Background: Cervical artery dissection (CAD) is a recognized cause of ischemic stroke. Hyperhomocysteinemia (HHcy), i.e. an elevated concentration of plasma homocysteine, is identified as an independent risk factor for stroke prevalence. However, an association between HHcy and CAD has so far remained unknown. Methods: A meta-analysis was performed to analyze the association between HHcy and CAD as well as the relevance of the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR), the key enzyme in homocysteine metabolism during CAD. We searched PubMed and Embase for studies reporting homocysteine concentrations or MTHFR genotype frequencies in CAD patients from 1990 to 2013. Outcomes were extracted from studies meeting the inclusion criteria and were subjected to a meta-analysis by the random-effect model. Heterogeneity was assessed by the I2 test. Results: Eight case-control studies with 2,146 individuals fulfilled the required criteria and were included in the meta-analysis. HHcy was found to be significantly associated with CAD (pooled standardized mean difference: 0.96; 95% confidence interval, CI: 0.42-1.49; p < 0.01). We also found a significantly increased risk of CAD in individuals with the MTHFR C677T polymorphism by both the recessive model (TT vs. CT+CC; odds ratio, OR = 1.81; 95% CI: 1.22-2.67; p = 0.003) and the dominant model (TT+CT vs. CC; OR = 1.47; 95% CI: 1.08-1.99; p = 0.014). Conclusion: Our data suggest positive correlations between HHcy and CAD and between the C677T polymorphism of MTHFR and CAD.

Bogousslavsky J, Pierre P: Ischemic stroke in patients under age 45. Neurol Clin 1992;10:113-124.
Campos-Herrera CR, Scaff M, Yamamoto FI, Conforto AB: Spontaneous cervical artery dissection: an update on clinical and diagnostic aspects. Arq Neuropsiquiatr 2008;66:922-927.
Schievink WI: Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;344:898-906.
Caplan LR: Dissections of brain-supplying arteries. Nat Clin Pract Neurol 2008;4:34-42.
Mokri B Jr, Sundt TM, Houser OW, Piepgras DG: Spontaneous dissection of the cervical internal carotid artery. Ann Neurol 1986;19:126-138.
Lucas C, Moulin T, Deplanque D, Tatu L, Chavot D: Stroke patterns of internal carotid artery dissection in 40 patients. Stroke 1998;29:2646-2648.
de Bray JM, Baumgartner RW: History of spontaneous dissection of the cervical carotid artery. Arch Neurol 2005;62:1168-1170.
Tzourio C, et al: Migraine and the risk of cervical artery dissection: a case-control study. Neurology 2002;59:435-437.
Tzourio C, Benslamia L, Guillon B, Aidi S, Bertrand M, Berthet K, et al: Association between acute cerebrovascular ischemia and chronic and recurrent infection. Stroke 1997;28:1724-1729.
Refsum H, Nurk E, Smith AD, Ueland PM, Gjesdal CG, Bjelland I, et al: The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr 2006;136(6 suppl):S1731-S1740.
Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al: Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995;274:1526-1533.
Kelly PJ, Rosand J, Kistler JP, Shih VE, Silveira S, Plomaritoglou A, et al: Homocysteine, MTHFR 677C>T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology 2002;59:529-536.
Takagi H, Umemoto T: Homocysteinemia is a risk factor for aortic dissection. Med Hypotheses 2005;64:1007-1010.
Clarke R, Bennett DA, Parish S, Verhoef P, Dotsch-Klerk M, Lathrop M, et al: Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med 2012;9:e1001177.
Minagawa H, Watanabe A, Akatsu H, Adachi K, Ohtsuka C, Terayama Y, et al: Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function. J Biol Chem 2010;285:38382-38388.
Zhang D, Fang P, Jiang X, Nelson J, Moore JK, Kruger WD, et al: Severe hyperhomocysteinemia promotes bone marrow-derived and resident inflammatory monocyte differentiation and atherosclerosis in LDLr/CBS-deficient mice. Circ Res 2012;111:37-49.
Guo YH, Chen FY, Wang GS, Chen L, Gao W: Diet-induced hyperhomocysteinemia exacerbates vascular reverse remodeling of balloon-injured arteries in rat. Chin Med J (Engl) 2008;121:2265-2271.
Jiang C, Zhang H, Zhang W, Kong W, Zhu Y, Zhang H, et al: Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin. Am J Physiol Cell Physiol 2009;297:C1466-C1476.
Fowler B: Disorders of homocysteine metabolism. J Inherit Metab Dis 1997;20:270-285.
Födinger M, Hörl WH, Sunder-Plassmann G: Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol 2000;13:20-33.
Sunder-Plassmann G, Födinger M: Genetic determinants of the homocysteine level. Kidney Int Suppl 2003;84:S141-S144.
Duncan IC, Terblanché JM: Spontaneous isolated posterior communicating artery dissection in a young adult with hyperhomocysteinemia. AJNR Am J Neuroradiol 2005;26:2030-2032.
Pezzini A, del Zotto E, Archetti S, Negrini R, Bani P, Albertini A, et al: Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke. Stroke 2002;33:664-669.
Liu Z, Luo H, Zhang L, Huang Y, Liu B, Ma K, et al: Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice. Circ Res 2012;111:1261-1273.
Gallai V, Caso V, Paciaroni M, Cardaioli G, Arning E, Bottiglieri T, et al: Mild hyperhomocyst(e)inemia: a possible risk factor for cervical artery dissection. Stroke 2001;32:714-718.
Arauz A, Hoyos L, Cantu C, Jara A, Martinez L, Garcia I, et al: Mild hyperhomocysteinemia and low folate concentrations as risk factors for cervical arterial dissection. Cerebrovasc Dis 2007;24:210-214.
