Objective To explore the role of clinical pharmacist in individualized treatment of hypertension. Methods A patient with "H" hypertension receiving pharmaceutical care from clinical pharmacists was retrospectively analyzed. Results Patient's MTHFR (C677T) gene type was TT homozygous. Clinical pharmacist suggested doctor modify treatment, and then patient's plasma homocysteine dropped from 61.5 to 16.0 μmol·L-1, and blood pressure dropped from 173/111 mmHg(1 mmHg=0.133 kPa) to 130/80 mmHg. Conclusion Clinical pharmacist provides individualized treatment for patient with hypertension to ensure the safety and effectiveness of the drug by genotyping.
Key words:
MTHFR gene type
;
Hypertension,H
;
MTHFR gene polymorphism
;
Pharmaceutical care
ILHANN,KUCUKSUM,KAMAND,et al.The 677 C/T MTHFR polymorphism is associated with essential hypertension,coronary artery disease,and higher homocysteine levels[J].Arch Med Res,2008,39(1):125-130.
<h4 id="absSec_N2a232570N2a7fe510">Background</h4><p id="">Essential hypertension (EH) and cardiovascular disease are common, multifactorial disorders likely to be influenced by multiple genes of modest effect. The C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is related to MTHFR enzyme activity and to plasma homocysteine (Hcy) concentration. This study was designed to investigate an association of this polymorphism with coronary artery disease (CAD), EH, and healthy subjects.</p><h4 id="absSec_N2a232570N2a7fe570">Methods</h4><p id="">In this study, we measured serum folate, serum vitamin B12, and plasma homocysteine and determined the <em>MTHFR</em> C677T genotype of 78 patients with essential hypertension, 100 patients with coronary artery disease, and 100 healthy subjects. MTHFR genotypes were assessed by real-time polymerase chain reaction.</p><h4 id="absSec_N2a232570N2a7fe600">Results</h4><p id="">CC, CT, and TT genotype frequencies were 52, 44.0, and 4.0% in patients with CAD, respectively. In patients with essential hypertension, the CC, CT, and TT genotype frequencies were 46.2, 41.0, and 12.8%, respectively. In control subjects, the CC, CT, and TT genotype frequencies were 72.0, 26.0, and 2.0%, respectively. The C allele was significantly more frequent in controls compared with patients with EH (<em>p</em> <0.05), and CC genotypes were more frequent in controls compared to patients with EH and CAD. Homocysteine level was higher in TT genotypes in CAD patients compared with CC and CT genotypes (<em>p</em> <0.01). MTHFR gene polymorphism is an independent risk factor for EH but not for CAD.</p><h4 id="absSec_N2a232570N2a7fe6c0">Conclusions</h4><p id="">The TT genotype of the 677C/T MTHFR polymorphism is associated with EH and CAD. In addition, TT genotypes had higher plasma Hcy levels in CAD patients compared with CC and CT genotypes. MTHFR gene polymorphism is an independent risk factor for EH but not for CAD.</p>
SHID,MENGQ,ZHOUX,et al.Factors influencing the relationship between atrial fibrillation and artery stiffness in elderly Chinese patients with hypertension[J].Aging Clin Exp Res,2015,28(4):653-658.
JIY,KONGX,WANGG,et al.Distribution and determinants of plasma homocysteine levels in rural Chinese twins across the lifespan[J].Nutrients,2014,6(12):5900-5914.
Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10-66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome.
PARVEENF,TUTEJAM,AGRAWALS.Polymorphisms in MTHFR,MTHFD,and PAI-1 and recurrent miscarriage among North Indian women[J].Arch Gynec Obst,2013,288(5):1171-1177.
ABSTRACT PURPOSE: The aim of this study was to investigate the association between MTHFR C677T, A1298C, MTHFD G1958A and plasminogen activator inhibitor type 1 (PAI-1) 4G/5G polymorphism among first trimester recurrent miscarriages. MATERIALS AND METHODS: DNA was extracted from peripheral blood samples from 200 patients and 300 controls. Polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and sequencing were used to identify the polymorphisms. We have analyzed the frequencies, odds ratio, Hardy-Weinberg equilibrium. RESULTS: MTHFR C677T, A1298C, and MTHFD G1958A variant alleles were found to be significantly more prevalent in patients than control. However, variant genotype of MTHFR C677T (OR = 2.54; 95 % CI = 1.23-5.24; p value = 0.014), 1298C (OR = 2.23; 95 % CI = 1.09-4.52; p value = 0.028), and MTHFD-1958 showed significant association with pregnancy loss (OR = 2.36; 95 % CI = 1.39-4.02; p value = 0.002). Both MTHFR 677 and MTHFD 1958 showed susceptible effect under recessive model of inheritance. PAI-1 mutations showed no significance. CONCLUSION: We observed significant susceptible effects of MTHFR C677T, A1298C, and MTHFD G1958A among RM cases. Our data points toward the multifactorial nature of the recurrent miscarriage as relative contribution of variant genotype of MTHFR C677T is only twofold and further decreased to only onefold, and MTHFD-1958 lost its significance upon meta-analysis.
