1,25(OH)2D3 improves diabetic wound healing by modulating inflammation and promoting angiogenesis.

Vitamin D was found to regulate inflammatory response and angiogenesis, which were often impaired in diabetic wound healing. This study aimed to investigate the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on diabetic wound healing both in vivo and in vitro. Diabetes was induced by high-fat diet combined with streptozotocin. After four weeks of establishing diabetic mouse model, full-thickness excisional wounds were created on their dorsal skin. Then 1,25(OH)2D3 was administered via intraperitoneal injection for 14 consecutive days. Human umbilical vein endothelial cells (HUVECs) were cultured with normal glucose, high glucose, high glucose plus 1,25(OH)2D3. Cell proliferation, migration, tube formation, and expression levels of relevant pathway components were measured. Intervention with 1,25(OH)2D3 significantly increased wound closure rates of diabetic mice. During the inflammatory phase, 1,25(OH)2D3 alleviated excessive inflammation and promoted the transition of macrophages from M1 to M2 phenotype. Regarding vascular endothelial function, 1,25(OH)2D3 significantly up-regulated eNOS protein expression and inhibited Vcam-1 mRNA expression in diabetic mice (P < 0.05). As for angiogenesis, 1,25(OH)2D3 markedly increased CD31-positive area, the protein and mRNA expression of VEGF, VEGFR2, PDGF, and PDGFRß, as well as the mRNA expression of Bfgf and Egfr (P < 0.05). In vitro, 1,25(OH)2D3 restored impaired cell proliferation, migration, and tube formation induced by high-glucose, and up-regulated expression of angiogenesis-related factors. These protective effects might be mediated through PI3K/AKT/HIF-1α pathway. These findings suggested that 1,25(OH)2D3 accelerated diabetic wound healing by modulating inflammation, restoring vascular endothelial dysfunction, and promoting angiogenesis.

Interactions of arsenic exposure, arsenic metabolism with red blood cell folate on the risk of hypertension: NHANES 2007-2016.

PURPOSE: Arsenic exposure was associated with hypertension, and arsenic metabolism might be influenced by folate concentrations. Thus, this study aimed to explore the interaction between arsenic exposure and metabolism with folate concentrations on hypertension. METHODS: We studied 6643 adults aged 20 years and older who participated in the National Health and Nutrition Examination Survey from 2007 through 2016. Urinary total arsenic (UTAs), the percentage of urinary dimethylarsinic acid (DMA%), serum and red blood cell (RBC) folate were collected. Logistic regression and restricted cubic spline (RCS) analyses were performed to determine the association and dose-response relationship. Interaction analyses were conducted on both additive and multiplicative scales. RESULTS: UTAs (median: 7.05 µg/L) was positively associated with hypertension risk, and the adjusted OR was 1.44 (95% CI: 1.06-1.95) when comparing the third with the lowest quartile. And participants with the highest quintile of RBC folate had increased hypertension risk than those with the lowest quintile (adjusted OR = 1.43, 95% CI: 1.06-1.94). Significant additive interaction was observed between excessive RBC folate with high UTAs (AP = 0.323, 95% CI: 0.083-0.564) and low DMA% (AP = 0.381, 95% CI: 0.119-0.643) on hypertension risk. CONCLUSION: Our results suggested significant interactions between high UTAs and low DMA% with excessive RBC folate on hypertension risk.

Additive interaction of urinary total arsenic concentrations with being overweight/obesity on the risk of insulin resistance: NHANES 2007-2016.

