Q J Med 2003; 96: 297-303
© 2003 Association of Physicians
5,10-Methylenetetrahydrofolate reductase 677C
T and 1298AC mutations are genetic determinants of elevated homocysteine
From the 1 Centro de Patogénese Molecular, Faculdade de Farmácia da Universidade de Lisboa, and 2 Centro de Nutrição e Metabolismo, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal, 3 Metabolic Unit, Department of Clinical Chemistry, VU University Medical Centre, Amsterdam, and 4 Department of Paediatrics, University Medical Center St. Radboud, Nijmegen, The Netherlands
Received 16 October 2002 Accepted for publication 3 January 2003.
Background: Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocysteine metabolism. Elevated plasma total homocysteine (tHcy) is a major risk for cardiovascular disease. A common 677C
T mutation in the MTHFR gene results in decreased enzymic activity, and contributes to increased plasma tHcy, in association with low plasma folate. A recently described 1298AC mutation in the MTHFR gene clearly reduces MTHFR activity (although to a lesser extent than the 677CT) but its effect on plasma tHcy levels is not yet clear.
Aim: To investigate the frequency of these two MTHFR polymorphisms in a Portuguese population, and to correlate the MTHFR genotype with the biochemical phenotype at the level of homocysteine and folate concentrations.
Design: Prospective population survey.
Methods: We studied 117 healthy volunteers (71 females, 46 males). The 677CT and 1298AC mutations were screened by PCR-RFLP. Levels of plasma tHcy and folate, and red blood cell folate, were determined.
Results: The allele frequencies of the 677CT and 1298AC mutations were 0.33 and 0.28, respectively. Homozygotes for the 677CT mutation had significantly elevated plasma tHcy and RBC folate levels and significantly lowered plasma folate concentrations than subjects without the mutation. The 1298AC mutation showed a significant effect on plasma tHcy, but not on plasma folate or RBC folate levels.
Discussion: The observed 677T allele frequency is not consistent with the idea of a north-south gradient as previously suggested. The 1298AC mutation is common in Portugal. Both MTHFR mutations showed effects on plasma tHcy levels.
Address correspondence to Professor I.T. de Almeida, Centro de Patogénese Molecular, Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649–039 Lisboa, Portugal. e-mail: italmeida{at}ff.ul.pt
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