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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2483-2488
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Genetic and nutritional factors contributing to
hyperhomocysteinemia in young adults
Leo A. J. Kluijtmans,
Ian
S. Young,
Colin A. Boreham,
Liam Murray,
Dorothy McMaster,
Helene McNulty,
J. J. Strain,
Joseph McPartlin,
John M. Scott, and
Alexander S. Whitehead
From the Department of Pharmacology and Center
for Pharmacogenetics, University of Pennsylvania School of Medicine,
Philadelphia, PA; the Cardiovascular Research Centre, Queen's
University Belfast, Belfast, Northern Ireland; the Northern Ireland
Centre for Diet and Health, University of Ulster, Coleraine, Northern
Ireland; and the Department of Clinical Medicine, Trinity College,
Dublin, Ireland.
A modestly elevated total plasma homocysteine
concentration (tHcy) is generally accepted as an independent and graded
risk factor for various pathologies, including vascular diseases,
neural tube defects, Alzheimer disease, and pregnancy complications. We
analyzed 5 common functional polymorphisms in enzymes involved in
homocysteine metabolism (ie,
methylenetetrahydrofolate reductase [MTHFR] 677C>T and
1298A>C, methionine synthase [MTR] 2756A>G, cystathionine
 -synthase [CBS] 844ins68, and methionine synthase reductase
[MTRR] 66A>G) in 452 young adults, and quantified their independent
and interactive effects on tHcy concentrations. Serum folate, red cell
folate, vitamin B12, and tHcy concentrations were
significantly influenced by MTHFR 677C>T genotypes. A
particularly strong interaction was observed between the
MTHFR 677TT genotype and serum folate, which led to a high
tHcy phenotype that was more pronounced in males. The genetic
contribution to the variance in tHcy was estimated to be
approximately 9%, compared with approximately 35% that could
be attributed to low folate and vitamin B12. Our study
indicates that dietary factors are centrally important in the control
of tHcy levels in young adults with additional, but somewhat weaker,
genetic effects. These data underscore the potential benefits that may
be gained by improving the dietary status of young adults, and provide
support for the implementation of folate/B-vitamin food fortification programs.
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