社区人群MTHFR基因多态性与大脑中动脉狭窄的相关研究

目的 研究社区汉族人群中亚甲基四氢叶酸还原酶(Methylenetetra-hydrofolate reductase,MTHFR)基因型的分布特征,进一步探讨社区人群中MTHFR C677T基因突变与大脑中动脉狭窄(middle cerebral artery stenosis,MCAS)是否关联.方法 整群抽取汉族成年居民1146人,记录其病史资料,并行经颅多普勒(transcranial doppler,TCD)检查.采用聚合酶链反应-限制性内切酶片段长度多态性技术(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)鉴定目标人群MTHFR 677位基因型. 结果 1146例居民中MTHFR 677位点C/C野生型占60.6％、T/C杂合型占34.1％、T/T纯合突变型占5.3％,C等位基因占77.6％,T等位基因占22.4％.MCAS组与非MCAS组的等位基因频率分布存在统计学差异(x2=6,828,P＜0.01)、两基因型联合对比(T/C+T/T与C/C:x2=4.602,P＜0.05)及T/T与C/C比较(x2=5.320,P＜0.05)差异也有统计学意义,但T/C与C/C比较(x2=2.590,P＞0.05)无统计学差异;logistic回归显示T/T基因型会增加患MCAS的风险(OR=3.393,95％CI 1.230～9.357).结论 中国社区汉族人群中存在MTHFR C677T 基因突变;MTHFR C677T突变存在种族和地域的差异.MTHFR C677T基因多态性与MCAS风险增加有关.     

粤西汉族人群血浆谷胱甘肽过氧化物酶基因启动子区-723C/T基因多态性与脑梗死的关系

目的 研究粤西汉族人群谷胱甘肽过氧化物酶(GPX-3)基因启动子区-723C/T基因多态性的分布及其与脑梗死的关系. 方法 检测佛广东医学院附属医院神经科自2007年2月至2008年2月收治的粤西地区汉族脑梗死患者102例(病例组)和同期粤西地区汉族健康体检者101例(对照组)的GPX-3基因启动子区-723C/T基因多态性,比较2组的一般资料、卒中危险因素及-723C/T基因多态性的分布特点,多元Logistic回归分析影响脑梗死发生的危险因素,并对筛选出的危险因素进行分层分析. 结果 与对照组比较,病例组高血压、糖尿病病史比例,血糖水平,-723C/T CC基因型频率及C等位基因频率均较高,差异有统计学意义(P＜0.05);多元Logistic回归分析显示-723C/T基因型、高血压病史、糖尿病史是脑梗死发生的独立危险因素;与没有任何危险因素亦不携带风险基因型者比较,有危险因素又携带CC基因型者脑梗死发病风险明显增加,差异有统计学意义(P＜0.05). 结论 中国粤西地区汉族人群GPX -3基因启动子区-723C/T位点存在多态性,C等位基因是脑梗死的危险因素,CC基因型为脑梗死的易感基因型,也是独立危险因素.     

亚甲基四氢叶酸还原酶基因多态性与脑出血的关系

目的　探讨上海地区人群亚甲基四氢叶酸还原酶 (MTHFR)基因多态性与脑出血的关系。方法应用聚合酶链反应 限制性片断长度多态性 (PCR RFLP)技术 ,检测 94例脑出血患者 (脑出血组 )和 10 0名正常人 (对照组 )的MTHFR基因。结果　MTHFR基因第 6 77位核苷酸呈多态性 ,可分为 3种类型 :CC、CT、TT。 3种基因型频率脑出血组分别为 2 2 %、6 3%、15 % ;对照组分别为 4 0 %、4 9%、11% ;两组基因型频率TT∶CC +CT ,差异无显著性 (P >0 0 5 )。T等位基因频率脑出血组 4 6 % ,对照组 35 % ,两组间比较差异有显著性 (P <0 0 5 )。结论　MTHFR基因等位基因 (T)频率与脑出血有关     