Arsenic exposure has been associated with the risk of diabetes or insulin resistance (IR), which are also related with overweight/obesity. This study aimed to explore the interaction between arsenic exposure and being overweight/obesity on diabetes or IR risk. Data from the National Health and Nutrition Examination Survey (NHANES) in cycles 2007-2016 were used to assess the interaction between arsenic exposure and being overweight/obesity on IR or diabetes risk among adults. Urinary total arsenic concentrations (UTAs) were used as a biomarker for arsenic exposure. The homeostasis model of insulin resistance (HOMA-IR) was calculated to index IR. Survey-weighted logistic regression and restricted cubic spline (RCS) analyses were performed to determine the association and dose-response relationship between UTAs and IR or diabetes risk. Additive interaction was evaluated by relative excess risk due to interaction (RERI), attributable proportion of interaction (AP), and synergy index (S). A total of 3,133 participants were included. The median (interquartile range) UTAs were 6.61 (3.83, 13.95) µg/L. The adjusted OR of IR was 1.40 (95% CI: 0.99-1.97) for UTAs, comparing the highest with the lowest quartile. And significant additive interaction was observed between high UTAs and being overweight/obesity on IR risk (RERI = 2.47, 95% CI: 0.30-4.63; AP = 0.29, 95% CI: 0.07-0.50; S = 1.48, 95% CI: 1.03-2.13). Our results suggested that there might be a potential additive interaction between high UTAs with being overweight/obesity on diabetes risk (AP = 0.27, 95%CI: 0.04-0.51). Our results indicated an additive interaction between arsenic exposure and being overweight/obesity on IR risk.

Effects of long-term vitamin D supplementation on metabolic profile in middle-aged and elderly patients with type 2 diabetes.

To evaluate the effects of long-term vitamin D supplementation on metabolic profiles in middle-aged to elderly patients with type 2 diabetes (T2D), a randomized controlled trial was conducted among patients with T2D aged 50-70 years. A total of 270 patients underwent randomization with 135 being allocated to the vitamin D group and 135 to the control group, and participants in the vitamin D group received oral vitamin D3 (800 IU/day) for 30 months. Serum 25(OH)D and metabolic variables were measured at baseline, and after 6, 12, 18, and 30 months of intervention. After 30 months, the vitamin D group showed a greater increase in serum 25(OH)D than the control group (12.39 ± 6.99 vs 5.35 ± 5.29 ng/ml, P < 0.001). Meanwhile, changes in the levels of fasting insulin, HOMA-IR, non-high-density-lipoprotein cholesterol (non-HDL-C), high-sensitivity C-reactive protein (hs-CRP), and uric acid differed significantly between the two groups (all P < 0.05). Stratified analysis indicated that change in uric acid differed significantly between the two groups in subgroup with baseline 25(OH)D ≥ 20 ng/ml (P = 0.042) or subgroup with female patients (P = 0.034). And the change in fasting blood glucose (FBG) differed significantly between the vitamin D group (-0.30 ± 2.52 mmol/L) and the control group (0.49 ± 1.78 mmol/L, P = 0.049) among patients achieving 25(OH)D concentrations of 30 ng/ml at the end of this trial. A significant difference in the change of triglyceride was observed between the two groups among patients with obesity at baseline [0.05(-0.59, 0.23) vs 0.41(-0.01, 0.80) mmol/L, P = 0.023]. These findings suggested that long-term vitamin D supplementation significantly reduced fasting insulin, HOMA-IR, and serum concentrations of non-HDL-C, hs-CRP, and uric acid among middle-aged to elderly patients with T2D. And vitamin D status, gender, and baseline obesity may modify the effects of vitamin D supplementation.

The modification of individual factors on association between serum 25(OH)D and incident type 2 diabetes: Results from a prospective cohort study.

