MTHFR C677T基因多态性与脑小血管病的相关性研究进展
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摘要
亚甲基四氢叶酸还原酶(MTHFR)影响了缺血性脑卒中发生的各个环节,其位点C677T基因突变会大大降低酶活性和耐热性,致使同型半胱氨酸在体内积蓄,高同型半胱氨酸血症(HHcy)通过损伤血管内皮功能造成靶器官的损害,尤其是对具有明显遗传易感性的脑小血管病(CSVD)。CSVD是导致老年人运动与认知功能障碍的重要危险因素,其在脑磁共振成像上以脑白质高信号、腔隙性脑梗死、血管周围间隙扩大、脑微出血及脑萎缩为特征。近年来,一些研究从MTHFR C677T基因型多态性的角度阐明了HHcy与CSVD各个亚型之间的关系及致病机制,从而为未来CSVD的防治提供了新途径。
Methylenetetrahydrofolate reductase( MTHFR) affects every link of ischemic stroke. The mutation of C677 T gene will greatly reduce the enzyme activity and heat resistance,resulting in the accumulation of homocysteine in the body.Hyperhomocysteinemia( HHcy) causes target organ damage by damaging vascular endothelial function,especially for cerebral small vessel disease( CSVD) with obvious genetic susceptibility. CSVD is an important risk factor leading to motor and cognitive dysfunction in the elderly,which is characterized by white matter hyperintensities,lacunar infarction,enlargement of perivascular space,cerebral microbleeds and cerebral atrophy on brain magnetic resonance imaging. In recent years,some studies have clarified the pathogenesis and relationship between HHcy and CSVD subtypes from the perspective of MTHFR C677 T genotype polymorphism,thus providing a new way for the prevention and treatment of CSVD in the future.
Methylenetetrahydrofolate reductase( MTHFR) affects every link of ischemic stroke. The mutation of C677 T gene will greatly reduce the enzyme activity and heat resistance,resulting in the accumulation of homocysteine in the body.Hyperhomocysteinemia( HHcy) causes target organ damage by damaging vascular endothelial function,especially for cerebral small vessel disease( CSVD) with obvious genetic susceptibility. CSVD is an important risk factor leading to motor and cognitive dysfunction in the elderly,which is characterized by white matter hyperintensities,lacunar infarction,enlargement of perivascular space,cerebral microbleeds and cerebral atrophy on brain magnetic resonance imaging. In recent years,some studies have clarified the pathogenesis and relationship between HHcy and CSVD subtypes from the perspective of MTHFR C677 T genotype polymorphism,thus providing a new way for the prevention and treatment of CSVD in the future.
引文
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[52]Vajtr D,Springer D,Staněk L,et al.Pathomorphology of inflammatory response following traumatic brain injury,serum values of interleukins,and gene polymorphisms[J].Soud Lek,2014,59(4):40-47.
[53]Haller S,Vernooij MW,Kuijer JPA,et al.Cerebral microbleeds:Imaging and clinical significance[J].Radiology,2018,287(1):11-28.
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[57]Tan B,Venketasubramanian N,Vrooman H,et al.Homocysteine and cerebral atrophy:The epidemiology of dementia in singapore study[J].J Alzheimers Dis,2018,62(2):877-855.
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[2]D'Angelo A,Coppola A,Madonna P,et al.The role of vitamin B12in fasting hyperhomocysteinemia and its interaction with the homozygous C677T mutation of the methylenetetrahydrofolate reductase(MTHFR)gene.A case-control study of patients with early-onset thrombotic events[J].Thromb Haemost,2000,83(4):563-570.
[3]Liew SC,Gupta ED.Methylenetetrahydrofolate reductase(MTHFR)C677T polymorphism:Epidemiology,metabolism and the associated diseases[J].Eur J Med Genet,2015,58(1):1-10.
[4]Aarabi M,Christensen KE,Chan D,et al.Testicular MTHFRdeficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation[J].Hum Mol Genet,2018,27(7):1123-1135.
[5]Colson NJ,Naug HL,Nikbakht E,et al.The impact of MTHFR677 C/T genotypes on folate status markers:A meta-analysis of folic acid intervention studies[J].Eur J Nutr,2017,56(1):247-260.
[6]Homocysteine Studies Collaboration.Homocysteine and risk of ischemic heart disease and stroke:A meta-analysis[J].JAMA,2002,288(16):2015-2022.
[7]Holmes MV,Newcombe P,Hubacek JA,et al.Effect modification by population dietary folate on the association between MTHFRgenotype,homocysteine,and stroke risk:A meta-analysis of genetic studies and randomised trials[J].Lancet,2011,378(9791):584-594.
[8]Wu XQ,Ding J,Ge AY,et al.Acute phase homocysteine related to severity and outcome of atherothrombotic stroke[J].Eur JIntern Med,2013,24(4):362-367.
