Genetic Determinants of Plasma Total Homocysteine

ABSTRACT

Hyperhomocysteinemia (Hhcy) is an established risk factor for various pathologies including arterial vascular disease and venous thrombosis, congenital malformations and other pregnancy complications, and dementia. Homocysteine remethylation, transsulfuration, and export to the blood/extracellular compartment determine homocysteine concentrations. Any disturbance in these routes may lead to Hhcy and potentially increase risk of disease. In this report, we aim to review all known polymorphisms involved in homocysteine and B-vitamin metabolism that have been assessed for their effect on tHcy. In the last section, we summarize the polymorphisms, for which the obtained data provides evidence for their involvement in Hhcy at the population level, and discuss how to continue our search for genetic determinants of tHcy.

KEYWORDS

Plasma total homocysteine (tHcy) - hyperhomocysteinemia - genetic variation - disease

REFERENCES

• 1 The Homocysteine Studies Collaboration . Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.  JAMA. 2002;  288 2015-2022
• 2 Wald D S, Law M, Morris J K. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.  BMJ. 2002;  325 1202
• 3 den Heijer M, Rosendaal F R, Blom H J, Gerrits W B, Bos G M. Hyperhomocysteinemia and venous thrombosis: a meta-analysis.  Thromb Haemost. 1998;  80 874-877
• 4 Ray J G. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease.  Arch Intern Med. 1998;  158 2101-2106
• 5 Nelen W L. Hyperhomocysteinaemia and human reproduction.  Clin Chem Lab Med. 2001;  39 758-763
• 6 Morris M S. Homocysteine and Alzheimer's disease.  Lancet Neurol. 2003;  2 425-428
• 7 Boers G H, Smals A G, Trijbels F J et al.. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease.  N Engl J Med. 1985;  313 709-715
• 8 Clarke R, Daly L, Robinson K et al.. Hyperhomocysteinemia: an independent risk factor for vascular disease.  N Engl J Med. 1991;  324 1149-1155
• 9 Engbersen A M, Franken D G, Boers G H, Stevens E M, Trijbels F J, Blom H J. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia.  Am J Hum Genet. 1995;  56 142-150
• 10 Nordstrom M, Kjellstrom T. Age dependency of cystathionine beta-synthase activity in human fibroblasts in homocyst(e)inemia and atherosclerotic vascular disease.  Atherosclerosis. 1992;  94 213-221
• 11 Kang S S, Zhou J, Wong P W, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase.  Am J Hum Genet. 1988;  43 414-421
• 12 Kang S S, Wong P W, Zhou J M et al.. Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease.  Metabolism. 1988;  37 611-613
• 13 Frosst P, Blom H J, Milos R et al.. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet. 1995;  10 111-113
• 14 Jacques P F, Bostom A G, Williams R R et al.. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.  Circulation. 1996;  93 7-9
• 15 De Bree A, Verschuren W M, Bjorke-Monsen A L et al.. Effect of the methylenetetrahydrofolate reductase 677C→T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample.  Am J Clin Nutr. 2003;  77 687-693
• 16 Kolling K, Ndrepepa G, Koch W et al.. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms, plasma homocysteine, folate, and vitamin B12 levels and the extent of coronary artery disease.  Am J Cardiol. 2004;  93 1201-1206
• 17 Dekou V, Whincup P, Papacosta O et al.. The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study.  Atherosclerosis. 2001;  154 659-666
• 18 Bailey L B, Duhaney R L, Maneval D R et al.. Vitamin B-12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms.  J Nutr. 2002;  132 1872-1878
• 19 Husemoen L L, Thomsen T F, Fenger M, Jorgensen H L, Jorgensen T. Contribution of thermolabile methylenetetrahydrofolate reductase variant to total plasma homocysteine levels in healthy men and women. Inter99 (2).  Genet Epidemiol. 2003;  24 322-330
