Relationship of MTHFR gene polymorphisms with renal and cardiac disease

AIM: To investigate the effects of different methylenetetrahydrofolate reductase(MTHFR) 677CT gene polymorphism and hyperhomocysteinemia for the development of renal failure and cardiovascular events, which are controversial.METHODS: We challenged the relationship, if any, of MTHFR 677CT and MTHFR 1298AC polymorphisms with renal and heart function. The present article is a reappraisal of these concepts, investigating within a larger population, and including a subgroup of dialysis patients, if the two most common MTHFR polymorphisms, C677 T and A1298 C, as homozygous, heterozygous or with a compound heterozygous state, show different association with chronic renal failure requiring hemodialysis. MTHFR polymorphism could be a favorable evolutionary factor, i.e., a protective factor for many ominous conditions, like cancer and renal failure. A similar finding was reported in fatty liver disease in which it is suggested that MTHFR polymorphisms could have maintained and maintain their persistence by an heterozygosis advantage mechanism. We studied a total of 630 Italian Caucasian subject aged 54.60 ± 16.35 years, addressing to the increased hazard of hemodialysis, if any, according to the studied MTHFR genetic polymorphisms. RESULTS: A favorable association with normal renal function of MTHFR polymorphisms, and notably of MTHFR C677 T is present independently of the negative effects of left ventricular hypertrophy, increased IntraRenal arterial Resistance and hyperparathyroidism. CONCLUSION: MTHFR gene polymorphisms could have a protective role on renal function as suggested by their lower frequency among our dialysis patients in end-stage renal failure; differently, the association with left ventricular hypertrophy and reduced left ventricular relaxation suggest some type of indirect, or concurrent mechanism.     

MTHFR和ABCG2单核苷酸多态性对晚期结直肠癌—线化疗疗效的预测作用

目的:探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)和乳腺癌耐药蛋白(breast cancer resistance protein,BCRP/ABCG2)基因单核苷酸多态性(single nucleotide polymorphism,SNP)对晚期结直肠癌一线化疗疗效的预测作用.方法:采用基因测序法检测154例接受FOLFOX、XELOX或FOLFIRI方案一线化疗的晚期结直肠癌患者外周血MTHFR 677C＞T、MTHFR 1298A＞C、ABCG2 34G＞A和ABCG2 421C＞A这4个位点的SNP,结合临床特征,分析其与近期疗效、无进展生存(progression-free survival,PFS)和总生存(overall survival,OS)之间的关系.结果:154例患者接受一线化疗的有效率为31.8％,中位PFS为8.1个月,中位OS为30.7个月.MTHFR和ABCG2 SNP与近期疗效和OS无显著相关性(P＞0.05).含3～4个优势基因型(MTHFR 677C/C、MTHFR 1298A/A、ABCG2 34G/A或A/A及ABCG2 421C/A或A/A)患者的中位PFS较含0～2个优势基因型患者的显著延长(分别为9.8和7.5个月,P=0.013).COX多因素分析结果显示,优势基因型数目(P=0.017)和原发灶是否根治切除(P=0.010)是影响PFS的独立因素.单因素和多因素分析结果均显示,原发灶是否根治切除是影响OS的独立因素(P=0.000,P=0.000).结论:联合分析MTHFR和ABCG2 SNP对一线化疗治疗晚期结直肠癌的PFS有一定的预测作用,原发灶是否根治切除是影响PFS和OS的独立因素.     

轻中度高血压患者中MTHFR C677T与血清叶酸水平变化的相关性研究

目的探讨轻中度高血压患者亚甲基四氢叶酸还原酶（MTHFR）C677T多态性位点与血清叶酸水平变化间的关系。方法从哈尔滨、沈阳、北京、西安、上海、南京6城市收集的480位28～75岁轻中度原发性高血压患者,按1：1：1的原则随机分为3组;对照组、0．4mg叶酸组、0．8mg叶酸组每日分别服用10mg马来酸依那普利、10mg马来酸依那普利＋0．4mg叶酸、10mg马来酸依那普利＋0．8mg叶酸,连续服用8周。收集治疗前后的血清叶酸水平、MTHFR C677T位点的基因型及其他相关指标。本研究对主要资料完整者371人（男156人,女215人）的MTHFR C677T位点与血清叶酸水平变化间的关系进行统计分析。结果①对照组中C677T基因型对叶酸变化水平无明显作用,各基因型间的差异均无统计学意义。②试验组中血清叶酸变化水平在C677T CC、CT和TT基因型间的变化趋势基本一致,TT型增加水平最少,CC型增加最多。以677CC基因型人群的叶酸变化水平为参照,合并叶酸组中TT基因型在调整前（β=3．99,P=0．034）后（β=5．68,P〈0．001）差异均有统计学意义;0．4mg叶酸组和0．8mg叶酸组TT基因型在调整前（β分别为5．33和2．64,P分别为0．061和0．280）差异无统计学意义,调整后（β分别为5．60和4．68,P分别为0．031和0．050）差异有统计学意义。各组中CT基因型调整前后的差异均无统计学意义（P〉0．05）。结论轻中度高血压患者中MTHFR C677T的基因型对叶酸的疗效具有一定的作用。     