四氢叶酸还原酶MTHFR C677T基因多态性与阿尔茨海默病发病风险的Meta分析

目的:探索四氢叶酸还原酶(MTHFR)基因C677T多态性与阿尔茨海默氏病(AD)的关系。方法:对符合条件的研究进行Meta分析,分别以2269例AD患者和2854例对照人群等位基因和基因型频率分布的OR值为效应指标,采用固定或随机效应模型进行合并分析,并进行偏倚评估。结果:等位基因、TT+TC基因型合并的OR值(95％CI)分别为1.18（1.05 ～1.32）和1.26（1.09 ～1.46）。按人群进行分层分析,亚洲人群等位基因频数T/C和基因型(TT +TC)/CC合并的OR值分别为1.32（1.09 ～1.59）和1.43（1.22 ～ 1.69）;高加索人群等位基因频数T/C和基因型(TT+ TC)/CC的OR值分别为0.98(0.85 ～1. 13)和1.05（0.86 ～1. 28）。入选文献无明显发表偏倚。结论:MTHFR C677T基因多态性与阿尔茨海默病发病具有相关性,并且该相关性仅存在于亚洲人群中。     

脑梗死疾病与血管紧张素转换酶基因多态性的相关性研究

目的 研究血管紧张素转换酶(ACE)基因、血管紧张素Ⅱ受体Ⅰ型(ATⅠR)基因多态性和多种危险因素与脑梗死疾病的相关性。方法 采用整群抽样的方法选取唐山开滦矿业集团职工1351人。所有样本均清晨空腹抽取静脉血测定其ACE、ATⅠR基因型及相关生化指标，并进行体检和问卷调查，然后依据头部CT或MRI结果将之分为脑梗死组和对照组。结果 ACE基因各基因受在脑梗死组和对照组的频率分布及各基因型人群中脑梗死患病率无明显差异，ATⅠR基因AA基因型频率分布在脑梗死组高于对照组，且AA型人群脑梗死患病率高于其它基因型，但两种基因各联合基因型人群中脑梗死患病率无差异。在与脑梗死有关的各种危险因素存在条件下，仅不吸烟人群和有高血压患者群中脑梗死组ATⅠR基因AA基因型频率分布高于对照组．Logistic回归发现脑梗死与ATⅠR基因多态性和性别有明显相关性。结论 在具有高血压病的ATⅠR的AA基因型人群发生脑梗死的危险性明显增加，说明脑梗死的发病可能是“基因与环境”因素共同作用的结果。     

维汉两民族原发性高血压伴颈动脉粥样病变与对氧磷酶2基因多态性的相关性：同一机构3年430例报告

背景：近年的研究发现对氧磷酶2(PON2)可降低低密度脂蛋白的过度氧化从而保护组织免受氧化破坏。 目的：分析对氧磷酶2基因多态性(PON2 C311S)与原发性高血压伴颈动脉粥样病变的关系。 方法：选择2006-01/2009-01新疆医科大学附属第一医院收治的高血压患者共430例,其中294例伴颈动脉粥样病变者为病变组,136例颈动脉内膜正常者为对照组。病变组中汉族214例,维族80例;对照组中汉族103例,维族33例。采用多聚酶链反应-限制性内切酶片断长度多态性技术分析对氧磷酶2基因多态性基因多态性。 结果与结论：汉族病变组的CC+CS基因型及C等位基因频率明显高于对照组;舒张压在对氧磷酶2基因多态性位点3种基因型(SS、CS、CC)之间差异有显著性意义(P=0.003),CC基因型舒张压最高。Logistic回归分析表明PON2C311等位基因、年龄、舒张压、脂蛋白(a)是高血压伴发颈动脉粥样病变的危险因素(P < 0.05)。维族病变组的CC+CS基因型及C等位基因频率高于对照组;低密度脂蛋白胆固醇在对氧磷酶2基因多态性位点3种基因型之间差异有显著性意义(P=0.005),CC基因型低密度脂蛋白胆固醇最高。结果提示,新疆地区汉族高血压人群对氧磷酶2基因多态性基因多态性与颈动脉粥样病变有关,C等位基因是高血压伴发颈动脉粥样病变的危险因素之一。     