• 20 Gudnason V, Stansbie D, Scott J, Bowron A, Nicaud V, Humphries S. C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group.  Atherosclerosis. 1998;  136 347-354
• 20a Kelemen L E, Anand S S, Hegele R A et al.. Associations of plasma homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism with carotid intima media thickness among South Asian, Chinese and European Canadians.  Atherosclerosis. 2004;  176 361-370
• 21 Kluijtmans L A, Young I S, Boreham C A et al.. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults.  Blood. 2003;  101 2483-2488
• 22 Girelli D, Martinelli N, Pizzolo F et al.. The interaction between MTHFR 677 C→T genotype and folate status is a determinant of coronary atherosclerosis risk.  J Nutr. 2003;  133 1281-1285
• 23 Bjelland I, Tell G S, Vollset S E, Refsum H, Ueland P M. Folate, vitamin B12, homocysteine, and the MTHFR 677C- > T polymorphism in anxiety and depression: the Hordaland Homocysteine Study.  Arch Gen Psychiatry. 2003;  60 618-626
• 24 Cappuccio F P, Bell R, Perry I J et al.. Homocysteine levels in men and women of different ethnic and cultural background living in England.  Atherosclerosis. 2002;  164 95-102
• 25 Frederiksen J, Juul K, Grande P et al.. Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: Prospective and case-control studies from the Copenhagen City Heart Study.  Blood. 2004;  , In press
• 26 Van Der Put N M, Gabreels F, Stevens E M et al.. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?.  Am J Hum Genet. 1998;  62 1044-1051
• 27 Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.  Mol Genet Metab. 1998;  64 169-172
• 28 Weisberg I S, Jacques P F, Selhub J et al.. The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine.  Atherosclerosis. 2001;  156 409-415
• 29 Chango A, Boisson F, Barbe F et al.. The effect of 677C→T and 1298A→C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects.  Br J Nutr. 2000;  83 593-596
• 30 Lievers K J, Boers G H, Verhoef P et al.. A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk.  J Mol Med. 2001;  79 522-528
• 31 Castro R, Rivera I, Ravasco P et al.. 5,10-Methylenetetrahydrofolate reductase 677C→T and 1298A→C mutations are genetic determinants of elevated homocysteine.  QJM. 2003;  96 297-303
• 32 Friedman G, Goldschmidt N, Friedlander Y et al.. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations.  J Nutr. 1999;  129 1656-1661
• 33 Van Der Put N M, van der Molen E F, Kluijtmans L A et al.. Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease.  QJM. 1997;  90 511-517
• 34 Hyndman M E, Bridge P J, Warnica J W, Fick G, Parsons H G. Effect of heterozygosity for the methionine synthase 2756 A→G mutation on the risk for recurrent cardiovascular events.  Am J Cardiol. 2000;  86 1144-1146,A9
• 35 Klerk M, Lievers K J, Kluijtmans L A et al.. The 2756A > G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study.  Thromb Res. 2003;  110 87-91
• 36 Harmon D L, Shields D C, Woodside J V et al.. Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations.  Genet Epidemiol. 1999;  17 298-309
• 37 Tsai M Y, Bignell M, Yang F, Welge B G, Graham K J, Hanson N Q. Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels.  Atherosclerosis. 2000;  149 131-137
• 38 Chen J, Stampfer M J, Ma J et al.. Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction.  Atherosclerosis. 2001;  154 667-672
• 39 Leclerc D, Wilson A, Dumas R et al.. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.  Proc Natl Acad Sci U S A. 1998;  95 3059-3064
• 40 Olteanu H, Munson T, Banerjee R. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase.  Biochemistry. 2002;  41 13378-13385
