Genetics of homocysteine metabolism and associated disorders.

Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.

[1]  Yuan-Yuan Shi,et al.  Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  M. Wandel,et al.  Changes in predictors and status of homocysteine in young male adults after a dietary intervention with vegetables, fruits and bread , 2008, European journal of nutrition.

[3]  R. Pandey,et al.  Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls , 2008, Pediatric Surgery International.

[4]  R. Stewart,et al.  Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression , 2008, British Journal of Psychiatry.

[5]  M. R. Rigual,et al.  Valores plasmáticos de homocisteína total en niños con diabetes mellitus tipo: 1. Factores condicionantes , 2008 .

[6]  K. Matsuo,et al.  One-carbon metabolism-related gene polymorphisms and risk of breast cancer. , 2008, Carcinogenesis.

[7]  C. Turner,et al.  The effect of oral folic acid upon plasma homocysteine, endothelial function and oxidative stress in patients with type 1 diabetes and microalbuminuria , 2008, International journal of clinical practice.

[8]  T. Kuntze,et al.  Plasma homocysteine levels & 677C-->T methylenetetrahydrofolate reductase gene polymorphism in patients with coronary artery disease of different severity. , 2008, The Indian journal of medical research.

[9]  M. Eberlin,et al.  Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil. , 2008, Genetics and molecular research : GMR.

[10]  K. Mccully.  Homocysteine, vitamins, and vascular disease prevention. , 2007, The American journal of clinical nutrition.

[11]  P. Striano,et al.  Antiepileptic Drugs and MTHFR Polymorphisms Influence Hyper‐Homocysteinemia Recurrence in Epileptic Patients , 2007, Epilepsia.

[12]  Y. Karaman,et al.  Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. , 2007, Clinical biochemistry.

[13]  S. Chanock,et al.  Genetic polymorphisms in the one‐carbon metabolism pathway and breast cancer risk: A population‐based case–control study and meta‐analyses , 2007, International journal of cancer.

[14]  E. Steegers,et al.  Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: A meta‐analysis , 2007, American journal of medical genetics. Part A.

[15]  R. T. Lie,et al.  Folic acid supplements and risk of facial clefts: national population based case-control study , 2007, BDJ.

[16]  J. Jolles,et al.  Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial , 2007, The Lancet.

[17]  Roger M Harbord,et al.  Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. , 2006, Journal of the National Cancer Institute.

[18]  R. Berry,et al.  Improvement in Stroke Mortality in Canada and the United States, 1990 to 2002 , 2006, Circulation.

[19]  M. Topbaş,et al.  Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, Vitamin B12, folic acid and Vitamin B6 , 2006, Seizure.

[20]  S. J. James,et al.  No association between common polymorphisms in genes of folate and homocysteine metabolism and the risk of Down's syndrome among French mothers , 2005, British Journal of Nutrition.

[21]  D. Brunoni,et al.  Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for Down syndrome in Brazil , 2005, American journal of medical genetics. Part A.

[22]  S. Vasikaran,et al.  Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life , 2005, Neurobiology of Aging.

[23]  T. Félix,et al.  Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil. , 2004, Birth defects research. Part A, Clinical and molecular teratology.

[24]  P. Bosco,et al.  Methionine synthase (MTR) 2756 (A → G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome , 2003, American journal of medical genetics. Part A.

[25]  S. Vollset,et al.  Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. , 2003, Archives of general psychiatry.

[26]  E. Falk,et al.  Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. , 2003, Atherosclerosis.

[27]  Hong Wang,et al.  Hyperhomocysteinemia accelerates atherosclerosis in cystathionine beta-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation. , 2003, Blood.

[28]  D. Brunoni,et al.  Methylenetetrahydrofolate reductase (MTHFR): incidence of mutations C677T and A1298C in Brazilian population and its correlation with plasma homocysteine levels in spina bifida , 2003, American journal of medical genetics. Part A.

[29]  V. Shotelersuk,et al.  Maternal 677CT/1298AC genotype of the MTHFR gene as a risk factor for cleft lip , 2003, Journal of medical genetics.

[30]  A. Hofman,et al.  Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. , 2002, The American journal of psychiatry.