Several epidemiological studies have suggested an association between low vitamin D status and increased risk for type 2 diabetes (T2D). This study aimed to explore the dose-response relationship of serum 25-hydroxyvitamin D [25(OH)D] concentrations with incident T2D and the interaction between serum 25(OH)D with individual factors on T2D risk. A total of 1,926 adults without diabetes (mean age: 52.08 ± 13.82 years; 42% men) were prospectively followed for 36 months. Cox proportional hazards model and restricted cubic spline analysis were performed to assess the association and dose-response relationship between serum 25(OH)D and T2D incidence. Both additive and multiplicative interactions were calculated between serum 25(OH)D and individual factors. The net reclassification index (NRI) was used to evaluate the improvement of risk prediction of T2D by adding serum 25(OH)D to traditional risk factors. There were 114 new T2D cases over a mean follow-up of 36 months. Serum 25(OH)D was not associated with T2D incidence, and no significant dose-response relationship was found in the total population. However, stratified analyses suggested a non-linear inverse relationship among individuals with baseline fasting plasma glucose (FPG) <5.6 mmol/L (P overall = 0.061, P non-linear = 0.048). And a significant multiplicative interaction was observed between serum 25(OH)D and FPG on T2D risk (P = 0.005). In addition, we found a significant additive interaction of low serum 25(OH)D with older age (RERI = 0.897, 95% CI: 0.080-1.714; AP = 0.468, 95% CI: 0.054-0.881), male (AP = 0.441, 95% CI: 0.010-0.871), and insufficient physical activity (RERI = 0.875, 95% CI: 0.204-1.545; AP = 0.575, 95% CI: 0.039-1.111) on T2D risk. Significant additive interactions were also observed between vitamin D deficiency/insufficiency with male, overweight/obesity, and insufficient physical activity on T2D risk. Moreover, adding low serum 25(OH)D to a model containing established risk factors yielded significant improvements in the risk reclassification of T2D (NRI = 0.205, 95% CI: 0.019-0.391). Our results indicated a non-linear relationship of serum 25(OH)D concentrations with T2D risk among individuals with normal FPG and additive interactions of serum 25(OH)D with gender, overweight/obesity, and physical activity on T2D risk, suggesting the importance of outdoor exercise.

Gender-specific differences of interaction between cadmium exposure and obesity on prediabetes in the NHANES 2007-2012 population.

PURPOSE: Data from National Health and Nutrition Examination Survey (NHANES) for the years 2007-2012 were used to evaluate the interactions of cadmium (Cd) exposure with being overweight/obesity on the risk of prediabetes among adults 20 years older. METHODS: A total of 3552 subjects were included in the analysis. Urinary cadmium levels (UCd) was used as a biomarker for long-term exposure to Cd. Additive interaction was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S). RESULTS: Following covariates adjustments, we found significant associations of UCd with higher prediabetes prevalence, and this association was more apparent in males (Q4 vs Q1: OR = 1.95, 95%CI: 1.34-2.84); while overweight/obesity was associated with prediabetes both in males and in females. Additionally, there was a significant interaction between Cd exposure and being overweight/obesity on prediabetes risk among males (RERI = 1.18, 95% CI: 0.42-1.93; AP = 0.35, 95% CI: 0.12-0.58; S = 2.00, 95% CI: 0.92-4.34). CONCLUSIONS: Our results suggest that being overweight/obesity may substantially amplify the adverse effects of long-term cadmium exposure on prediabetes risk, and this interaction is more severe in male adults. Further studies are needed to confirm these findings.

Interactions of homocysteine and conventional predisposing factors on hypertension in Chinese adults.

This study aimed to investigate whether conventional predisposing factors modify the associations of homocysteine with blood pressure levels and hypertension. A total of 2615 adults were recruited from Liaoning province. An elevated homocysteine level was significantly associated with increased hypertension risk and blood pressure (all P<.05). Interaction analyses showed that homocysteine acted synergistically with age, overweight/obesity, dyslipidemia, and family history of hypertension to affect hypertension risk, and the relative excess risk due to interaction was 1.21 (95% confidence interval, 0.07-2.35), 0.72 (95% confidence interval, 0.07-1.36), 0.45 (95% confidence interval, 0.06-0.85), and 1.87 (95% confidence interval, 0.77-2.97), respectively. Increases in blood pressure were higher in patients who were overweight/obese or had a family history of hypertension than in their counterparts (all Pinteraction <.05). This study provides some strong evidence for interactions of homocysteine with conventional predisposing factors on hypertension.

Neck circumference associated with arterial blood pressures and hypertension: A cross-sectional community-based study in northern Han Chinese.

Although several studies have investigated the associations of neck circumference (NC) with arterial blood pressures (BPs) and hypertension, no such studies have been conducted among Northern Chinese population. Between April and June 2015, a total of 2631 subjects aged ≥35 years old were recruited from Northeastern China. NC and arterial BPs were measured by trained personnel. Generalized linear and logistic regression analyses were applied to examine the associations of NC with arterial BPs and hypertension risk. The optimal cut-off points of NC for predicting hypertension were assessed by the receiver operating characteristic analysis. We found that NC was significantly associated with arterial BPs and hypertension risk in the Northeastern Chinese adults, even after adjusting for many covariates including body mass index, waist circumference or waist-to-hip ratio. The optimal cut-off values for NC to predict hypertension differed with sex, age, and body mass index. Our study suggests that NC may play an independent role in predicting hypertension beyond the classical anthropometric indices, and that it could be used as a valuable anthropometric measurement for routine assessment in primary care clinics and future epidemiological studies.