[9]Frosst P,Blom HJ,Milos R,et al.A candidate genetic risk factor for vascular disease:A common mutation in methylenetetrahydrofolate reductase[J].Nat Genet,1995,10(1):111-113.
[10]Yamaji T,Iwasaki M,Sasazuki S,et al.Methionine synthase A2756G polymorphism interacts with alcohol and folate intake to influence the risk of colorectal adenoma[J].Cancer Epidemiol Biomarkers Prev,2009,18(1):267-274.
[11]Selhub J.Homocysteine metabolism[J].Annu Rev Nutr,1999,19:217-246.
[12]Pushpakumar S,Kundu S,Sen U.Endothelial dysfunction:The link between homocysteine and hydrogen sulfide[J].Curr Med Chem,2014,21(32):3662-3672.
[13]Kim CS,Kim YR,Naqvi A,et al.Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc[J].Cardiovasc Res,2011,92(3):466-475.
[14]Liu S,Sun Z,Chu P,et al.EGCG protects against homocysteineinduced human umbilical vein endothelial cells apoptosis by modulating mitochondrial-dependent apoptotic signaling and PI3K/Akt/e NOS signaling pathways[J].Apoptosis,2017,22(5):672-680.
[15]胡大一,徐希平.有效控制“H型”高血压---预防卒中的新思路[J].中华内科杂志,2008,47(12):976-977.
[16]O'Donnell MJ,Xavier DL,Liu L,et al.Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries(the INTER-STROKE study):A case-control study[J].Lancet,2010,376(9735):112-123.
[17]Men X,Li J,Zhang B,et al.Homocysteine and C-reactive protein associated with progression and prognosis of intracranial branch atheromatous disease[J].PLo S One,2013,8(9):e73030.
[18]Wang W,Jiang B,Sun H,et al.Prevalence,incidence and mortality of stroke in China:Results from a nationwide population-based survey of 480 687 adults[J].Circulation,2017,135(8):759-771.
[19]Wald DS,Law M,Morris JK.Homocysteine and cardiovascular disease:Evidence on causality from a meta-analysis[J].BMJ,2002,325(7374):1202.
[20]Park SY,An SA,Lee HB,et al.Different impact of hyperhomocysteinemia on cerebral small vessel ischemia and cervico-cerebral atherosclerosis in non-stroke individuals[J].Thromb Res,2013,131(1):e12-16.
[21]Ilhan N,Kucuksu M,Kaman D,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.
[22]李建平,霍勇,刘平,等.马来酸依那普利叶酸片降压、降同型半胱氨酸的疗效和安全性[J].北京大学学报(医学版),2007,39(6):614-618.
[23]Sen U,Mishra PK,Tyagi N,et al.Homocysteine to hydrogen sulfide or hypertension[J].Cell Biochem Biophys,2010,57(2/3):49-58.
[24]Mc Nulty H,Strain JJ,Hughes CF,et al.Riboflavin,MTHFR genotype and blood pressure:A personalized approach to prevention and treatment of hypertension[J].Mol Aspects Med,2017,53:2-9.
[25]Steluti J,Carvalho AM,Carioca AAF,et al.Genetic variants involved in one-carbon metabolism:Polymorphism frequencies and differences in homocysteine concentrations in the folic acid fortification era[J].Nutrients,2017,9(6).pii:E539.
[26]Wang CY,Chen ZW,Zhang T,et al.Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients[J].Eur J Intern Med,2014,25(6):538-544.
[27]Zhao M,Wang X,He M,et al.Homocysteine and stroke risk:Modifying effect of methylenetetrahydrofolate reductase C677Tpolymorphism and folic acid intervention[J].Stroke,2017,48(5):1183-1190.
[28]脑小血管病诊治专家共识组.脑小血管病的诊治专家共识[J].中华内科杂志,2013,52(10):893-896.
[29]Wardlaw JM,Smith C,Dichgans M.Mechanisms of sporadic cerebral small vessel disease:Insights from neuroimaging[J].Lancet Neurol,2013,12(5):483-497.
[30]Thompson CS,Hakim AM.Living beyond our physiological means:Small vessel disease of the brain is an expression of a systemic failure in arteriolar function:A unifying hypothesis[J].Stroke,2009,40(5):e322-330.
[31]Cai C,Xiao R,Halm-Lutterodt N,et al.Association of MTHFR,SLC19A1 genetic polymorphism,serum folate,vitamin B12and hcy status with cognitive functions in Chinese adults[J].Nutrients,2016,8(10).pii:E665.
[32]Wardlaw JM,Smith EE,Biessels GJ,et al.Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration[J].Lancet Neurol,2013,12(8):822-838.