WILLIAMSC,KINGWELL BA,BURKEK,et al.Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype[J].Am J Clin Nutr,2005,82(1):26-31.
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LIF,CHENQ,SONGX,et al.MiR-30b is involved in the homocysteine-induced apoptosis in human coronary artery endothelial cells by regulating the expression of caspase 3[J].Intern J Mol Scien,2015,16(8):17682-17695.
Homocysteine (Hcy) is an independent risk factor for a variety of cardiovascular diseases, such as coronary heart disease, hypertension, stroke, etc. There is a close relationship between the vascular endothelial cell apoptosis and these diseases. Recent studies have shown homocysteine can induce apoptosis in endothelial cells, which may be an important mechanism for the development of theses cardiovascular diseases. Although there are several reports about how the Hcy induces apoptosis in endothelial cells, the exact mechanism is not fully understood. MicroRNAs are small, non-coding RNA. Previous studies have shown that there is a close relationship between several microRNAs and cell apoptosis. However, there are no studies about the role of microRNAs in Hcy-induced apoptosis in endothelial cells so far. In this study, we constructed the model of homocysteine-induced apoptosis in human coronary artery endothelial cells (HCAECs) and found miR-30b was significantly down-regulated by 1 mmol/L Hcy. In addition, overexpression of miR-30b can improve the Hcy-induced apoptosis in HCAECs by downregulating caspase-3 expression. Therefore, miR-30b may play an important role in Hcy-induced apoptosis in endothelial cells.
BASZCZUKA,KOPCZYN'SKI Z,KOPCZYN'SKI J et al.Impact of administration of folic acid on selected indicators of inflammation in patients with primary arterial hypertension[J].Postepy Hig Med Dosw(Online),2015,69:429.
Abstract Unlabelled: The results of epidemiological and clinical tests have shown that in patients with primary arterial hypertension, a chronic mild inflammation develops. The purpose of the study was to determine whether administration of folic acid to patients with primary arterial hypertension influences concentrations of indicators of inflammation: hsCRP, sICAM-1 and sVCAM-1. Material and methods: The examination was carried out in 41 patients with primary arterial hypertension, aged 19-65 (21 men and 20 women), without complications of hypertension and/or coexisting diseases. The examined patients were administered 15 mg of folic acid once a day for 45 days. Before and after administration of folic acid, concentrations of folic acid, homocysteine, hsCRP, sICAM-1 and sVCAM-1 in serum were assessed. Concentrations of folic acid and homocysteine were determined using the immunoenzymatic method (Abbott) on an AxSYM analyzer. The level of C-reactive protein (CRP) was determined with an ultra-sensitive turbidimetric assay on a Dimension analyzer (Siemens). Next, concentrations of adhesion particles sICAM-1 and sVCAM-1 were assessed with the ELISA technique (R&D). Results: After the administration of folic acid in patients with primary arterial hypertension, a significant decrease in median concentrations of homocysteine in blood was observed. Simultaneously, the median hsCRP, ICAM-1 and VCAM-1 concentrations in serum in patients with primary arterial hypertension were significantly reduced. Conslusions: Administration of folic acid to persons with primary arterial hypertension in a dose of 15 mg/ day for 45 days caused a decrease in the concentration of homocysteine in serum. That could indirectly result in the decrease in concentrations of the indicators of inflammation (hsCRP, ICAM-1 and VCAM-1), as it is apparent from previous studies that hyperhomocysteinemia stimulates the synthesis of CRP and the expression of adhesion molecules.
SONTAG JM,WASEKB,TALESKIG,et al.Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice[J].Front Ag Neurosc,2014,6(8):1-10.
Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of complex disorders, including developmental, vascular, and neurological diseases. MTHFR deficiency is associated with elevation of homocysteine levels and alterations in the methylation cycle. Here, using young and aged Mthfr knockout mouse models, we show that mild MTHFR deficiency can lead to brain-region specific impairment of the methylation of Ser/Thr protein phosphatase 2A (PP2A). Relative to wild-type controls, decreased expression levels of PP2A and leucine carboxyl methyltransferase (LCMT1) were primarily observed in the hippocampus and cerebellum, and to a lesser extent in the cortex of young null Mthfr-/- and aged heterozygous Mthfr+/- mice. A marked down regulation of LCMT1 correlated with the loss of PP2A/Balpha holoenzymes. Dietary folate deficiency significantly decreased LCMT1, methylated PP2A and PP2A/Balpha levels in all brain regions examined from aged Mthfr+/+ mice, and further exacerbated the regional effects of MTHFR deficiency in aged Mthfr+/- mice. In turn, the down regulation of PP2A/Balpha was associated with enhanced phosphorylation of Tau, a neuropathological hallmark of Alzheimer disease (AD). Our findings identify hypomethylation of PP2A enzymes, which are major CNS phosphatases, as a novel mechanism by which MTHFR deficiency and Mthfr gene-diet interactions could lead to disruption of neuronal homeostasis, and increase the risk for a variety of neuropsychiatric disorders, including age-related diseases like sporadic AD.