• 41 Olteanu H, Wolthers K R, Munro A W, Scrutton N S, Banerjee R. Kinetic and thermodynamic characterization of the common polymorphic variants of human methionine synthase reductase.  Biochemistry. 2004;  43 1988-1997
• 42 Gaughan D J, Kluijtmans L A, Barbaux S et al.. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations.  Atherosclerosis. 2001;  157 451-456
• 43 Gaughan D J, Kluijtmans L A, Barbaux S et al.. Corrigendum to “The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations” [ATH 157 (2001) 451-456].  Atherosclerosis. 2003;  167 373
• 44 Wilson A, Platt R, Wu Q et al.. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.  Mol Genet Metab. 1999;  67 317-323
• 45 Feix A, Winkelmayer W C, Eberle C, Sunder-Plassmann G, Fodinger M. Methionine synthase reductase MTRR 66A > G has no effect on total homocysteine, folate, and Vitamin B12 concentrations in renal transplant patients.  Atherosclerosis. 2004;  174 43-48
• 46 Jacques P F, Bostom A G, Selhub J et al.. Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study.  Atherosclerosis. 2003;  166 49-55
• 47 Brilakis E S, Berger P B, Ballman K V, Rozen R. Methylenetetrahydrofolate reductase (MTHFR) 677C > T and methionine synthase reductase (MTRR) 66A > G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid.  Atherosclerosis. 2003;  168 315-322
• 48 Brown C A, McKinney K Q, Kaufman J S, Gravel R A, Rozen R. A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease.  J Cardiovasc Risk. 2000;  7 197-200
• 49 Olteanu H, Banerjee R. Redundancy in the pathway for redox regulation of mammalian methionine synthase: reductive activation by the dual flavoprotein, novel reductase 1.  J Biol Chem. 2003;  278 38310-38314
• 50 Henderson G B. Folate-binding proteins.  Annu Rev Nutr. 1990;  10 319-335
• 51 Antony A C. Folate receptors.  Annu Rev Nutr. 1996;  16 501-521
• 52 Brzezinska A, Winska P, Balinska M. Cellular aspects of folate and antifolate membrane transport.  Acta Biochim Pol. 2000;  47 735-749
• 53 Matherly L H. Molecular and cellular biology of the human reduced folate carrier.  Prog Nucleic Acid Res Mol Biol. 2001;  67 131-162
• 54 Devlin A M, Ling E H, Peerson J M et al.. Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia.  Hum Mol Genet. 2000;  9 2837-2844
• 55 Lievers K J, Kluijtmans L A, Boers G H et al.. Influence of a glutamate carboxypeptidase II (GCPII) polymorphism (1561C→T) on plasma homocysteine, folate and vitamin B(12) levels and its relationship to cardiovascular disease risk.  Atherosclerosis. 2002;  164 269-273
• 56 Afman L A, Trijbels F J, Blom H J. The H475Y polymorphism in the glutamate carboxypeptidase II gene increases plasma folate without affecting the risk for neural tube defects in humans.  J Nutr. 2003;  133 75-77
• 57 Vargas-Martinez C, Ordovas J M, Wilson P W, Selhub J. The glutamate carboxypeptidase gene II (C > T) polymorphism does not affect folate status in the Framingham Offspring cohort.  J Nutr. 2002;  132 1176-1179
• 58 Morin I, Devlin A M, Leclerc D et al.. Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk.  Mol Genet Metab. 2003;  79 197-200
• 59 Whetstine J R, Gifford A J, Witt T et al.. Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers.  Clin Cancer Res. 2001;  7 3416-3422
• 60 Fodinger M, Dierkes J, Skoupy S et al.. Effect of glutamate carboxypeptidase II and reduced folate carrier polymorphisms on folate and total homocysteine concentrations in dialysis patients.  J Am Soc Nephrol. 2003;  14 1314-1319
• 61 Chango A, Emery-Fillon N, de Courcy G P et al.. A polymorphism (80G- > A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia.  Mol Genet Metab. 2000;  70 310-315
• 62 Spiegelstein O, Eudy J D, Finnell R H. Identification of two putative novel folate receptor genes in humans and mouse.  Gene. 2000;  258 117-125