[33]Rutten-Jacobs LC,Traylor M,Adib-Samii P,et al.Association of MTHFR C677T Genotype with ischemic stroke is confined to cerebral small vessel disease subtype[J].Stroke,2016,47(3):646-651.
[34]Hachinski VC,Potter P,Merskey H.Leuko-araiosis:An ancient term for a new problem[J].Can J Neurol Sci,1986,13(4 Suppl):533-534.
[35]Anstrom JA,Brown WR,Moody DM,et al.Anatomical analysis of the developing cerebral vasculature in premature neonates:Absence of precapillary arteriole-to-venous shunts[J].Pediatr Res,2002,52(4):554-560.
[36]Meissner A.Hypertension and the brain:A risk factor for more than heart disease[J].Cerebrovasc Dis,2016,42(3/4):255-262.
[37]Rensma SP,van Sloten TT,Launer LJ,et al.Cerebral small vessel disease and risk of incident stroke,dementia and depression,and all-cause mortality:A systematic review and meta-analysis[J].Neurosci Biobehav Rev,2018,90:164-173.
[38]Szolnoki Z,Szaniszlo I,Szekeres M,et al.Evaluation of the MTHFRA1298C variant in leukoaraiosis[J].J Mol Neurosci,2012,46(3):492-496.
[39]Boxer AL,Kramer JH,Johnston K,et al.Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment[J].Neurology,2005,64(8):1431-1434.
[40]Fernàndez-Roig S,Lai SC,Murphy MM,et al.Vitamin B12 deficiency in the brain leads to DNA hypomethylation in the TCblR/CD320 knockout mouse[J].Nutr Metab(Lond),2012,9:41.
[41]Jeon SB,Kang DW,Kim JS,et al.Homocysteine,small-vessel disease,and atherosclerosis:An MRI study of 825 stroke patients[J].Neurology,2014,83(8):695-701.
[42]Rutten-Jacobs LCA,Markus HS,UK Young Lacunar Stroke DNAStudy.Vascular risk factor profiles differ between magnetic resonance imaging-defined subtypes of younger-onset lacunar stroke[J].Stroke,2017,48(9):2405-2411.
[43]Thong JY,Hilal S,Wang Y,et al.Association of silent lacunar infarct with brain atrophy and cognitive impairment[J].J Neurol Neurosurg Psychiatry,2013,84(11):1219-1225.
[44]Del Bene A,Makin SD,Doubal FN,et al.Variation in risk factors for recent small subcortical infarcts with infarct size,shape,and location[J].Stroke,2013,44(11):3000-3006.
[45]Choi BO,Kim NK,Kim SH,et al.Homozygous C677T mutation in the MTHFR gene as an independent risk factor for multiple smallartery occlusions[J].Thromb Res,2003,111(1/2):39-44.
[46]Moat SJ,Lang D,Mc Dowell IF,et al.Folate,homocysteine,endothelial function and cardiovascular disease[J].J Nutr Biochem,2004,15(2):64-79.
[47]Heier LA,Bauer CJ,Schwartz L,et al.Large Virchow-Robin spaces:MR-clinical correlation[J].AJNR Am J Neuroradiol,1989,10(5):929-936.
[48]Oreskovi D,Klarica M.The formation of cerebrospinal fluid:Nearly a hundred years of interpretations and misinterpretations[J].Brain Res Rev,2010,64(2):241-262.
[49]Yakushiji Y,Charidimou A,Hara M,et al.Topography and associations of perivascular spaces in healthy adults:The Kashima scan study[J].Neurology,2014,83(23):2116-2123.
[50]Charidimou A,Meegahage R,Fox Z,et al.Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage:A multicentre MRI cohort study[J].J Neurol Neurosurg Psychiatry,2013,84(6):624-629.
[51]Riba-Llena I,Jiménez-Balado J,Casta1éX,et al.Arterial stiffness is associated with basal ganglia enlarged perivascular spaces and cerebral small vessel disease load[J].Stroke,2018,49(5):1279-1281.
[52]Vajtr D,Springer D,Staněk L,et al.Pathomorphology of inflammatory response following traumatic brain injury,serum values of interleukins,and gene polymorphisms[J].Soud Lek,2014,59(4):40-47.
[53]Haller S,Vernooij MW,Kuijer JPA,et al.Cerebral microbleeds:Imaging and clinical significance[J].Radiology,2018,287(1):11-28.
[54]Park JH,Seo SW,Kim C,et al.Pathogenesis of cerebral microbleeds:In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment[J].Ann Neurol,2013,73(5):584-593.
[55]Wang BR,Ou Z,Jiang T,et al.Independent correlation of serum homocysteine with cerebral microbleeds in patients with acute ischemic stroke due to large-artery atherosclerosis[J].J Stroke Cerebrovasc Dis,2016,25(11):2746-2751.
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