Hermans, Michel
[UCL]
Gala, Jean-Luc
[UCL]
Buysschaert, Martin
[UCL]
OBJECTIVE: Individuals with Type 2 diabetes are at increased risk of stroke. Plasma homocysteine (tHcy) is an independent risk factor for cardiovascular (CV) disease. The methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism (thermolabile variant C(677)T) is associated with CV risk, partly as a result of increased Hcy, especially in homozygous subjects. AIM: To relate the occurrence of the MTHFR polymorphism with stroke prevalence by examining allelic frequency and genotype distribution in 165 subjects with Type 2 diabetes studied for the presence of thermolabile C(677)T MTHFR mutation. RESULTS: Mean age was 67.7 years, and tHcy 18.2 micromol/l. T allele frequency was 38.5%. MTHFR genotypes were: normal (CC) 40%; heterozygous (CT) 43%; homozygous (TT) 17%. Serum levels of folic acid and B12 vitamin were within normal limits. Stroke prevalence was 14%. Sixty-four per cent of stroke-free subjects had the normal C allele vs. 46% in stroke subjects. The frequencies of genotypes (CC-CT-TT) were (%): 44-41-15 in stroke-free vs. 17-57-26 in stroke patients. Coronary (CAD) and peripheral artery disease (PAD) were common in all groups, with no differences according to genotypes. Stroke prevalence was markedly higher in genotypes CT and TT (18 and 21%) compared with CC (6%). Mean tHcy levels were higher in TT subjects. CONCLUSION: The allelic frequency of C(677)T MTHFR mutation in Type 2 diabetes subjects with stroke is markedly different from that of subjects without stroke. Genotypic characteristics suggest that C(677)T MTHFR mutation confers a higher risk for stroke to both homozygous and heterozygous T allele carriers that cannot be ascribed solely to raised tHcy and/or lower folate status in CT subjects, nor to phenotypic expression of conventional risk factors for stroke. The impact of the MTHFR polymorphism on stroke may result from T allele-linked deleterious effects, or C allele-linked protection. Confirmatory studies are warranted, as this cohort was not randomly selected, and a type 1 error cannot be ruled out.
- de Bree A, Am J Clin Nutr, 77, 687 (2003)
- Kluijtmans L. A. J., Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults, 10.1182/blood.v101.7.2483
- Manson J. E., A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women, 10.1001/archinte.151.6.1141
- Stamler J, Diabetes Care, 16, 434 (1993)
- Kothari V., Stevens R. J., Adler A. I., Stratton I. M., Manley S. E., Neil H. A., Holman R. R., UKPDS 60: Risk of Stroke in Type 2 Diabetes Estimated by the UK Prospective Diabetes Study Risk Engine, 10.1161/01.str.0000020091.07144.c7
- Boushey C. J., A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes, 10.1001/jama.274.13.1049
- Munshi Medha N., Stone Angie, Fink Louis, Fonseca Vivian, Hyperhomocysteinemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease, 10.1016/s0026-0495(96)90211-5
- Nygård Ottar, Nordrehaug Jan Erik, Refsum Helga, Ueland Per Magne, Farstad Mikael, Vollset Stein Emil, Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease, 10.1056/nejm199707243370403
- Hoogeveen E. K., Kostense P. J., Beks P. J., Mackaay A. J. C., Jakobs C., Bouter L. M., Heine R. J., Stehouwer C. D. A., Hyperhomocysteinemia Is Associated With an Increased Risk of Cardiovascular Disease, Especially in Non Insulin-Dependent Diabetes Mellitus : A Population-Based Study, 10.1161/01.atv.18.1.133