MMP-3启动子基因多态性与大脑中动脉狭窄的关联性研究

目的探讨基质金属蛋白酶3(MMP3)启动子基因5A/6A多态性与大脑中动脉狭窄的关联。方法采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)测定119例经颅多普勒超声(TCD)证实为大脑中动脉狭窄的病例组与TCD检测正常的92例对照组的MMP-3启动子-1171(5A/6A)基因型,进行基因型、等位基因频率分析,应用统计学软件分析其基因多态性与大脑中动脉狭窄的相关性。结果MMP-35A/5A、5A/6A、6A/6A基因型频率分布在两组间无明显差异。MMP-3的5A、6A等位基因频率在病例组和对照组中分别为15.97%、84.03%和15.76%、84.24%,两组比较,差异无统计学意义(P>0.05);结论基质金属蛋白酶-3(MMP-3)启动子-1171(5A/6A)基因多态性与中国北方汉族人群大脑中动脉狭窄无明显相关性。     

缺血性青年脑卒中脑动脉狭窄与血浆HCY水平及MTHFR C677T基因多态性的相关性研究

目的研究缺血性青年脑卒中脑动脉狭窄与同型半胱氨酸(HCY)的水平及亚甲基四氢叶酸还原酶(MTHFR) C677T基因多态性的关系。方法在吉林大学中日联谊医院神经内科二病区随机选取缺血性青年脑卒中的住院患者50例,其中符合纳入标准的41例,根据有无脑血管狭窄分为狭窄组(20例)及非狭窄组(21例),分别对其血浆HCY的水平及MTHFR C677T基因多态性进行测定并进行统计学分析。结果在41例患者中HCY的水平CC基因型(10. 61±2. 66)μmol/L低于TT基因型(19. 65±14. 43)μmol/L(P=0. 033)及CT+TT基因型(16. 65±12. 48)μmol/L(P=0. 015)。脑动脉狭窄组与非狭窄组HCY的水平分别为(20. 44±14. 70)μmol/L、(11. 03±4. 40)μmol/L(P=0. 012);其中狭窄组HCY的水平CC基因型(12. 23±2. 18)μmol/L低于TT基因型为(28. 55±16. 82)μmol/L(P=0. 043)及CT+TT基因型(22. 48±15. 82)μmol/L(P=0. 023);非狭窄组的HCY水平CC基因型(8. 46±1. 40)μmol/L低于TT基因型为(11. 86±5. 0)μmol/L(P=0. 161)及CC+TT基因型(11. 46±4. 60)μmol/L(P=0. 048);两组同一基因型HCY的水平TT基因型分别为(28. 55±16. 82)μmol/L、(11. 86±5. 02)μmol/L(P=0. 040),CC基因型分别为(12. 23±2. 18)μmol/L,(8. 46±1. 40)μmol/L(P=0. 049),CT基因型分别为(17. 77±14. 12)μmol/L、(11. 14±4. 48)μmol/L(P=0. 178)。两组MTHFR C677T的TT、CT、CT+TT基因型分别与CC基因型比较P 0. 05,T与C等位基因比较P 0. 05; Logistic回归分析可知HCY(OR=1. 168、95%CI1. 015～1. 344、P=0. 030)是脑血管狭窄的危险因素。结论 HCY的水平是缺血性青年脑卒中患者脑动脉狭窄的高危因素。MTHFR C677T的TT基因型是影响血浆HCY水平的关键因素,但C677T基因型及等位基因频率与脑动脉狭窄无直接的相关性。     