MTHFR C677T基因多态性与晚期非小细胞肺癌化疗不良反应的关系

背景与目的：亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)是叶酸代谢的关键酶,在DNA甲基化中起重要作用。本研究旨在探讨MTHFR C677T多态性与晚期非小细胞肺癌(nonsmall cell lung cancer,NSCLC)化疗不良反应的关系。方法：收集2007年6月-2009年5月在浙江省肿瘤医院经病理学确诊的晚期NSCLC患者100例。所有患者均接受铂类药物联合吉西他滨的方案化疗。用等位基因特异-PCR技术检测患者MTHFR基因型。结果：100例晚期NSCLC患者中,MTHFR C677T T/T、T/C和C/C基因型频率分别为20%、44%和36%。在血液学不良反应中,C/C基因型血小板减少发生率较T/T、T/C基因型低,差异有统计学意义(P=0.039)。本研究未发现MTHFR各基因型与化疗后恶心、呕吐不良反应相关。结论：MTHFRC677T基因多态性对预测晚期NSCLC含铂类药物方案化疗后不良反应有临床意义。     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility

AIM: To identify the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and gastric cancer (GC) susceptibility.METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I² statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed.RESULTS: Increased risk was found for the MTHFR C677T polymorphism under four genetic models (TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations (CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04).CONCLUSION: MTHFR C677T polymorphism is a risk factor for GC, and the A1298C polymorphism may be a protective factor against GC in eastern populations.     

Lack of Association between the MTHFR C677T Polymorphism and Lung Cancer in a Turkish Population

Background: In this case-control study, we aimed to investigate the relationship between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and lung cancer. Materials and Methods: Total 200 individuals including 100 patients with lung cancer and 100 controls were analyzed. Genotyping of MTHFR C677T was performed using PCR and RFLP methods. Results: The majority of the patients were men and 90% were smokers. We found that the risk ratio for development of LC was 13-times higher in smokers compared with non-smokers between patient and control groups in our study (OR:13.5, 95%CI:6.27-29.04,p:0.0001). Besides, the risk ratio for development of LC was nine times higher in individuals with cancer history in their family than those without cancer history (OR:9.65, 95%CI: 2.79-33.36; p:0.0001). When genotype distributions and allele frequencies were analyzed in the study groups, no significant difference was apparent (χ2:0.53, p=0.76). In addition, no correlation between genotypes of MTHFRC677T polymorphism and histological type of LC was found (χ2:0.99, p=0.60). Conclusions: These results suggest that there was no association between the MTHFR C677T polymorphism and lung cancer in the Turkish population.     

急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系

目的：探讨亚甲基四氢叶酸还原酶（MTHFR）基因单核苷酸多态性对急性淋巴细胞白血病（ALL）患儿使用大剂量甲氨蝶呤（HD-MTX）化疗后毒副反应的影响。方法：应用RT-PCR-变性梯度凝胶电泳结合DNA测序技术,对52例ALL患儿MTHFR C677T、A1298C和G1793A基因型进行检测。按照国立癌症研究所常规毒性判定标准（NCI-CTC）对患儿HD-MTX化疗后的不良反应统一评价。结果：MTHFR 1298AC基因型患儿发生血小板减少的风险较AA型提高了13.7倍（OR=13.7,95%CI=1.18～159.36,P=0.036）。MTHFR C677T和G1793A各基因型发生各类HD-MTX化疗不良反应的差异无统计学意义（P>0.05）。结论：MTHFR A1298C多态性可能与ALL患儿HD-MTX化疗后的毒副反应相关。     