- Okada E, Diabetes Care, 22, 484 (1999)
- Hoogeveen E. K., Kostense P. J., Jakobs C., Dekker J. M., Nijpels G., Heine R. J., Bouter L. M., Stehouwer C. D. A., Hyperhomocysteinemia Increases Risk of Death, Especially in Type 2 Diabetes : 5-Year Follow-Up of the Hoorn Study, 10.1161/01.cir.101.13.1506
- Becker A., Kostense P. J., Bos G., Heine R. J., Dekker J. M., Nijpels G., Bouter L. M., Stehouwer C. D. A., Hyperhomocysteinaemia is associated with coronary events in type 2 diabetes, 10.1046/j.1365-2796.2003.01113.x
- Buysschaert M, Mises Au Point Cliniques D'endocrinologie, Nutrition et Metabolisme., 169 (2003)
- Buysschaert M, Journees de Diabetologie Hotel-Dieu 2003., 229 (2003)
- Lawrence de Koning A.B., Werstuck Geoff H., Zhou Ji, Austin Richard C., Hyperhomocysteinemia and its role in the development of atherosclerosis, 10.1016/s0009-9120(03)00062-6
- Soinio Minna, Marniemi Jukka, Laakso Markku, Lehto Seppo, Rönnemaa Tapani, Elevated Plasma Homocysteine Level Is an Independent Predictor of Coronary Heart Disease Events in Patients with Type 2 Diabetes Mellitus, 10.7326/0003-4819-140-2-200401200-00009
- Welch George N., Loscalzo Joseph, Homocysteine and Atherothrombosis, 10.1056/nejm199804093381507
- Stanger O., Herrmann W., Pietrzik K., Fowler B., Geisel J., Dierkes J., Weger M., DACH-LIGA Homocystein (German, Austrian and Swiss Homocysteine Society): Consensus Paper on the Rational Clinical Use of Homocysteine, Folic Acid and B-Vitamins in Cardiovascular and Thrombotic Diseases: Guidelines and Recommendations, 10.1515/cclm.2003.214
- Geisel Jürgen, Hübner Ulrich, Bodis Marion, Schorr Heike, Knapp Jean-Pierre, Obeid Rima, Herrmann Wolfgang, The Role of Genetic Factors in the Development of Hyperhomocysteinemia, 10.1515/cclm.2003.219
- Buysschaert M, Diabetes Metab, 30, 349 (2004)
- Casas Juan P, Bautista Leonelo E, Smeeth Liam, Sharma Pankaj, Hingorani Aroon D, Homocysteine and stroke: evidence on a causal link from mendelian randomisation, 10.1016/s0140-6736(05)17742-3
- Frosst P., Blom H.J., Milos R., Goyette P., Sheppard C.A., Matthews R.G., Boers G.J.H., den Heijer M., Kluijtmans L.A.J., van den Heuve L.P., Rozen R., A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase, 10.1038/ng0595-111
- Girelli D, Blood, 91, 4158 (1998)
- Fodinger M, J Nephrol, 13, 1 (1999)
- Fodinger M, Kidney Int, 52, 517 (1997)
- Lim Paik-Seong, Hung Wan-Ru, Wei Yau-Huei, Polymorphism in Methylenetetrahydrofolate Reductase Gene: Its Impact on Plasma Homocysteine Levels and Carotid Atherosclerosis in ESRD Patients Receiving Hemodialysis, 10.1159/000045922
- Buysschaert M, Diabetes Care, 23, 1816 (2000)
- Kang S., Hyperhomocyst(e)inemia as a Risk Factor for Occlusive Vascular Disease, 10.1146/annurev.nutr.12.1.279
- , Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 10.2337/diacare.20.7.1183
- 28The Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults . Third report. Available from: http://www.nhlbi.nih.gov/guidelines/cholesterol/.
- , UK prospective diabetes study (UKPDS) : VIII. Study design, progress and performance, 10.1007/bf00400195
- Buysschaert M, Diabetes Metab, 27, 655 (2001)
- Hermans MP, Diabetes, 48, 1779 (1999)
- 32OMIM'. Online Mendelian inheritance in man. Available from: http://www.ncbi.nlm.nih.gov/omim/.