• 63 Heil S G, Van Der Put N M, Trijbels F J, Gabreels F J, Blom H J. Molecular genetic analysis of human folate receptors in neural tube defects.  Eur J Hum Genet. 1999;  7 393-396
• 64 Barber R C, Shaw G M, Lammer E J et al.. Lack of association between mutations in the folate receptor-alpha gene and spina bifida.  Am J Med Genet. 1998;  76 310-317
• 65 Barber R, Shalat S, Hendricks K et al.. Investigation of folate pathway gene polymorphisms and the incidence of neural tube defects in a Texas Hispanic population.  Mol Genet Metab. 2000;  70 45-52
• 66 Nilsson T K, Borjel A K. Novel insertion and deletion mutations in the 5′-UTR of the folate receptor-alpha gene: an additional contributor to hyperhomocysteinemia?.  Clin Biochem. 2004;  37 224-229
• 67 O'Leary V B, Mills J L, Kirke P N et al.. Analysis of the human folate receptor beta gene for an association with neural tube defects.  Mol Genet Metab. 2003;  79 129-133
• 68 Wang H, Ross J F, Ratnam M. Structure and regulation of a polymorphic gene encoding folate receptor type gamma/gamma'.  Nucleic Acids Res. 1998;  26 2132-2142
• 69 Seetharam B, Alpers D H, Allen R H. Isolation and characterization of the ileal receptor for intrinsic factor-cobalamin.  J Biol Chem. 1981;  256 3785-3790
• 70 Afman L A, Van Der Put N M, Thomas C M, Trijbels J M, Blom H J. Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects.  QJM. 2001;  94 159-166
• 71 Lievers K J, Afman L A, Kluijtmans L A et al.. Polymorphisms in the transcobalamin gene: association with plasma homocysteine in healthy individuals and vascular disease patients.  Clin Chem. 2002;  48 1383-1389
• 72 McCaddon A, Blennow K, Hudson P, Regland B, Hill D. Transcobalamin polymorphism and homocysteine.  Blood. 2001;  98 3497-3499
• 73 Miller J W, Ramos M I, Garrod M G, Flynn M A, Green R. Transcobalamin II 775G > C polymorphism and indices of vitamin B12 status in healthy older adults.  Blood. 2002;  100 718-720
• 74 Wans S, Schuttler K, Jakubiczka S, Muller A, Luley C, Dierkes J. 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.  Clin Chem Lab Med. 2003;  41 1532-1536
• 75 Namour F, Olivier J, Abdelmouttaleb I et al.. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood.  Blood. 2001;  97 1092-1098
• 76 Afman L A, Lievers K J, Van Der Put N M, Trijbels F J, Blom H J. Single nucleotide polymorphisms in the transcobalamin gene: relationship with transcobalamin concentrations and risk for neural tube defects.  Eur J Hum Genet. 2002;  10 433-438
• 77 Herbig K, Chiang E P, Lee L R, Hills J, Shane B, Stover P J. Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses.  J Biol Chem. 2002;  277 38381-38389
• 78 Appling D R. Compartmentation of folate-mediated one-carbon metabolism in eukaryotes.  FASEB J. 1991;  5 2645-2651
• 79 Heil S G, Van Der Put N M, Waas E T, den Heijer M, Trijbels F J, Blom H J. Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects?.  Mol Genet Metab. 2001;  73 164-172
• 80 Geisel J, Hubner U, Bodis M et al.. The role of genetic factors in the development of hyperhomocysteinemia.  Clin Chem Lab Med. 2003;  41 1427-1434
• 81 Heil S G, Lievers K J, Boers G H et al.. Betaine-homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans.  Mol Genet Metab. 2000;  71 511-519
• 82 Weisberg I S, Park E, Ballman K V et al.. Investigations of a common genetic variant in betaine-homocysteine methyltransferase (BHMT) in coronary artery disease.  Atherosclerosis. 2003;  167 205-214
• 83 Hol F A, Van Der Put N M, Geurds M P et al.. Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects.  Clin Genet. 1998;  53 119-125
• 84 Brody L C, Conley M, Cox C et al.. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group.  Am J Hum Genet. 2002;  71 1207-1215