Additive Interaction of MTHFR C677T and MTRR A66G Polymorphisms with Being Overweight/Obesity on the Risk of Type 2 Diabetes.

Although both methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms have been associated with type 2 diabetes (T2D), their interactions with being overweight/obesity on T2D risk remain unclear. To evaluate the associations of the two polymorphisms with T2D and their interactions with being overweight/obesity on T2D risk, a case-control study of 180 T2D patients and 350 healthy controls was conducted in northern China. Additive interaction was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S). After adjustments for age and gender, borderline significant associations of the MTHFR C677T and MTRR A66G polymorphisms with T2D were observed under recessive (OR = 1.43, 95% CI: 0.98-2.10) and dominant (OR = 1.43, 95% CI: 1.00-2.06) models, respectively. There was a significant interaction between the MTHFR 677TT genotype and being overweight/obesity on T2D risk (AP = 0.404, 95% CI: 0.047-0.761), in addition to the MTRR 66AG/GG genotypes (RERI = 1.703, 95% CI: 0.401-3.004; AP = 0.528, 95% CI: 0.223-0.834). Our findings suggest that individuals with the MTHFR 677TT or MTRR 66AG/GG genotypes are more susceptible to the detrimental effect of being overweight/obesity on T2D. Further large-scale studies are still needed to confirm our findings.

Combined genotype and haplotype distributions of MTHFR C677T and A1298C polymorphisms: A cross-sectional descriptive study of 13,473 Chinese adult women.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are, independently and/or in combination, associated with many disorders. However, data on the combined genotype and haplotype distributions of the 2 polymorphisms in Chinese population were limited.We recruited 13,473 adult women from 9 Chinese provinces, collected buccal cell samples, and determined genotypes, to estimate the combined genotype and haplotype distributions of the MTHFR C677T and A1298C polymorphisms.In the total sample, the 6 common combined genotypes were CT/AA (29.5%), TT/AA (21.9%), CC/AA (15.4%), CC/AC (14.9%), CT/AC (13.7%), and CC/CC (3.4%); the 3 frequent haplotypes were 677T-1298A (43.6%), 677C-1298A (37.9%), and 677C-1298C (17.6%). Importantly, we observed that there were 51 (0.4%) individuals with the CT/CC genotype, 92 (0.7%) with the TT/AC genotype, 17 (0.1%) with the TT/CC genotype, and that the frequency of the 677T-1298C haplotype was 0.9%. In addition, the prevalence of some combined genotypes and haplotypes varied among populations residing in different areas and even showed apparent geographical gradients. Further linkage disequilibrium analysis showed that the D' and r values were 0.883 and 0.143, respectively.In summary, the findings of our study provide further strong evidence that the MTHFR C677T and A1298C polymorphisms are usually in trans and occasionally in cis configurations. The frequencies of mutant genotype combinations were relatively higher in Chinese population than other populations, and showed geographical variations. These baseline data would be useful for future related studies and for developing health management programs.

Gender-specific interactions of MTHFR C677T and MTRR A66G polymorphisms with overweight/obesity on serum lipid levels in a Chinese Han population.