2型糖尿病患者大脑中动脉狭窄与肾素-血管紧张素系统基因多态性的关系

目的 探讨大脑中动脉(MCA)狭窄与肾素-血管紧张素系统(renin angiotensin system,RAS)基因多态性的关系。方法 对2202个汉族2型糖尿病人用经颅多普勒(transcranial Doppler,TCD)筛选,MCA狭窄者为病例组,其余为对照组,然后经年龄、性别、糖尿病病程配对后选择病例组218例,对照组489例,用PCR、PCR-RFLP检测ACE、ATIR、AGT基因型。结果 病例组和对照组的三种基因的基因型、等位基因频率分布无差异;但在AGT基因的基因型为TT时,病例组的ACE基因的ID、DD基因型比例较高(P<0.1,OR=1.40),而在ACE基因的基因型为ID、DD时,病例组的AGT基因的TT基因型比例也较高(P<0.05,OR=1.71);在ATIR基因的基因型为AA时,病例组的AGT基因的TT基因型比例较高(P<0.1,OR=1.66)。结论 RAS单个基因的多态性与MCA狭窄不相关,但RAS的几个基因之间的相互作用与MCA狭窄有关。     

血栓素A2受体基因多态性与脑梗死的相关性研究

目的 探讨上海地区汉族人群血栓素A2 受体(TXA2R)基因多态性与脑梗死的关系.方法 采用聚合酶链反应-限制性片段长度多态性方法对138例脑梗死患者和135例正常老年对照者TXA2R 基因rs768963位点多态性进行分析,计算其基因型频率和等位基因频率.结果 Logistic回归分析结果显示,血压和血糖水平是脑梗死的独立危险因素.脑梗死组与正常老年对照组受试者TXA2R 基因rs768963位点的基因型(TT 基因型、TC 基因型和CC 基因型)和等位基因(T 和C)频率比较,差异均无统计学意义(P >0.05);进一步Logistic回归分析结果显示,TXA2R 基因rs768963位点基因突变与性别、年龄、血脂、血压和血糖水平均无相关性(P > 0.05).结论 TXA2R 基因rs768963位点多态性可能与上海地区汉族人群脑梗死无关.     

Endothelial nitric oxide synthase gene interactions and the risk of ischaemic stroke

OBJECTIVE: Endothelial nitric oxide synthase (eNOS), which produces NO, plays an important role in the endothelial function under a wide range of physiological conditions. eNOS exon 7 polymorphism (Glu298Asp, G894T) has been considered to influence the risk of coronary artery disease. Alone, however, it has not been shown to be a genetic risk factor for ischaemic stroke. With the assumption of additive interactions, we examined whether the eNOS G894T or eNOS 894TT genotypes in combination with the methylenetetrahydrofolate reductase 677TT (MTHFR 677TT) or angiotensin-converting enzyme (ACE) D/D genotype could contribute to acute ischaemic stroke. MATERIAL AND METHODS: The data on 407 consecutive patients with acute ischaemic stroke who had never suffered a previous stroke event were analysed. As a control group, 295 stroke and neuroimaging alteration-free Caucasian subjects were examined. With the use of the PCR technique, the eNOS G894T, eNOS 894TT, MTHFR 677TT and ACE D/D mutations, as unfavourable common genotypes were determined in the participants. Logistic regression models were used to evaluate the roles of the genotypes and their combinations in the development of ischaemic stroke. RESULTS: The MTHFR C677TT genotype combined with the eNOS G894T or eNOS 894TT genotypes occurred significantly more frequently in the subjects with ischaemic stroke (7.1%; P < 0.025) than in the control group (3.1%). The co-occurrence of the ACE D/D genotype and eNOS G894T or eNOS 894TT was calculated to be more frequent in the ischaemic stroke group (20.9%, P < 0.0001) than in the control group (5.4%). CONCLUSION: The eNOS G894T or eNOS 894TT genotypes in combination with the MTHFR 677TT or ACE D/D genotype increases the risk of ischaemic stroke.     

