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Methylenetetrahydrofolate Reductase C677T Mutation,
Plasma Homocysteine, and Folate in Subjects From Northern Italy
With or Without Angiographically Documented Severe Coronary
Atherosclerotic Disease: Evidence for an Important
Genetic-Environmental Interaction
Domenico Girelli,
Simonetta Friso,
Elisabetta Trabetti,
Oliviero Olivieri,
Carla Russo,
Renzo Pessotto,
Giovanni Faccini,
Pier Franco Pignatti,
Alessandro Mazzucco, and
Roberto Corrocher
From the Institute of Medical Pathology, Chair of Internal Medicine,
the Institute of Biology and Genetics, the Institute of Cardiovascular
Surgery, and the Institute of Clinical Chemistry, University of Verona,
Verona, Italy.
Moderate elevation of plasma total homocysteine (tHcy) is a strong
and independent risk factor for coronary artery disease (CAD). It can
result from genetic or nutrient-related disturbances in the
transsulfuration or remethylation pathways for Hcy metabolism. A point
mutation (C677T; Ala-to-Val) in the gene encoding the 5,10-methylenetetrahydrofolate reductase (MTHFR) has been recently reported to render the enzyme thermolabile and less active. Studies on
the role of this mutation as a risk factor for CAD have given conflicting results. We studied a total of 415 subjects, 278 with angiographically documented multivessel CAD and 137 with
angiographically documented normal coronary arteries. The overall
frequency of the MTHFR V/V homozygous genotype was 15.7% (with 52.5%
heterozygous and 31.8% normal). Subgroup analysis showed no
significant differences between CAD and CAD-free subjects. A
genotype/phenotype correlation study showed a marked effect of folate
on the association between MTHFR genotypes and tHcy. Among individuals
with folate levels below the median (11.5 nmol/L), fasting
tHcy was significantly increased not only in V/V homozygotes (by 59%)
but also, at intermediate values, in A/V heterozygotes (by 21% on
average). Conversely, the mutation resulted neutral with respect to
tHcy levels in subjects with adequate folate levels. We conclude that,
in our population, the MTHFR C677T mutation is rather
common, but it does not appear to be associated per se to CAD. A
genetic-environmental interaction may contribute to the vascular risk
by elevating tHcy when folate status is low.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4158-4163
© 1998 by The American Society of Hematology.
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