• 85 Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A. Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia.  Pharmacogenomics J. 2004;  4 66-72
• 86 Johnson W G, Stenroos E S, Spychala J R, Chatkupt S, Ming S X, Buyske S. New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): a risk factor for spina bifida acting in mothers during pregnancy?.  Am J Med Genet A. 2004;  124 339-345
• 87 Kaneda S, Nalbantoglu J, Takeishi K et al.. Structural and functional analysis of the human thymidylate synthase gene.  J Biol Chem. 1990;  265 20277-20284
• 88 Ulrich C M, Bigler J, Velicer C M, Greene E A, Farin F M, Potter J D. Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene.  Cancer Epidemiol Biomarkers Prev. 2000;  9 1381-1385
• 89 Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase.  Cell Struct Funct. 1995;  20 191-197
• 90 Kawakami K, Salonga D, Park J M et al.. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression.  Clin Cancer Res. 2001;  7 4096-4101
• 91 Trinh B N, Ong C N, Coetzee G A, Yu M C, Laird P W. Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels.  Hum Genet. 2002;  111 299-302
• 92 Brown K S, Kluijtmans L A, Young I S et al.. The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects.  Hum Genet. 2004;  114 182-185
• 93 Mandola M V, Stoehlmacher J, Zhang W et al.. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels.  Pharmacogenetics. 2004;  14 319-327
• 94 Sebastio G, Sperandeo M P, Panico M, de Franchis R, Kraus J P, Andria G. The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations.  Am J Hum Genet. 1995;  56 1324-1333
• 95 Kraus J P, Oliveriusova J, Sokolova J et al.. The human cystathionine beta-synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms.  Genomics. 1998;  52 312-324
• 96 Lievers K J, Kluijtmans L A, Heil S G et al.. A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels.  Eur J Hum Genet. 2001;  9 583-589
• 97 Yang F, Hanson N Q, Schwichtenberg K, Tsai M Y. Variable number tandem repeat in exon/intron border of the cystathionine beta-synthase gene: a single nucleotide substitution in the second repeat prevents multiple alternate splicing.  Am J Med Genet. 2000;  95 385-390
• 98 Afman L A, Lievers K J, Kluijtmans L A, Trijbels F J, Blom H J. Gene-gene interaction between the cystathionine beta-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C > T polymorphism on homocysteine levels and risk for neural tube defects.  Mol Genet Metab. 2003;  78 211-215
• 99 Sperandeo M P, de Franchis R, Andria G, Sebastio G. A 68-bp insertion found in a homocystinuric patient is a common variant and is skipped by alternative splicing of the cystathionine beta-synthase mRNA.  Am J Hum Genet. 1996;  59 1391-1393
• 100 Tsai M Y, Bignell M, Schwichtenberg K, Hanson N Q. High prevalence of a mutation in the cystathionine beta-synthase gene.  Am J Hum Genet. 1996;  59 1262-1267
• 101 Pepe G, Vanegas O C, Rickards O et al.. World distribution of the T833C/844INS68 CBS in cis double mutation: a reliable anthropological marker.  Hum Genet. 1999;  104 126-129
• 102 De Stefano V, Dekou V, Nicaud V et al.. Linkage disequilibrium at the cystathionine beta synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine.  Ann Hum Genet. 1998;  62 481-490
• 103 Tsai M Y, Yang F, Bignell M, Aras O, Hanson N Q. Relation between plasma homocysteine concentration, the 844ins68 variant of the cystathionine beta-synthase gene, and pyridoxal-5′-phosphate concentration.  Mol Genet Metab. 1999;  67 352-356
• 104 Kluijtmans L A, Boers G H, Trijbels F J, Lith-Zanders H M, van den Heuvel L P, Blom H J. A common 844INS68 insertion variant in the cystathionine beta-synthase gene.  Biochem Mol Med. 1997;  62 23-25
