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The Role of Genetic Factors in the Development of Hyperhomocysteinemia

  • Jürgen Geisel , Ulrich Hübner , Marion Bodis , Heike Schorr , Jean-Pierre Knapp , Rima Obeid and Wolfgang Herrmann
Published/Copyright: June 1, 2005
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Volume 41 Issue 11

Abstract

Moderate hyperhomocysteinemia has been identified as a new independent risk factor for cardiovascular and neurodegenerative diseases. This fact has produced interest in the study of genetic variants involved in homocysteine metabolism and its relationship to pathogenesis. Recently, more than 15 different genes were studied for their relationship to plasma homocysteine levels. We determined the influence of genetic variants in five genes (5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T, serine hydroxymethyltransferase (SHMT) 1420C→T, thymidylate synthase (TS) 2R→3R, catechol-O-methyltransferase (COMT) 1947G→A and transcobalamin (TC) 776C→G) on plasma homocysteine, folic acid and parameters of vitamin B12 metabolism in 111 vegetarians (mean age: 46±15 years) and 118 healthy seniors (mean age: 82±6.5 years). Median homocysteine concentration in plasma was significantly influenced by the MTHFR genotypes in both populations. In the vegetarians the median homocysteine level was increased by 8 μmol/l in individuals homozygous for the mutation as compared to wild-type or heterozygous genotypes (20.4 μmol/l vs. 12.9 and 12.7 μmol/l, respectively). This unexpected increase was observed although the folate levels were in medium to elevated ranges. Our results suggest that vegetarians have a higher demand for folate to neutralize the genotype effect. Preclinical vitamin B12 deficiency in vegetarians may be the cause for disturbed remethylation and folate trap. Plasma homocysteine was not significantly influenced by the SHMT, TS, COMT and TC mutations. In addition, for the TC mutation a trend toward cellular vitamin B12 deficiency was observed. The methylmalonic acid (MMA) levels were slightly elevated and the holotranscobalamin-II (holoTC-II) levels decreased. In the vegetarian group a significant relationship between the COMT genotype and holoTC-II concentration in plasma was determined, whereas the high activity COMT genotype (G/G) resulted in increased levels (35 μmol/l vs. 21 μmol/l for heterozygous and low activity genotypes). The MMA levels were inversely correlated to holoTC-II concentrations. In conclusion, the study on vegetarians and seniors documents interesting lifestyle-genotype interactions. Although the TC and COMT mutations influence cellular vitamin B12 metabolism, this effect did not result in overt homocysteine elevation.

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Published Online: 2005-06-01
Published in Print: 2003-11-17

Copyright © 2003 by Walter de Gruyter GmbH & Co. KG

Articles in the same Issue

  1. Where Are We Standing in Homocysteine Research?
  2. 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
  3. Hyperhomocysteinaemia as a Risk Factor for Venous Thrombosis: An Update of the Current Evidence
  4. Does Homocysteine Cause Hypertension?
  5. Homocysteine Metabolism in Renal Disease
  6. Hyperhomocysteinemia and B-Vitamin Deficiencies in Infants and Children
  7. The Role of Genetic Factors in the Development of Hyperhomocysteinemia
  8. New Basis of the Neurotrophic Action of Vitamin B12
  9. Hyperhomocysteinemia and Immune Activation
  10. Interactions of Homocysteine, Nitric Oxide, Folate and Radicals in the Progressively Damaged Endothelium
  11. Influence of Hyperhomocysteinemia on the Cellular Redox State – Impact on Homocysteine-Induced Endothelial Dysfunction
  12. Homocysteine-Thiolactone and S-Nitroso-Homocysteine Mediate Incorporation of Homocysteine into Protein in Humans
  13. Association of Asymmetric Dimethylarginine and Endothelial Dysfunction
  14. Genetic Determinants of Folate and Vitamin B12 Metabolism: A Common Pathway in Neural Tube Defect and Down Syndrome?
  15. Functional Vitamin B12 Deficiency and Determination of Holotranscobalamin in Populations at Risk
  16. Holotranscobalamin as a Predictor of Vitamin B12 Status
  17. Hyperhomocysteinemia and B-Vitamin Status after Discontinuation of Oral Anticoagulation Therapy in Patients with a History of Venous Thromboembolism
  18. Measurement of Carotid Plaque and Effect of Vitamin Therapy for Total Homocysteine
  19. Folate Improves Endothelial Function in Patients with Coronary Heart Disease
  20. The Impact of Hyperhomocysteinemia as a Cardiovascular Risk Factor in the Prediction of Coronary Heart Disease
  21. Homocysteine Increases during Endurance Exercise
  22. Comparison of the Influence of Volume-Oriented Training and High-Intensity Interval Training on Serum Homocysteine and Its Cofactors in Young, Healthy Swimmers
  23. Analysis of the Transcobalamin II 776C>G (259P>R) Single Nucleotide Polymorphism by Denaturing HPLC in Healthy Elderly: Associations with Cobalamin, Homocysteine and Holo-Transcobalamin II
  24. Meetings and Awards
https://doi.org/10.1515/CCLM.2003.219

Articles in the same Issue

  1. Where Are We Standing in Homocysteine Research?
  2. 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
  3. Hyperhomocysteinaemia as a Risk Factor for Venous Thrombosis: An Update of the Current Evidence
  4. Does Homocysteine Cause Hypertension?
  5. Homocysteine Metabolism in Renal Disease
  6. Hyperhomocysteinemia and B-Vitamin Deficiencies in Infants and Children
  7. The Role of Genetic Factors in the Development of Hyperhomocysteinemia
  8. New Basis of the Neurotrophic Action of Vitamin B12
  9. Hyperhomocysteinemia and Immune Activation
  10. Interactions of Homocysteine, Nitric Oxide, Folate and Radicals in the Progressively Damaged Endothelium
  11. Influence of Hyperhomocysteinemia on the Cellular Redox State – Impact on Homocysteine-Induced Endothelial Dysfunction
  12. Homocysteine-Thiolactone and S-Nitroso-Homocysteine Mediate Incorporation of Homocysteine into Protein in Humans
  13. Association of Asymmetric Dimethylarginine and Endothelial Dysfunction
  14. Genetic Determinants of Folate and Vitamin B12 Metabolism: A Common Pathway in Neural Tube Defect and Down Syndrome?
  15. Functional Vitamin B12 Deficiency and Determination of Holotranscobalamin in Populations at Risk
  16. Holotranscobalamin as a Predictor of Vitamin B12 Status
  17. Hyperhomocysteinemia and B-Vitamin Status after Discontinuation of Oral Anticoagulation Therapy in Patients with a History of Venous Thromboembolism
  18. Measurement of Carotid Plaque and Effect of Vitamin Therapy for Total Homocysteine
  19. Folate Improves Endothelial Function in Patients with Coronary Heart Disease
  20. The Impact of Hyperhomocysteinemia as a Cardiovascular Risk Factor in the Prediction of Coronary Heart Disease
  21. Homocysteine Increases during Endurance Exercise
  22. Comparison of the Influence of Volume-Oriented Training and High-Intensity Interval Training on Serum Homocysteine and Its Cofactors in Young, Healthy Swimmers
  23. Analysis of the Transcobalamin II 776C>G (259P>R) Single Nucleotide Polymorphism by Denaturing HPLC in Healthy Elderly: Associations with Cobalamin, Homocysteine and Holo-Transcobalamin II
  24. Meetings and Awards
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