BACKGROUND: Little is known regarding the interactions of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with overweight/obesity on serum lipid profiles. The aim of the current study was to explore interactions between the two polymorphisms and overweight/obesity on four common lipid levels in a Chinese Han population and further to evaluate whether these interactions exhibit gender-specificity. METHODS: A total of 2239 participants (750 females and 1489 males) were enrolled into this study. The genotypes of the MTHFR C677T and MTRR A66G were determined by a TaqMan assay. Overweight and obesity were defined as a body mass index between 24 and 27.99 and ≥ 28 kg/m2, respectively. The interactions were examined by factorial design covariance analysis, and further multiple comparisons were conducted by Bonferroni correction. RESULTS: There was no significant difference in the genotypic and allelic frequencies between females and males (MTHFR 677 T allele: 54.47 % for females and 54.40 % for males; MTRR 66G allele: 24.73 % for females and 24.71 % for males). Interaction between the MTHFR C677T polymorphism and overweight/obesity on serum triglyceride levels, and interaction between the MTRR A66G polymorphism and overweight/obesity on serum high-density lipoprotein cholesterol levels were detected in women (P = 0.015 and P = 0.056, respectively). For female subjects with overweight/obesity, the serum triglyceride levels in MTHFR 677TT genotype [1.09 (0.78-1.50) mmol/L] were significantly higher as compared with MTHFR 677CC genotype [0.90 (0.60-1.15) mmol/L, P = 0.007], and the MTRR 66GG genotype carriers had higher serum high-density lipoprotein cholesterol levels than those with MTRR 66AG genotype (1.46 ± 0.50 vs. 1.19 ± 0.31 mmol/L, P = 0.058). Furthermore, in male subjects with overweight/obesity, the MTHFR 677CT genotype carriers had higher low-density lipoprotein cholesterol levels than those with MTHFR 677TT genotype (2.96 ± 1.07 vs. 2.74 ± 0.88 mmol/L, P = 0.015). CONCLUSIONS: Our results indicate that there exist interactive effects of the MTHFR C677T and MTRR A66G polymorphisms with overweight/obesity on some lipid traits in Chinese Han population, and the effects were gender-specific.

Interactions of Methylenetetrahydrofolate Reductase C677T Polymorphism with Environmental Factors on Hypertension Susceptibility.

Hypertension is considered to be the result of genes, environment, and their interactions. Among them age, sex, tobacco use, alcohol consumption, and being overweight/obesity are well documented environmental determinants, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is nominated as a potential genetic candidate. However, the synergistic effect of the MTHFR C677T polymorphism with these environmental factors on the risk of hypertension has received little attention. The aim of this study was to explore the associations of the MTHFR C677T polymorphism, environmental factors, and their interactions with hypertension predisposition in a Northern Chinese Han population. A total of 708 participants were enrolled in the study. The genotypes of the MTHFR C677T were determined by a TaqMan assay. We found that participants of an older age, being overweight/obesity, with a smoking habit, drinking habit, or carrying the 677T allele were at an increased risk of hypertension. Additionally, there existed marginally significant interactions of the polymorphism with age and overweight/obesity. However, future large, well-designed studies in Chinese and other populations, as well as mechanistic studies, are still needed to validate our findings, especially considering that the interactions observed in our study were only marginally significant.

Are MTHFR C677T and MTRR A66G Polymorphisms Associated with Overweight/Obesity Risk? From a Case-Control to a Meta-Analysis of 30,327 Subjects.

Several studies have examined the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms with being overweight/obesity. However, the results are still controversial. We therefore conducted a case-control study (517 cases and 741 controls) in a Chinese Han population and then performed a meta-analysis by combining previous studies (5431 cases and 24,896 controls). In our case-control study, the MTHFR C677T polymorphism was not significantly associated with being overweight/obesity when examining homozygous codominant, heterozygous codominant, dominant, recessive and allelic genetic models. The following meta-analysis confirmed our case-control results. Heterogeneity was minimal in the overall analysis, and sensitivity analyses and publication bias tests indicated that the meta-analytic results were reliable. Similarly, both the case-control study and meta-analysis found no significant association between the MTRR A66G polymorphism and being overweight/obesity. However, sensitivity analyses showed that the associations between the MTRR A66G polymorphism and being overweight/obesity became significant in the dominant, heterozygous codominant and allelic models after excluding our case-control study. The results from our case-control study and meta-analysis suggest that both of the two polymorphisms are not associated with being overweight/obesity. Further large-scale population-based studies, especially for the MTRR A66G polymorphism, are still needed to confirm or refute our findings.