Specific APO E genotypes in combination with the ACE D/D or MTHFR 677TT mutation yield an independent genetic risk of leukoaraiosis

OBJECTIVE: Ischaemic demyelination of the white matter of the brain is a frequent clinical entity. In the neuroimaging terms, it is referred to as leukoaraiosis. We earlier found that the co-occurrence of the homozygous methylenetetrahydrofolate reductase (MTHFR) 677TT and angiotensin-converting enzyme D/D (ACE D/D) genotypes yielded a highly significant moderate risk of leukoaraiosis. On the assumption of further genetic interactions, we have now investigated whether the different apolipoprotein E (APO E) genotypes, in pairwise combinations with the MTHFR 677TT or ACE D/D mutation, could lead to an increased risk of leukoaraiosis. MATERIAL AND METHODS: We analysed the occurrence of the APO E genotypes in pairwise combinations with the MTHFR 677TT or ACE D/D mutation in 315 consecutive Caucasian patients with leukoaraiosis. A total of 646 neuroimaging-free subjects acted as a control group. RESULTS: The APO E 2/2 and 2/3 or APO E 4/4 and 4/3 genotypes in combination with the MTHFR 677TT or ACE D/D mutation exhibited independent genetic risks of leukoaraiosis. CONCLUSION: The interactions of certain unfavourable genetic mutations can contribute to the evolution of leukoaraiosis.     

Influence of combined methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase enhancer region (TSER) polymorphisms to plasma homocysteine levels in Korean patients with recurrent spontaneous abortion

OBJECTIVES: Methylenetetrahydrofolate reductase (MTHFR) mutations known to be associated with hyperhomocysteinemia may be a risk factor for recurrent spontaneous abortion. Recently 28-bp tandem repeat polymorphism in thymidylate synthase enhancer region (TSER) was reported to affect plasma homocysteine level. We investigated the association between plasma homocysteine level and MTHFR and TSER genotypes. METHODS: Plasma homocysteine level was measured by fluorescent polarizing immunoassay. MTHFR mutations (C677T and A1298C) were identified by PCR-restriction fragment length polymorphism assay. TSER mutation was analyzed by PCR method. RESULTS: Average homocysteine level was significantly higher in MTHFR 677TT genotype (9.80+/-3.87 micromol/L) than in MTHFR 677CT (7.04+/-1.99 micromol/L) in MTHFR 677CC genotype (8.14+/-1.74 micromol/L) in Korean patients with unexplained recurrent spontaneous abortion (p=0.0143). While MTHFR 1298AA showed the highest level, plasma homocysteine levels were not significantly different among MTHFR 1298AA (8.42+/-2.65 micromol/L), 1298AC (6.98+/-2.44 micromol/L) and 1298CC (6.09+/-0.32 micromol/L) (p=0.2058). There was no significant difference among TSER genotypes (2R2R, 8.61+/-1.68 micromol/L; 2R3R, 7.84+/-2.16 micromol/L; 3R3R, 8.05+/-2.81 micromol/L; p=0.9319). Among the combined genotypes of MTHFR C677T and TSER, 677TT-3R3R genotype had the highest homocysteine level (11.47+/-4.66 micromol/L). 1298AA-3R3R had the highest level (8.54+/-3.05 micromol/L) among the combined genotypes of MTHFR A1298C and TSER. CONCLUSION: Although there was no significant difference found among combined genotypes, 3R3R showed elevated homocysteine levels in MTHFR 677TT and 1298AA in Korean patients with unexplained recurrent spontaneous abortion. Thus TSER polymorphism may be a genetic determinant of plasma homocysteine level in Korean patients as well as MTHFR C677T polymorphism.     

Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene in patients with essential tremor in Turkey.

Essential tremor (ET) is a most common human movement disorder of unknown etiology. Previous reports have shown that the C677T polymorphism of methylenetetrahydrofolate reductase gene has been associated with neurodegenerative disorders. To investigate the role of methylenetetrahydrofolate reductase gene polymorphisms in essential tremor, we analyzed the alleles and genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in a total of 158 unrelated essential tremor patients and compared them with those of 246 unrelated healthy control subjects, using a polymerase chain reaction restriction fragment length polymorphism method. The allele frequency of MTHFR 677T was 35.76% in the essential tremor cases and 30.08% in the controls. We obtained statistically significant results for MTHFR677 and also for MTHFR1298. The MTHFR T677T genotype was overrepresented and was statistically significant. The T677T/A1298A and C677C/C1298C compound genotypes were similarly statistically significant. The C677C/A1298A compound genotype provided protection for essential tremor. In conclusion, the MTHFR 677T, 1298C alleles and MTHFR T677T genotype and T677T/A1298A, and C677C/C1298C compound genotypes are genetic risk factors for essential tremor in Turkey.     