Konrad C, Muller GA, Langer C, Kuhlenbaumer G, Berger K, Nabavi DG, et al: Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections. J Neurol 2004;251:1242-1248.
Benninger DH, Herrmann FR, Georgiadis D, Kretschmer R, Sarikaya H, Schiller A, et al: Increased prevalence of hyperhomocysteinemia in cervical artery dissection causing stroke: a case-control study. Cerebrovasc Dis 2009;27:241-246.
Debette S, Markus HS: The genetics of cervical artery dissection: a systematic review. Stroke 2009;40:e459-e466.
McColgan P, Sharma P: The genetics of carotid dissection: meta-analysis of a MTHFR/C677T common molecular variant. Cerebrovasc Dis 2008;25:561-565.
Jara-Prado A, Alonso ME, Martinez Ruano L, Guerrero Camacho J, Leyva A, Lopez M, et al: MTHFR C677T, FII G20210A, FV Leiden G1691A, NOS3 intron 4 VNTR, and APOE ε4 gene polymorphisms are not associated with spontaneous cervical artery dissection. Int J Stroke 2010;5:80-85.
Krings T, Choi IS: The many faces of intracranial arterial dissections. Interv Neuroradiol 2010;16:151-160.
Andersson A, Brattström L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B: Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest 1992;22:79-87.
Thelle DS: STROBE and STREGA: instruments for improving transparency and quality of reporting scientific results. Eur J Epidemiol 2009;24:7-8.
Higgins JP, Green S (eds): Cochrane Handbook for Systematic Reviews of Interventions. Chichester, John Wiley & Sons, 2011.
Hardy RJ, Thompson SG: Detecting and describing heterogeneity in meta-analysis. Stat Med 1998;17:841-856.
Higgins JP, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-1558.
Sharp S: Meta-analysis regression. Stata J 1998;42:16-22.
Kuritz SJ, Landis JR, Koch GG: A general overview of Mantel-Haenszel methods: applications and recent developments. Annu Rev Public Health 1988;9:123-160.
DerSimonian R, Kacker R: Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials 2007;28:105-114.
Minelli C, Thompson JR, Abrams KR, Thakkinstian A, Attia J: The choice of a genetic model in the meta-analysis of molecular association studies. Int J Epidemiol 2005;34:1319-1328.
Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-634.
Pezzini A, Grassi M, del Zotto E, Giossi A, Monastero R, dalla Volta G, et al: Migraine mediates the influence of C677T MTHFR genotypes on ischemic stroke risk with a stroke-subtype effect. Stroke 2007;38:3145-3151.
Kloss M, Wiest T, Hyrenbach S, Werner I, Arnold ML, Lichy C, et al: MTHFR 677TT genotype increases the risk for cervical artery dissections. J Neurol Neurosurg Psychiatry 2006;77:951-952.
Ridker PM, Stampfer MJ, Rifai N: Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001;285:2481-2485.
Lentz SR: Homocysteine and vascular dysfunction. Life Sci 1997;61:1205-1215.
Coppola A, Davi G, de Stefano V, Mancini FP, Cerbone AM, DiMinno G: Homocysteine, coagulation, platelet function, and thrombosis. Semin Thromb Hemost 2000;26:243-254.
Dayal S, Wilson KM, Leo L, Arning E, Bottiglieri T, Lentz SR: Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood 2006;108:2237-2243.
Mohsin Y, Naushad M, Siddiqa P, Bushra C, Iqbal A, Mohammad PI: Polymorphisms in MTHFR, MS and CBS genes and homocysteine levels in a Pakistani population. PLoS One 2012;7:e33222.
Waśkiewicz A, Piotrowski W, Broda G, Sobczyk-Kopcioł A, Płoski R: Impact of MTHFR C677T gene polymorphism and vitamin intake on homocysteine concentration in the Polish adult population. Kardiol Pol 2011;69:1259-1264.
Brattström L, Wilcken DE, Ohrvik J, Brudin L: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 1998;98:2520-2526.
Pezzini A, del Zotto E, Mazzioti G, Ruggeri G, Franco F, Giossi A, et al: Thyroid autoimmunity and spontaneous cervical artery dissection. Stroke 2006;37:2375-2377.
Meng S, Ciment S, Jan M, Tran T, Pham H, Cueto R, et al: Homocysteine induces inflammatory transcriptional signaling in monocytes. Front Biosci 2013;18:685-695.
Herrmann W, Herrmann M, Obeid R: Hyperhomocysteinemia: a critical review of old and new aspects. Curr Drug Metab 2007;8:17-31.
Sheweita SA, Baghdadi H, Allam AR: Role of genetic changes in the progression of cardiovascular diseases. Int J Biomed Sci 2011;7:238-248.
Mansoori N, Tripathi M, Luthra K, Alam R, Lakshmy R, Sharma S, et al: MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction. Neurobiol Aging 2012;33:1003e1-e8.
Castro R, Rivera I, Ravasco P, Jakobs C, Blom HJ, Camilo ME, et al: 5,10-Methylenetetrahydrofolate reductase 677C>T and 1298A>C mutations are genetic determinants of elevated homocysteine. QJM 2003;96:297-303.
Bleich S, Carl M, Bayerlein K, Reulbach U, Biermann T, Hillemacher T, Bönsch D, Kornhuber J: Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS). Alcohol Clin Exp Res 2005;29:334-336.
van Guldener C, Stehouwer CD: Homocysteine-lowering treatment: an overview. Expert Opin Pharmacother 2001;2:1449-1460.
Miller JW, Nadeau MR, Smith D, Selhub J: Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr 1994;59:1033-1039.
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