Use status and metabolism of realgar in Chinese patent medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar is widely used in combination with other herbs as Chinese patent medicine to treat a wide range of diseases in China. It is also a well known arsenical toxicant. Chronic arsenic poisoning events caused by long-term usage of realgar-containing medicines have been reported in literatures. Given to the paradoxical role of realgar, comprehensive outline of its usage status in Chinese patent medicine might provide basal data for evaluating its toxicology risks in populations. Unfortunately, the relevant information is limited. Also, a metabolic process after intake of realgar-containing medicine in humans is poorly understood. MATERIALS AND METHODS: The Traditional Chinese Patent Medicine Prescription Database was reviewed to get the information on the usage status of realgar. Realgar powder was dissolved in different pH-value solutions (1, 3, 5, 7, 9 and 11) to determine the soluble arsenic concentrations from realgar. Ten volunteers aged 24-26 years old were recruited to take four pills of Niu Huang Jie Du Pian (NHJDP), a very common Chinese patent medicine with realgar, to analyze the arsenic metabolism after exposure to realgar-containing medicine. The four pills were taken according to the medical instruction. Concentrations of soluble arsenic from realgar and urinary arsenic metabolites in humans were determined by hydride generation atomic absorption spectrometry. RESULTS: A total of 191 (2.25%) realgar-containing traditional Chinese patent medicines were obtained from the database, and almost 86.91% of them were for oral application. 73 (38.22%) medicines were found to be available for children. The mass fraction of arsenic in realgar-containing medicine ranged from 0.11% to 27.52%. According to medical instructions, the amount of average daily arsenic intake ranged from 0.47 to 2895.53mg. Nearly 86% medicines with daily intake of arsenic >10mg. Only inorganic arsenic (iAs) was detected from realgar in dissolution experiment and the levels of soluble iAs increased with pH values. After intake NHJDP, arsenic excretion in urine significantly increased, with a maximum excretion of iAs and monomethylarsonic acid at 6h post-ingestion and a peak excretion of dimethylarsinic acid at 9h post-ingestion. Arsenic methylation capacity was decreased after intake NHJDP. Females carried a more efficient arsenic methylation process than males. CONCLUSIONS: Realgar is widely used in traditional Chinese medicine. The arsenic solubility from realgar may be enhanced under alkaline conditions. The levels of urinary arsenic metabolites significantly increased while the arsenic methylation capacity significantly decreased after intaking realgar-containing medicine, which may suggest that a potential health hazard exists if people use arsenical medicines for long-term.

Associations of MTHFR C677T and MTRR A66G gene polymorphisms with metabolic syndrome: a case-control study in Northern China.

Prior evidence indicates that homocysteine plays a role in the development of metabolic syndrome (MetS). Methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms are common genetic determinants of homocysteine levels. To investigate the associations of the MTHFR C677T and MTRR A66G polymorphisms with MetS, 692 Chinese Han subjects with MetS and 878 controls were recruited. The component traits of MetS and the MTHFR C677T and MTRR A66G genotypes were determined. A significant association was observed between the MTHFR 677T allele and increased risk of MetS, high fasting blood glucose, high waist circumference, and increasing number of MetS components. The MTRR A66G polymorphism was associated with an increased risk of MetS when combined with the MTHFR 677TT genotype, although there was no association found between MetS and MTRR A66G alone. Furthermore, the MTRR 66GG genotype was associated with high fasting blood glucose and triglycerides. Our data suggest that the MTHFR 677T allele may contribute to an increased risk of MetS in the northern Chinese Han population. The MTRR A66G polymorphism is not associated with MetS. However, it may exacerbate the effect of the MTHFR C677T variant alone. Further large prospective population-based studies are required to confirm our findings.

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.

Associations of MTHFR gene polymorphisms with hypertension and hypertension in pregnancy: a meta-analysis from 114 studies with 15411 cases and 21970 controls.