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal)

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population.     

抑郁症患者MTHFR基因多态性的研究

目的:探讨抑郁症患者5,10-亚甲基四氢叶酸还原酶(MTHFR)基因多态性与抑郁症发病的相关性。方法:将94例抑郁症患者作为研究组,选98名身心健康正常人为对照组,用荧光偏振免疫法检测血清同型半胱氨酸水平,运用聚合酶链反应-限制性内切酶片段长度多态性分析技术(PCR-RFLP)检测MTHFR基因C677T多态性。入组时对患者组进行汉密尔顿抑郁量表(HAMD)评定。结果:研究组患者血清同型半胱氨酸水平显著高于对照组[(16.72±3.94)μmol/L,(10.99±3.51)μmol/L;P<0.05],研究组高同型半胱氨酸血症发生率显著高于对照组[(41.5%,14.3%)(χ2=14.89,P<0.05)]。患者组与对照组基因型频率和等位基因频率分布差异有统计学意义(P<0.05)。患者组和对照组TT基因型血清同型半胱氨酸浓度均较CT型、CC型高,且患者组TT基因型HAMD评分也比后两者高(P<0.05)。结论:TT基因型可能是抑郁症发病的重要危险因素之一,它可能是通过影响血清同型半胱氨酸水平而影响抑郁症的严重程度。     

Evaluation of the roles of common genetic mutations in leukoaraiosis

OBJECTIVES: Leukoaraiosis, a relatively frequent neuroimaging entity, is presumed to be primarily a vascular problem. However, it can be explained only in part by vascular risk factors. With the assumption of genetic susceptibility, the roles of common genetic polymorphisms and mutations in leukoaraiosis were examined in this study. MATERIAL AND METHODS: A detailed clinical scrutiny of 843 Hungarian neurological patients with mild cognitive-like complaints revealed 229 subjects with leukoaraiosis that was probably vascular in origin: 143 with leukoaraiosis alone (group 1), and 86 with leukoaraiosis plus cerebral infarction (group 2). In all 229 patients, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutation and angiotensin-converting enzyme (ACE I/D) polymorphism were examined by means of the PCR technique. The prevalences of the different genotypes for the examined mutations in the 2 groups were analysed in comparison with the data on 362 neuroimaging alteration-free subjects as controls. RESULTS: The ACE D/D genotype (38.37%, P<0.0005; OR 2.46, 95% CI, 1.49-4.08) and ACE D allele (61%; P<0.001) were more frequent in group 2 than in the control group (20.17%; 47%). Neither the homozygous nor the heterozygous MTHFR C677T mutation alone was found to be a risk factor for leukoaraiosis. The homozygous MTHFR C677T mutation combined with the ACE D/D genotype was significantly more frequent in group 1 (11.89%, P<0.0005; OR 4.75, 95% CI, 2.12-10.65), in group 2 (12.79%, P<0.0005; OR 5.16, 95% CI, 2.12-12.6) and in combined group 1+2 (12.23%, P<0.0005; OR 4.9, 95% CI, 2.33-10.3) than in the control group (2.76%). CONCLUSION: These data indicate that the contributions of the ACE D/D genotype and the homozygous MTHFR C677T mutation to leukoaraiosis should be taken into consideration not as major, but as additive factors. These findings draw attention to the fact that genetic polymorphisms that alone are insignificant can be risk factors for leukoaraiosis if they cluster in the same subjects.     

