Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction |
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Authors: | Adams M; Smith PD; Martin D; Thompson JR; Lodwick D; Samani NJ |
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Affiliation: | Departments of Cardiology, Medicine and Ophthalmology, University of Leicester, Leicester, UK; Correspondence to: Dr NJ Samani, Department of Cardiology, Clinical Sciences Wing, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK |
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Abstract: | Hyperhomocyst(e)inemia is associated with an increased risk of coronary
artery disease and myocardial infarction. Both genetic and environmental
factors influence the plasma level of homocysteine. One of the metabolic
pathways for homocysteine involves the enzyme methylenetetrahydrofolate
reductase (MTHFR), which regulates the conversion of homocysteine to
methionine. A thermolabile variant of MTHFR is associated with reduced
enzyme activity and increased plasma homocysteine levels. Recently, the
cause of this variant of MTHFR has been identified as a single base change
altering an alanine to a valine residue in the protein. Using a PCR-based
assay to distinguish the normal and thermolabile variants of MTHFR in this
study, we investigated whether the thermolabile variant is a genetic risk
factor for myocardial infarction. In a study of 532 subjects (310
myocardial infarction patients and 222 population-based controls), we found
no difference in either MTHFR genotype distribution (<it>p</it>
= 0.57) or allele frequencies (<it>p</it> = 0.68) between cases
and controls. The allele frequencies of the thermolabile variant were 0.34
and 0.35 in cases and controls, respectively. The age- and sex-stratified
odds ratio for risk of myocardial infarction associated with homozygosity
for the thermolabile variant was 0.85 (95% CI 0.50-1.50,
<it>p</it> = 0.57) and that with carriage of the thermolabile
allele was 1.06 (95% CI 0.73-1.52, <it>p</it> = 0.76). The odds
ratio remained non-significant when restricted to young subjects
(<60 years) or males, and were not influenced by several other risk
factors for myocardial infarction considered either singly or in
combination. Interestingly, in both cases and controls, there was a trend
toward a higher prevalence of hypertension in subjects carrying the normal
allele, although as this is a <it>post-hoc</it> finding it
needs to be interpreted with caution. The thermolabile variant of MTHFR is
not a major risk factor for myocardial infarction and is unlikely to
explain a significant proportion of the reported association of
hyperhomocyst(e)inemia with coronary artery disease.
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