Low fasting methionine concentration as a novel risk factor for recurrent venous thrombosis

Summary

Hyperhomocysteinemia is a risk factor for venous thrombosis, but the underlying mechanism is unclear. If the thiol-group of homocysteine interferes with components of the clotting system, we expect that high cysteine will be alsoa risk factor for venous thrombosis. If high homocysteine reflects a disturbed methyl-group donation by S-adenosylmethionine, we expect that low methionine will be a risk factor for thrombosis. We performeda case-control study in 185 patients with recurrent venous thrombosis and in 500 control subjects.

We determined methionine, homocysteine, cysteine and assessed the associated thrombotic risk. Low fasting methionine was associated with an increased risk on recurrent venous thrombosis [OR_{bottom vs. top quartile} = 3.3 (95%CI 1.9–5.7)]. Low methionine remained a risk factor [OR_{bottom vs. top quartile}= 3.5 (95%CI 2.0–6.0)] after adjusting for homocysteine and cysteine, whereas the thrombotic risk for homocysteine was lost [OR= 1.0 (95%CI 0.6–1.9)] after adjustment. Cysteine yielded a highest odds ratio of 2.1_{top vs. bottom quartile} (95%CI 1.0–4.0) after adjustment. In conclusion, we found that low fasting methionine is a risk factor for recurrent venous thrombosis.This risk association was stronger for methionine than for homocysteine or cysteine.This supports the hypothesis that impaired methylation may be involved in the pathogenesis of venous thrombosis.

Keywords

Methionine - homocysteine - cysteine - venous thrombosis

• References

• 1 The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. J Am Med Assoc 2002; 288: 2015-22.
• 2 Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis:a metaanalysis of published epidemiological studies. Thromb Haemost 2005; 03: 292-9.
• 3 Majors AK, Sengupta S, Willard B. et al. Homocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin. Arterioscler Thromb Vasc Biol 2002; 22: 1354-9.
• 4 Harpel PC, Chang VT, Borth W. Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin:A potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 1992; 89: 10193-7.
• 5 Undas A, Williams EB, Butenas S. et al. Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem 2001; 276: 4389-97.
• 6 Lauricella AM, Quintana IL, Kordich LC. Effects of homocysteine thiol group on fibrin networks: another possible mechanism of harm. Thromb Res 2002; 107: 75-9.
• 7 Castro R, Rivera I, Struys EA, Jansen EEW, Ravasco P, Camilo ME, Blom HJ, Jakobs C, Tavares de Almeida I. Increased homocysteine and S-Adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin Chem 2003; 49: 1292-6.
• 8 Den Heijer M, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?. Lancet 1995; 345: 882-5.
• 9 Keijzer MBAJ, den Heijer M, Blom HJ. et al. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolate reductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 2002; 88: 723-8.
• 10 Fiskerstrand T, Refsum H, Kvalheim G. et al. Homocysteine and other thiols in plasma and urine: automated determination and sample stability. Clin Chem 1993; 39: 263-71.
• 11 Te Poele-Pothoff MT, van den Berg M, Franken DG. et al. Three different methods for the determination of total homocysteine in plasma. Ann Clin Biochem 1995; 32: 218-20.
• 12 De Graaf-Hes A, Trijbels F, Blom HJ. New method for determining cystine in leucocytes and fibroblasts. Clin Chem 1999; 45: 2224-8.
• 13 Holm PI, Ueland PM, Kvalheim G. et al. Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal phase chromatography-tandem mass spectrometry. Clin Chem 2003; 49: 286-94.
• 14 Midttun O, Hustad S, Solheim E. et al. Multianalyte quantification of vitamin B6 and B2 species in the nanomolar range in human plasma by liquid chromatography-tandem mass spectrometry. Clin Chem 2005; 51: 1206-16.
• 15 Selhub J, Miller JW. The pathogenesis of homocysteinemia: Interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 1992; 55: 131-8.
• 16 Quéré I, Perneger TV, Zittoun J. et al. Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. Lancet 2002; 359: 747-52.
• 17 Fenton WA, Rosenblatt DS. Inherited Disorders of Folate and Cobalamin Transport and Metabolism. In: The Metabolic and Molecular Bases of Inherited Disease. 8th ed.,. McGraw-Hill; NewYork: 2001: 3897-933.
• 18 Frosst P, Blom HJ, Milos R. et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydofolate reductase. Nat Genet 1995; 10: 111-3.
• 19 Mills BJ, Weiss MM, Lang CA. et al. Blood glutathione and cysteine changes in cardiovascular disease. J Lab Clin Med 2000; 135: 396-401.
• 20 Marcucci R, Brunelli T, Giusti B. et al. The role of cysteine and homocysteine in venous and arterial thrombotic disease. Am J Clin Pathol 2001; 116: 56-60.
• 21 Jacob N, Bruckert E, Giral P. et al. Cysteine is a cardiovascular risk factor in hyperlipidemic patients. Atherosclerosis 1999; 146: 53-9.
• 22 Mansoor MA, Bergmark C, Svardal AM. et al. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Arterioscler Thromb Vasc Biol 1995; 15: 232-40.
• 23 Araki A, Sako Y, Fukushima Y. et al. Plasma sulfhydryl-containing amino acids in patients with cerebral infarction and in hypertensive subjects. Atherosclerosis 1989; 79: 139-46.
• 24 Özkan Y, Özkan E, Simsek B. Plasma total homocysteine and cysteine levels as cardiovascular risk factors in coronary heart disease. Intern J Cardiol 2002; 82: 269-77.
• 25 Verhoef P, Stampfer MJ, Buring JE. et al. Homocysteine metabolism and risk of myocardial infarction: Relation with vitamins B6, B12, and folate. Am J Epidemiol 1996; 143: 845-59.
• 26 El-Khairy L, Ueland PM, Refsum H. et al. Plasma total cysteine as a risk factor for vascular disease: The European Concerted Action Project. Circulation 2001; 103: 2544-9.