Homocysteine serum levels and MTHFR C677T genotype in patients with Parkinson's disease, with and without levodopa therapy

Both methylenetetrahydrofolate (MTHFR) C677T genotype and levodopa treatment may give rise to elevated serum homocysteine levels in parkinsonian patients. We aimed to clarify the interplay of these factors in pathogenesis of Parkinson's disease (PD)-related hyperhomocysteinemia. Total serum levels of homocysteine (tHcy) and MTHFR C677T genotype were investigated in levodopa-treated and -untreated parkinsonian ("de novo") patients, as well as in control healthy subjects matched by age and gender (N=83, 30 and 53, respectively). MTHFR C677T genotypes were equally distributed in PD patients and control subjects, the T allele homozygosity being observed in app. 12-17% cases. tHcy concentrations were significantly higher in both levodopa-treated and -untreated PD patients than in control subjects, and in TT homozygotes than in CT or CC genotype carriers. tHcy levels significantly correlated with the duration of the disease in PD treated patients only, reaching the maximum after 3-6 years. However, there was no correlation between tHcy levels and total daily intake of levodopa in the same group of PD patients. In conclusion, MTHFR C677T genotype is a significant factor for hyperhomocysteinemia in patients with PD, levodopa-untreated and probably even more in levodopa-treated PD patients.     

Gene--nutrition interactions in coronary artery disease: correlation between the MTHFR C677T polymorphism and folate and homocysteine status in a Korean population

INTRODUCTION: Elevated plasma total homocysteine is a major risk for coronary artery disease (CAD). Methyltetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in homocysteine metabolism; a common C677T mutation in the MTHFR gene results in decreased enzyme activity, and contributes to increased homocysteine levels and decreased folate levels. We investigated the frequency of MTHFR C677T alleles in a Korean population, determined the genotype-specific threshold levels of folate or vitamin B12, and investigated the relationship between the TT genotype and the risk of CAD. MATERIALS AND METHODS: We enrolled a study population of 163 CAD patients and 50 control subjects, and screened the MTHFR C677T polymorphism using real-time PCR with melting point analysis. Levels of plasma homocysteine, folate and vitamin B12 were also determined. We then defined the genotype-specific threshold values of folate and vitamin B12 required to keep homocysteine levels in a normal range for individuals of each MTHFR C677T genotype. RESULTS: The frequency of the TT genotype was 18% in control subjects and 26% in patients group (P>0.05). Individuals homozygous for the TT genotype had significantly elevated homocysteine levels (P<0.05). The genotype-specific folate threshold level was significantly higher in TT individuals than in the CC or CT genotypes. The OR of individuals with low folate status and the TT genotype to estimate the relative risk of CAD was 2.2 and the OR of those with high folate status and the TT genotype was 1.5 (95% CI, 0.5-9.6 and 0.7-3.2, respectively). CONCLUSION: We were able to define a gene-nutrient interaction that shows a higher risk for CAD based on specific threshold folate levels required by different MTHFR C677T genotypes in a Korean population.     

Genetic variants of angiotensin converting enzyme and methylenetetrahydrofolate reductase may act in combination to increase migraine susceptibility

Migraine, with and without aura (MA and MO), is a prevalent and complex neurovascular disorder that is likely to be influenced by multiple genes some of which may be capable of causing vascular changes leading to disease onset. This study was conducted to determine whether the ACE I/D gene variant is involved in migraine risk and whether this variant might act in combination with the previously implicated MTHFR C677T genetic variant in 270 migraine cases and 270 matched controls. Statistical analysis of the ACE I/D variant indicated no significant difference in allele or genotype frequencies (P > 0.05). However, grouping of genotypes showed a modest, yet significant, over-representation of the DD/ID genotype in the migraine group (88%) compared to controls (81%) (OR of 1.64, 95% CI: 1.00-2.69, P = 0.048). Multivariate analysis, including genotype data for the MTHFR C677T, provided evidence that the MTHFR (TT) and ACE (ID/DD) genotypes act in combination to increase migraine susceptibility (OR = 2.18, 95% CI: 1.15-4.16, P = 0.018). This effect was greatest for the MA subtype where the genotype combination corresponded to an OR of 2.89 (95% CI:1.47-5.72, P = 0.002). In Caucasians, the ACE D allele confers a weak independent risk to migraine susceptibility and also appears to act in combination with the C677T variant in the MTHFR gene to confer a stronger influence on the disease.