients, and/or tested any effect modification by the methylene tetrahydrofolate reductase (MTHFR) C677T genotype. METHODS This was a post hoc analysis of the China Stroke Primary Prevention Trial. Serum tHcy and folate were measured at baseline. Individual MTHFR C677T genotype (CC, CT, and TT) was determined. Evidence for death included death certificates or home visits. Cumulative hazards of all-cause mortality by tHcy quartiles were estimated using the Kaplan-Meier method, and group differences were compared by log-rank tests. Hazard ratios (HRs) and 95% confidence intervals were estimated by Cox proportional-hazard regression models, adjusting for age, sex, baseline folate, vitamin B12, blood pressure, body mass index, smoking and alcohol drinking status, study center, total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting glucose, creatinine, and treatment group. Potential effect modification by the MTHFR genotype on the relationship between tHcy and all-cause mortality was tested. RESULTS The analyses included 20,424 hypertensive patients (41% males) without a history of myocardial infarction or stroke. Baseline mean age (SD) was 60 ± 7.5 years and mean (SD) serum tHcy was 14.5 ± 8.4 μmol/L. After a mean follow-up period of 4.5 years, there were 612 (3%) all-cause deaths. Kaplan-Meier survival curves revealed a graded relationship between tHcy quartiles and all-cause mortality. The HRs, using the lowest quartile as the reference, were 1.2, 1.2, and 1.5 in Q2, Q3, and Q4, respectively. A linear trend test, using natural log-transformed tHcy, resulted in an HR of 1.5 (95% confidence interval 1.2-1.9, P < .001) after adjustment for lifestyle and health-related variables. Whereas the MTHFR genotype alone had little effect on mortality, it significantly modified the tHcy-mortality association, which was much stronger in the CC/CT genotype than in the TT genotype (P for interaction < 0.05). CONCLUSIONS Among Chinese hypertensive patients without cardiovascular comorbidities, elevated tHcy was a significant risk marker for death from all causes, and the association was subject to effect modification by MTHFR genotypes. If confirmed that tHcy and MTHFR genotypes may serve as useful biomarkers for mortality risk assessment and targeted intervention.
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MTHFR C677T polymorphism contributes to colorectal cancer susceptibility: evidence from 61 case-control studies.
Sheng, X, Zhang, Y, Zhao, E, Lu, S, Zheng, X, Ge, H, Lu, W
Molecular biology reports. 2012;(10):9669-79
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is believed to be involved in folate metabolism which plays a critical role in carcinogenesis. To date, many case-control studies have investigated the association between MTHFR C677T polymorphism and colorectal cancer risk. However, the results were inconsistent. In order to derive a more precise estimation of the association, we conducted this meta-analysis. This meta-analysis recruited 61 published studies which were selected by a search of PubMed up to 31st September 2011, including 16,111 colorectal cancer cases and 23,192 controls. We used crude odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association between MTHFR C677T polymorphism and colorectal cancer susceptibility. Our results showed that MTHFR C667T polymorphism contributed to the decreased colorectal cancer risk in overall population (for TT vs. CC: OR = 0.89, 95 % CI = 0.82-0.97; for TT vs. CT/CC: OR = 0.88, 95 % CI = 0.83-0.92). In subgroup analysis by ethnicity, the results also indicated a correlation between the T allele of MTHFR C667T and the colorectal cancer risk in Asian population (for TT vs. CC: OR = 0.82, 95 % CI = 0.69-0.97; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.74-0.90). Additionally, the correlation was also observed in male subgroup in sub-analysis by gender (for TT vs. CC: OR = 0.82, 95 % CI = 0.71-0.93; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.71-0.92). In summary, our meta-analysis strongly indicated the MTHFR C667T polymorphism was associated with a reduced risk of CRC.