- Szolnoki Z, Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke, 10.1136/jnnp.74.12.1615
- Kim Robert J, Becker Richard C, Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies, 10.1016/s0002-8703(03)00519-2
- Kissela BM, Diabetes Care, 28, 355 (2005)
- Fonseca V., Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis, 10.1210/er.20.5.738
- Chango A, Br J Nutr, 83, 593 (2000)
- Meleady R, Am J Clin Nutr, 77, 63 (2003)
- Homocysteine Studies Collaboration, Homocysteine and Risk of Ischemic Heart Disease and Stroke : A Meta-analysis, 10.1001/jama.288.16.2015
- Klerk Mariska, Verhoef Petra, Clarke Robert, Blom Henk J., Kok Frans J., Schouten Evert G., and the MTHFR Studies Collaboration Group, MTHFR 677C→T Polymorphism and Risk of Coronary Heart Disease : A Meta-analysis, 10.1001/jama.288.16.2023
- Geisel Jürgen, Hennen Benno, Hübner Ulrich, Knapp Jean-Pierre, Herrmann Wolfgang, The Impact of Hyperhomocysteinemia as a Cardiovascular Risk Factor in the Prediction of Coronary Heart Disease, 10.1515/cclm.2003.232
- Stanger Olaf, Weger Martin, Interactions of Homocysteine, Nitric Oxide, Folate and Radicals in the Progressively Damaged Endothelium, 10.1515/cclm.2003.222
- Aso Y., Okumura K., Yoshida N., Tayama K., Kanda T., Kobayashi I., Takemura Y., Inukai T., Plasma interleukin-6 is associated with coagulation in poorly controlled patients with Type 2 diabetes, 10.1046/j.1464-5491.2003.01058.x
- Selhub J, Am J Clin Nutr, 71, 614S (2000)
- Mutus B., Rabini R. A., Staffolani R., Ricciotti R., Fumelli P., Moretti N., Martarelli D., Mazzanti L., Homocysteine-induced inhibition of nitric oxide production in platelets: a study on healthy and diabetic subjects, 10.1007/s001250100581
- Uçar Fahri, Sönmez Mehmet, Ovalı Ercüment, Özmenoǧlu Mehmet, Kartı S. Sami, Yılmaz Mustafa, Pakdemir Alper, MTHFR C677T polymorphism and its relation to ischemic stroke in the Black Sea Turkish population : MTHFR Polymorphism and Ischemic Stroke, 10.1002/ajh.20050
- Li Z., Sun L., Zhang H., Liao Y., Wang D., Zhao B., Zhu Z., Zhao J., Ma A., Han Y., Wang Y., Shi Y., Ye J., Hui R., Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke: A Multicenter Case-Control Study in China, 10.1161/01.str.0000086753.00555.0d
- Kohara K., Fujisawa M., Ando F., Tabara Y., Niino N., Miki T., Shimokata H., MTHFR Gene Polymorphism as a Risk Factor for Silent Brain Infarcts and White Matter Lesions in the Japanese General Population: The NILS-LSA Study, 10.1161/01.str.0000069163.02611.b0
- Rodríguez‐Esparragón Francisco, Hernández‐Perera Octavio, Rodríguez‐Pérez José C., Anabitarte Aránzazu, Díaz‐Cremades Juan M., Losada Antonio, Fiuza Dolores, Hernández Enrique, Yunis Carla, Ferrario Carlos M., The Effect of Methylenetetrahydrofolate Reductase C677T Common Variant on Hypertensive Risk Is Not Solely Explained by Increased Plasma Homocysteine Values, 10.1081/ceh-120020391
- Stehouwer Coen D. A., Guldener Coen van, Does Homocysteine Cause Hypertension?, 10.1515/cclm.2003.216
- Kelly P. J., Rosand J., Kistler J. P., Shih V. E., Silveira S., Plomaritoglou A., Furie K. L., Homocysteine, MTHFR 677C->T polymorphism, and risk of ischemic stroke: Results of a meta-analysis, 10.1212/wnl.59.4.529
Bibliographic reference |
Hermans, Michel ; Gala, Jean-Luc ; Buysschaert, Martin. The MTHFR CT polymorphism confers a high risk for stroke in both homozygous and heterozygous T allele carriers with Type 2 diabetes.. In: Diabetic medicine : a journal of the British Diabetic Association, Vol. 23, no. 5, p. 529-36 (2006) |
Permanent URL |
http://hdl.handle.net/2078.1/10579 |