• 105 Lievers K J, Kluijtmans L A, Heil S G et al.. Cystathionine beta-synthase polymorphisms and hyperhomocysteinaemia: an association study.  Eur J Hum Genet. 2003;  11 23-29
• 106 Kruger W D, Evans A A, Wang L et al.. Polymorphisms in the CBS gene associated with decreased risk of coronary artery disease and increased responsiveness to total homocysteine lowering by folic acid.  Mol Genet Metab. 2000;  70 53-60
• 107 Aras O, Hanson N Q, Yang F, Tsai M Y. Influence of 699C→T and 1080C→T polymorphisms of the cystathionine beta-synthase gene on plasma homocysteine levels.  Clin Genet. 2000;  58 455-459
• 108 Wang J, Huff A M, Spence J D, Hegele R A. Single nucleotide polymorphism in CTH associated with variation in plasma homocysteine concentration.  Clin Genet. 2004;  65 483-486
• 109 Gellekink H, den Heijer M, Kluijtmans L A, Blom H J. Effect of genetic variation in the human S-adenosylhomocysteine hydrolase gene on total homocysteine concentrations and risk of recurrent venous thrombosis.  Eur J Hum Genet. 2004;  12 942-948
• 110 Goodman J E, Lavigne J A, Wu K et al.. COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk.  Carcinogenesis. 2001;  22 1661-1665
• 111 Souto J C, Almasy L, Borrell M et al.. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia.  Am J Hum Genet. 2000;  67 1452-1459
• 112 Jee S H, Song K S, Shim W H et al.. Major gene evidence after MTHFR-segregation analysis of serum homocysteine in families of patients undergoing coronary arteriography.  Hum Genet. 2002;  111 128-135
• 113 Riksen N P, Rongen G A, Blom H J, Russel F G, Boers G H, Smits P. Potential role for adenosine in the pathogenesis of the vascular complications of hyperhomocysteinemia.  Cardiovasc Res. 2003;  59 271-276
• 114 Foraker A B, Khantwal C M, Swaan P W. Current perspectives on the cellular uptake and trafficking of riboflavin.  Adv Drug Deliv Rev. 2003;  55 1467-1483
• 115 Said H M, Ortiz A, Ma T Y. A carrier-mediated mechanism for pyridoxine uptake by human intestinal epithelial Caco-2 cells: regulation by a PKA-mediated pathway.  Am J Physiol Cell Physiol. 2003;  285 C1219-C1225
• 116 Xu Q, Jia Y B, Zhang B Y et al.. Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders.  Mol Psychiatry. 2004;  9 510-521
• 117 van Hylckama Vlieg, Sandkuijl L A, Rosendaal F R, Bertina R M, Vos H L. Candidate gene approach in association studies: would the factor V Leiden mutation have been found by this approach?.  Eur J Hum Genet. 2004;  12 478-482
• 118 Meyer K, Fredriksen A, Ueland P M. High-level multiplex genotyping of polymorphisms involved in folate or homocysteine metabolism by matrix-assisted laser desorption/ionization mass spectrometry.  Clin Chem. 2004;  50 391-402
• 119 Linnebank M, Homberger A, Kraus J P, Harms E, Kozich V, Koch H G. Haplotyping of wild type and I278T alleles of the human cystathionine beta-synthase gene based on a cluster of novel SNPs in IVS12.  Hum Mutat. 2001;  17 350-351
• 120 Wilcox M A, Wyszynski D F, Panhuysen C I et al.. Empirically derived phenotypic subgroups - qualitative and quantitative trait analyses.  BMC Genet. 2003;  4(Suppl 1) S15
• 121 Dekou V, Gudnason V, Hawe E, Miller G J, Stansbie D, Humphries S E. Gene-environment and gene-gene interaction in the determination of plasma homocysteine levels in healthy middle-aged men.  Thromb Haemost. 2001;  85 67-74
• 122 den Heijer M, Graafsma S, Lee S Y et al.. Homocysteine levels-before and after methionine loading-in 51 Dutch families.  Eur J Hum Genet. 2005;  13 753-762
• 123 Sellick G S, Longman C, Tolmie J et al.. Genomewide linkage searches for Mendelian disease loci can be efficiently conducted using high-density SNP genotyping arrays.  Nucleic Acids Res. 2004;  32 e164