CAIW,YINL,YANGF,et al.Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension[J].Biom Rep,2014,2(6):861-868.
Abstract The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies ((2)=6.658,(2)=4.410, P0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH.
WANGY,XUX,HUOY,et al.Predicting hyperhomocysteinemia by methylenetetrahydrofolate reductase C677T polymorphism in Chinese patients with hypertension[J].Clin Appl Thromb/Hemost,2015,21(7):661-666.
To evaluate the performance of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in predicting hyperhomocysteinemia (HHcy) in Chinese patients with hypertension.We measured plasma total homocysteine tHcy level and C677T genotype in 1058 Chinese patients with hypertension from 4 previous studies. We used 10, 15, and 20 mol/L as cutoff values for the definition of mild, modest, and severe HHcy, respectively. Logistic models for HHcy were built from the study sample using the C677T genotype as well as age and gender as predictors. The receiver-operating characteristics of the models were evaluated.Our major findings are that (1) C677T TT genotype is consistently associated with a higher tHcy across the 4 studies, with an increase in size ranging from 38% to 68% in the 4 studies and 51% overall. The C677T polymorphism independently explained about 14% of the total variance of the normalized tHcy. (2) The TT genotype is associated with a large increase in odds ratio (OR) for HHcy. Overall, the multivariate-adjusted ORs for the TT genotype are 3.9 (95% confidence interval [CI]: 2.4-6.4), 6.5 (95% CI: 4.0-10.6), and 17.9 (95% CI: 8.4-38.1) for mild, modest, and severe HHcy, respectively. (3) Overall, the predicting performance increased with HHcy severity, with sensitivity improving from 31.0% for mild HHcy to 70.3% for severe HHcy, and with specificity slightly decreasing from 85.4% to 80.3%. Inclusion of gender and age as predictors significantly improves the sensitivity, especially for predicting mild HHcy.With an excellent sensitivity and a modest specificity, C677T could be a useful screening marker for severe HHcy.
SHANQUNJ,RUIMENGZ,MINGLUOP,et al.Associations of MTHFR and MTRR polymorphisms with serum lipid levels in Chinese hypertensive patients[J].Clin Appl Thromb/Hemost,2014,20(4):400-410.
To examine the effects of the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms and their interactions with environmental factors on serum lipid levels.We investigated totally 340 patients with essential hypertension, from Dongzhi community, Anhui, China. High-throughput TaqMan allelic discrimination assay was used for the genotyping of MTHFR C677T (Ala222Val), MTHFR A1298C (Glu429Ala), MTRR A66G (Ile22Met), and MTRR His595Tyr.Compared with the MTRR 66AA genotype carriers, the GG genotype carriers had lower serum total cholesterol (TC) levels (adjusted β ± standard error [SE]: -0.5 ± 0.2 mmol/L; P = .003) and low-density lipoprotein cholesterol (LDL-C) levels (adjusted β ± SE: -0.4 ± 0.2 mmol/L; P = .005). Their false discovery rate (FDR)-adjusted P values were 0.056 and 0.056, respectively. We further found that there was a statistically significant interaction between 677TT genotype and sex in their associations with LDL levels (P interaction = .020), and significant interaction between 677TT genotype and smoking on LDL levels (P interaction = .036). A similar pattern of interaction was found between 66GG and drinking on levels of TC (P interaction = .034) and LDL (P interaction = .020). However, there were no significant interactions observed after FDR adjustment.Both MTHFR and MTRR gene polymorphisms could be important genetic determinants of serum lipid levels in Chinese patients with hypertension. These findings need to be replicated in a larger sample.
KOO HS,LEE HS,HONG YM,et al.Methylenetetrahydrofolate reductase TT genotype as a predictor of cardiovascular risk in hypertensive adolescents[J].Ped Card,2008,29(1):136-141.
Methylenetetrahydrofolate reductase (MTHFR) is associated with homocysteine level. In deficit of MTHFR, cardiovascular risk is increased with hyperhomocysteinemia and hypomethionemia. Mutation of the MTHFR gene is associated with the risk for premature cardiovascular diseases. However, the association between MTHFR mutation and cardiovascular risk is still controversial. The purposes of this study were to determine whether MTHFR genotype is associated with cardiovascular risks in hypertensive adolescents and to investigate the association between MTHFR genotype and carotid intima-media thickness (IMT). Forty-three hypertensive adolescents were included in this study. Serum lipid levels, insulin, vitamin B 12 , folate, renin, aldosterone, angiotensin converting enzyme, and homocysteine levels were evaluated. The carotid IMT and diameter were estimated by ultrasound. Brachial nkle pulse wave velocity was also measured. Polymerase chain reaction was conducted to amplify genomic DNA fragment containing C677T position of the MTHFR gene. The height, weight, body mass index, obesity index, arm circumference, fat mass, and fat distribution were significantly greater in patients with C677T mutation. The C677T mutation group showed significantly greater carotid IMT, higher homocysteine, and lower folic acid levels than the normal genotype group. Interpretation of MTHFR genotype might be useful in predicting the development of premature coronary artery disease in hypertensive adolescents.
Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice
, 韩勇