BACKGROUND: Several epidemiological studies have investigated the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with hypertension (H) or hypertension in pregnancy (HIP). However, the results were controversial. We therefore performed a comprehensive meta-analysis to provide empirical evidences on the associations. METHODOLOGIES: The English and Chinese databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, cumulative meta-analysis and assessment of publication bias were performed in our study. PRINCIPAL FINDINGS: A total of 114 studies with 15411 cases and 21970 controls were included, 111 studies with 15094 cases and 21633 controls for the C677T polymorphism and 21 with 2533 cases and 2976 controls for the A1298C polymorphism. Overall, the C677T polymorphism was significantly associated with H and HIP (H & HIP: OR = 1.26, 95% CI = 1.17-1.34; H: OR = 1.36, 95% CI = 1.20-1.53; HIP: OR = 1.21, 95% CI = 1.08-1.32). Stratified analysis by ethnicity revealed a significant association among East Asians and Caucasians, but not among Latinos, Black Africans, and Indians and Sri Lankans. In the stratified analyses according to source of controls, genotyping method, sample size and study quality, significant associations were observed in all the subgroups, with the exception of population based subgroup in H studies and large sample size and "others" genotyping method subgroups in HIP studies. For the A1298C polymorphism, no significant association was observed either in overall or subgroup analysis under all genetic models. CONCLUSIONS: This meta-analysis suggests that the MTHFR C677T rather than A1298C polymorphism may be associated with H & HIP, especially among East Asians and Caucasians.

Prevalence of hyperhomocysteinemia in China: a systematic review and meta-analysis.

Hyperhomocysteinemia (HHcy, total homocysteine concentrations > 15 µmol/L) has been associated with increased risk of many diseases. A systematic review was performed to summarize the prevalence of HHcy in China. We searched multiple international and Chinese scientific databases for relevant literature, and further manually screened reference lists and corresponded with original authors. Pooled prevalence of HHcy was calculated using random effects model. Subgroup analysis, meta-regression and sensitivity analysis were also performed. A total of 36 studies consisting 60,754 subjects (57.3% male; age range, 3-97 years) were finally included. The overall pooled prevalence of HHcy was 27.5%. Geographically, the prevalence was high in north areas, intermediate in central areas, and low in south areas, and was higher in inland versus coastal areas. The prevalence increased with age and was significantly higher in men than in women. Rural residents had a slightly higher HHcy prevalence than urban residents, and the studies conducted during 2006 to 2012 presented a higher HHcy prevalence than those during 1990 to 2005. In summary, the prevalence of HHcy in China is high, particularly in northern populations, the inlanders, males, and the elderly. Homocysteine-lowering strategies are necessary to reduce this highly preventable disorder.

Geographical distribution of MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in China: findings from 15357 adults of Han nationality.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms are important genetic determinants for homocysteine (Hcy) levels, and are associated with several disorders. These polymorphisms are heterogeneously distributed worldwide. Our objective was to explore the geographical distributions of these polymorphisms in China. METHODOLOGIES: 15357 healthy adults were recruited from 10 regions. Buccal samples were collected and genomic DNA was isolated. Genotyping was performed using the fluorogenic 5'-nuclease assay. PRINCIPAL FINDINGS: The prevalence of the three polymorphisms among different populations from China varied significantly and showed apparent geographical gradients. For MTHFR C677T, the frequencies of the 677T allele and the 677TT genotype were significantly higher among northern populations and ranged from the lowest values (24.0% and 6.4%, respectively) in Hainan (southern) to the highest values (63.1% and 40.8%, respectively) in Shandong (northern). For MTHFR A1298C, the 1298C allele and the 1298CC genotype frequencies were significantly higher among southern populations and increased from low values (13.1% and 1.4%, respectively) in Shandong to high values (25.7% and 6.7%, respectively) in Hainan. For A66G, the 66G allele and the 66GG genotype frequencies increased from lower values (23.7% and 5.4%, respectively) in Shandong to higher values (29.2% and 8.6%, respectively) in Hainan. The overall frequency of the 677T allele, 677TT genotype, 1298C allele, 1298CC genotype, 66G allele and 66GG genotype in the Chinese Han population was 45.2%, 23.2%, 18.6%, 3.9%, 25.7%, and 6.6%, respectively. No gender differences were found in the prevalence of both the MTHFR C677T and MTRR A66G polymorphisms. CONCLUSIONS: This study indicates that there are marked geographical variations in the prevalence of the three polymorphisms among Chinese Han populations. Our baseline data may be useful for future researches in related fields.