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Departments of
1
Pediatrics and
2 Internal Medicine and
4 Internal Medicine, Division of Endocrinology, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands.
3 Wageningen Center for Food Sciences and Division of Human Nutrition and Epidemiology, Wageningen University, 6703 HD Wageningen, The Netherlands.
aAddress correspondence to this author at: Department of Pediatrics, University Medical Center Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Fax 31-24-3618900; e-mail H.Blom{at}cukz.umcn.nl.
Background: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (CVD). Intracellular vitamin B12 deficiency may lead to increased plasma total homocysteine (tHcy) concentrations and because transcobalamin (TC) is the plasma transporter that delivers vitamin B12 to cells, genetic variation in the TC gene may affect intracellular vitamin B12 availability and, consequently, tHcy concentrations.
Methods: We examined five sequence variants, i.e., I23V, G94S, P259R, S348F, and R399Q, in the TC gene as possible determinants of tHcy and, concordantly, as possible risk factors for CVD in 190 vascular disease patients and 601 controls. We also studied potential effect-modification of vitamin B12 by genotype.
Results: In individuals with high vitamin B12, 259PP individuals had lower tHcy concentrations than 259PR and 259RR individuals. Homozygous 23VV individuals had lower fasting tHcy concentrations than their 23IV and 23II peers. None of the genotypes defined by the three other sequence variants showed an association with tHcy concentrations, nor was any TC genotype associated with an increased CVD risk.
Conclusions: In individuals in the highest quartile of the vitamin B12 distribution (>299 pmol/L), tHcy concentrations are lower in 259PP homozygotes than in 259PR and 259RR individuals. Therefore, 259PP individuals, who represent >25% of the general population, may be more susceptible to reduction of plasma tHcy concentrations by increasing the vitamin B12 status.
The following articles in journals at HighWire Press have cited this article:
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  J.-L. Gueant, N. W Chabi, R.-M. Gueant-Rodriguez, O. M Mutchinick, R. Debard, C. Payet, X. Lu, C. Villaume, J.-P. Bronowicki, E. V Quadros, et al. Environmental influence on the worldwide prevalence of a 776C->G variant in the transcobalamin gene (TCN2) J. Med. Genet., June 1, 2007; 44(6): 363 - 367. [Abstract] [Full Text] [PDF]
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 J. Wuerges, G. Garau, S. Geremia, S. N. Fedosov, T. E. Petersen, and L. Randaccio Structural basis for mammalian vitamin B12 transport by transcobalamin PNAS, March 21, 2006; 103(12): 4386 - 4391. [Abstract] [Full Text] [PDF]
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 J. W. Miller, M. G. Garrod, A. L. Rockwood, M. M. Kushnir, L. H. Allen, M. N. Haan, and R. Green Measurement of Total Vitamin B12 and Holotranscobalamin, Singly and in Combination, in Screening for Metabolic Vitamin B12 Deficiency Clin. Chem., February 1, 2006; 52(2): 278 - 285. [Abstract] [Full Text] [PDF]
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 L. R. Solomon Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing Blood, February 1, 2005; 105(3): 978 - 985. [Abstract] [Full Text] [PDF]
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K. Meyer, A. Fredriksen, and P. M. Ueland High-Level Multiplex Genotyping of Polymorphisms Involved in Folate or Homocysteine Metabolism by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Clin. Chem., February 1, 2004; 50(2): 391 - 402. [Abstract] [Full Text] [PDF]
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 H Refsum and A D Smith Low vitamin B-12 status in confirmed Alzheimer's disease as revealed by serum holotranscobalamin J. Neurol. Neurosurg. Psychiatry, July 1, 2003; 74(7): 959 - 961. [Abstract] [Full Text] [PDF]
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