[31]  R. Virmani,et al.  Increased Serum Homocysteine and Sudden Death Resulting from Coronary Atherosclerosis With Fibrous Plaques , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[32]  H. McNulty,et al.  The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs , 2002, Epilepsy Research.

[33]  J. Loscalzo,et al.  Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia , 2002, Vascular medicine.

[34]  G. Varela-Moreiras,et al.  Homocysteine modifies development of neurulation and dorsal root ganglia in chick embryos. , 2002, Teratology.

[35]  S. Vollset,et al.  Biological and clinical implications of the MTHFR C677T polymorphism. , 2001, Trends in pharmacological sciences.

[36]  J D Erickson,et al.  Racial and temporal variations in the prevalence of heart defects. , 2001, Pediatrics.

[37]  G. Riccardi,et al.  Plasma homocysteine and microvascular complications in type 1 diabetes. , 2000, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[38]  Z. Li,et al.  Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. , 2000, The New England journal of medicine.

[39]  S. Acton,et al.  Amniotic fluid homocysteine levels, 5,10-methylenetetrahydrafolate reductase genotypes, and neural tube closure sites. , 2000, American journal of medical genetics.

[40]  Hong Wang,et al.  Correction: Prevention of Neural-Tube Defects with Folic Acid in China. , 1999, The New England journal of medicine.

[41]  A. Kuijpers-Jagtman,et al.  Nonsyndromic orofacial clefts: association with maternal hyperhomocysteinemia. , 1999, Teratology.

[42]  Graeme N. Smith,et al.  Changes in homocysteine levels during normal pregnancy. , 1999, American journal of obstetrics and gynecology.

[43]  F. Gabreëls,et al.  A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? , 1998, American journal of human genetics.

[44]  H. Blom,et al.  Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease. , 1997, QJM : monthly journal of the Association of Physicians.

[45]  R. Rozen.  Genetic Predisposition to Hyperhomocysteinemia: Deficiency of Methylenetetrahydrofolate Reductase (MTHFR) , 1997, Thrombosis and Haemostasis.

[46]  H. Savoia,et al.  The Significance of Subnormal Serum Vitamin B12 Concentration in Older People: A Case Control Study , 1996, Journal of the American Geriatrics Society.

[47]  D. Matthias,et al.  Homocysteine induced arteriosclerosis-like alterations of the aorta in normotensive and hypertensive rats following application of high doses of methionine. , 1996, Atherosclerosis.

[48]  P. Lønning,et al.  Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Homocysteine and peripheral vascular disease. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[49]  J. Mills,et al.  Homocysteine metabolism in pregnancies complicated by neural-tube defects , 1995, The Lancet.

[50]  H. Blom,et al.  Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? , 1994, Metabolism: clinical and experimental.

[51]  E. Trabetti.  Homocysteine,MTHFR gene polymorphisms, and cardio-cerebrovascular risk , 2010, Journal of Applied Genetics.

[52]  A. Baldellóu Vázquez,et al.  [Total homocysteine levels in children with diabetes type 1. Conditional factors]. , 2008, Anales de pediatria.

[53]  M. Marszałł,et al.  [Smoking influence on the level of homocysteine and 5-methyltetrahydrofolic acid in active and non smokers]. , 2007, Przeglad lekarski.

[54]  J. Gajewska,et al.  [Serum folate and homocysteine concentrations in women smoking during pregnancy and in umbilical cord blood of newborns]. , 2007, Przeglad lekarski.

[55]  A. Sobczak,et al.  [The influence of tobacco smoke on homocysteine level in plasma of healthy males]. , 2007, Przeglad lekarski.

[56]  E. Porcellini,et al.  Homocysteine and folate as risk factors for dementia and Alzheimer disease. , 2005, The American journal of clinical nutrition.

[57]  P. Ueland,et al.  Plasma Total Homocysteine Is Influenced by Prandial Status in Humans: The Hordaland Homocysteine Study 1 , 2001 .

[58]  R. Wolfe,et al.  Homocysteine metabolism. , 1999, Annual review of nutrition.

[59]  S. Duthie,et al.  Folic acid deficiency and cancer: mechanisms of DNA instability. , 1999, British medical bulletin.

[60]  I. Rosenberg,et al.  Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. , 1996, Circulation.

[61]  R. Matthews,et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase , 1995, Nature Genetics.