瑞舒伐他汀联合脐血间充质干细胞移植改善急性心肌梗死后心功能

BACKGROUND:In recent years, it has been a hot topic that stem cell transplantation is used to improve cardiac insufficiency after acute myocardial infarction by inducing regeneration of cardiomyocytes in the infarction regions. OBJECTIVE:To observe the effect of rosuvastatin combined with umbilical cord blood mesenchymal stem cells transplantation on rat cardiac function after acute myocardial infarction. METHODS:Forty-five Sprague-Dawley rats were enrolled to prepare myocardial infarction models by ligaturing the left anterior descending coronary artery. Then they were equivalently divided into model group, transplantation group and combination group. At 7 days after modeling, rats in the combination group were given injection of 300 μL umbilical cord blood mesenchymal stem cells (15.0×10⁸) via the tail vein and by gavage once a day for 28 days with 1 mg/kg rosuvastatin; rats in the transplantation group and model group were injected with 300 μL umbilical cord blood mesenchymal stem cell suspension through the tail veins or the same amount of LG-DMEM medium, respectively, followed by intragastrical administration of the same amount normal saline. At 5 weeks after modeling, indexes of cardiac function, level of plasma Lp-PLA2 and heat shock protein 70 in the infarction regions were detected by color Doppler ultrasound, enzyme-linked immunosorbent assay and western blot assay, respectively. In addition, pathological changes of myocardial tissues were observed using hematoxylin-eosin staining. RESULTS AND CONCLUSION:Left ventricular ejection fraction and left ventricular end-systolic pressure were significantly higher in the combination group than in the transplantation group as well as higher in the transplantation group than the model group (P < 0.05); compared with the transplantation group, left ventricular end-diastolic pressure was significantly decreased in the combination group, but significantly increased in the model group (P < 0.05); the number of cardiomyocytes in the infarction regions was significantly higher in the combination group than the other groups. Additionally, expression of heat shock protein 70 in the infarction regions was significantly increased in the combination group (P < 0.05). To conclude, rosuvastatin combined with umbilical cord blood mesenchymal stem cell transplantation can significantly improve rat cardiac function after myocardial infarction.     

Comparison of Mechanism and Functional Effects of Magnesium and Statin Pharmaceuticals

Since Mg²⁺-ATP is the controlling factor for the rate-limiting enzyme in the cholesterol biosynthesis sequence that is targeted by the statin pharmaceutical drugs, comparison of the effects of Mg²⁺ on lipoproteins with those of the statin drugs is warranted. Formation of cholesterol in blood, as well as of cholesterol required in hormone synthesis, and membrane maintenance, is achieved in a series of enzymatic reactions that convert HMG-CoA to cholesterol. The rate-limiting reaction of this pathway is the enzymatic conversion of HMG CoA to mevalonate via HMG CoA. The statins and Mg inhibit that enzyme. Large trials have consistently shown that statins, taken by subjects with high LDL-cholesterol (LDL-C) values, lower its blood levels 35 to 65%. They also reduce the incidence of heart attacks, angina and other nonfatal cardiac events, as well as cardiac, stroke, and total mortality. These effects of statins derive less from their lowering of LDL-C than from their reduction of mevalonate formation which improves endothelial function, inhibits proliferation and migration of vascular smooth muscle cells and macrophages, promotes plaque stabilization and regression, and reduces inflammation, Mg has effects that parallel those of statins. For example, the enzyme that deactivates HMG-CoA Reductase requires Mg, making Mg a Reductase controller rather than inhibitor. Mg is also necessary for the activity of lecithin cholesterol acyl transferase (LCAT), which lowers LDL-C and triglyceride levels and raises HDL-C levels. Desaturase is another Mg-dependent enzyme involved in lipid metabolism which statins do not directly affect. Desaturase catalyzes the first step in conversion of essential fatty acids (omega-3 linoleic acid and omega-6 linolenic acid) into prostaglandins, important in cardiovascular and overall health. Mg at optimal cellular concentration is well accepted as a natural calcium channel blocker. More recent work shows that Mg also acts as a statin.     

华中地区神经管缺陷家庭叶酸代谢相关基因的单核苷酸多态性研究

目的 通过对叶酸代谢相关基因的单核苷酸多态性(single nucleotide polymorphism,SNP)与环境危险因子交互作用的关联分析,寻找神经管缺陷(neural tube defects,NTD)致病基因及环境危险因素. 方法收集NTD流产胎儿组织标本或患儿血标本(n=278)及其正常双亲的血标本(n=478),记录母亲围孕期补充叶酸、糖尿病、服药史等情况.采用CEQ 8800系统进行多重SNP分析,对所有样本叶酸代谢相关的12个基因共28个SNP测序.通过病例-双亲对照研究及传递/不平衡检验,分析SNP与环境危险因子(孕期补充叶酸、母亲糖尿病、孕期服药史)的交互作用对NTD发病的影响. 结果 亚甲基四氢叶酸还原酶(基因为MTHFR)rs1801133与NTD的关联具有统计学意义,而且环境风险因子(未补充叶酸、母亲糖尿病)对NTD的发生起增效作用;而甜菜碱同型半胱氨酸甲基转移酶(基因为BHMT)rs3733890仅在未补充叶酸层与NTD存在连锁不平衡,基因型本身并不能单独导致疾病;而其他基因的SNP与NTD的发生没有显著关联. 结论 MTHFRrs1801133是NTD的危险因子,而BHMT rs3733890不是NTD的独立危险因子.未来尚需要对更大的样本进行基因与基因、基因与环境交互作用的研究以探讨NTD的发病原因.