| |
Methylenetetrahydrofolate
Reductase (MTHFR)
Determination of the C677T polymorphism in
the coronary artery disease Marker gene MTHFR
RDB2060
|
|
CLINICAL RELEVANCE
Hyperhomocysteinemia has emerged as a riskfactor for coronary artery
disease (1).
The metabolism of homocysteine occurs through two pathways. Genetic
defects in genes of the involved enzymes are associated with hyperhomocysteinemia.
One of the pathways contains the enzyme methylenetetrahydrofolate
reductase (MTHFR), which catalyses the remethylation of homocysteine
to methionine.
A common polymorphism in the MTHFR gene correlates with the characteristics
of a thermolabile MTHFR protein. The heat-sensitive variant of the
enzyme has only 50% of the activity of the normal enzyme (2). The
mutation responsible for this form is a C (cytosin) to T (thymidine)
substitution at nucleotide 677 of the coding sequence which converts
an alanine to a valine residue (3).
The plasma homocysteine levels in individuals homozygous for this
mutation were significantly higher than those of other individuals
(3).
The MTHFR-C677T polymorphism is very common. About 40% of the population
are homozygous for the wildtype C677, 45% are heterozyous for both
alleles C677 and T677 and about 15% are homozygous carrier for the
T677 mutated allele (4).
Several investigations have shown that the homozygous mutated genotype
is a independent risk factor for coronary artery disease (3, 5-7).
|
 |
Literature
(1)
McCully KS (1996)
Homocysteine and vascular disease
Nat Med 2: 386-389
(2)
Kang SS, Wong PWK, Susmano A ... (1991)
Thermolabile methylenetetrahydrofolate reductase: an inherited risk
factor for coronary artery disease
Am J Hum Genet 48: 536-545
(3)
Frosst P, Blom HJ, Milos R ... (1995)
A candidate genetic risk factor for vascular disease: a common mutation
in methylenetetrahydrofolate reductase
Nat Genet 10: 111-113
(4)
Bowen DJ, Bowley S, John M ... (1998)
Factor V Leiden (G1691A), the Prothrombin 3´-Untranslated Region
Variant (G20210A) and Thermolabile Methylenetetrahydrofolat Reductase
(C677T): A Single Genetic Test Genotypes all Three Loci - Determination
of Frequencies in the S. Wales Population of the UK
Thromb Haemost 79: 949-954
(5)
Lastrucci RM, Dawson DA, Munster M (1999)
Development of an internal restriction control in the PCR detection
of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation
Mol Diagn 4: 159-161
(6)
Morita H, Taguchi J, Kurihara H ... (1997)
Genetic Poymorphism of 5,10-Methylenetetrahydro-folate Reductase (MTHFR)
as a Risk Factor for Coronary Artery Disease
Circulation 95: 2032-2036
(7)
Kluijtmans LA, van den Heuvel LP Boers GH ... (1996)
Molecular genetic analysis in mild hyperhomocysteinemia: a common
mutation in the methylenetetrahydrofolate reductase gene is a genetic
risk factor for cardiovascular disease
Am J hum Genet 58: 35-41
|
|
|
|
