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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1316-1324.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Determinants of Fasting and Post-Methionine Homocysteine Levels in Families Predisposed to Hyperhomocysteinemia and Premature Vascular Disease

S. C. de Jong; C. D. A. Stehouwer; M. van den Berg; P. J. Kostense; D. Alders; C. Jakobs; G. Pals; J. A. Rauwerda

From the Institute for Cardiovascular Research (S.C.d.J., C.D.A.S., M.v.d.B., D.A., C.J., J.A.R.); Department of Surgery, Division of Vascular Surgery, Academisch Ziekenhuis (S.C.d.J., M.v.d.B., J.A.R.); Department of Internal Medicine, Academisch Ziekenhuis (C.D.A.S.); Department of Epidemiology and Biostatistics, and Institute for Research in Extramural Medicine (P.J.K.); Department of Clinical Chemistry, Academisch Ziekenhuis (C.J.); Department of Anthropogenetics (G.P.), Vrije Universiteit, Amsterdam, The Netherlands.

Correspondence to Dr C.D.A. Stehouwer, Department of Internal Medicine, Academisch Ziekenhuis Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail cda.stehouwer{at}azvu.nl

Abstract—Elevated plasma total homocysteine (tHcy) levels, either measured in the fasting state or after oral methionine loading, are associated with an increased risk of atherothrombotic disease. Fasting and post-methionine hyperhomocysteinemia (HHC) overlap to a limited extent; both can occur as familial traits. We investigated determinants of fasting, postmethionine and delta (ie, post-methionine minus fasting levels) tHcy levels in 510 subjects of 192 HHC-prone families including 161 patients with clinical vascular disease and 349 without vascular disease. We focused on tHcy levels in relation to levels of vitamin B₁₂, B₆ and folate and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Multivariate linear analyses adjusted for the presence of vascular disease showed that fasting tHcy was significantly related to folate and vitamin B₁₂, and the presence of the MTHFR TT genotype and the T allele, and to age, smoking habits, and serum levels of creatinine. Both post-methionine and delta tHcy levels were related to serum folate levels, and the presence of the MTHFR TT genotype and the T allele, and to postmenopausal status, and body mass index. An interaction was found between MTHFR TT genotype and serum folate levels for both fasting and post-methionine tHcy, ie, for a given decrease in serum folate, homocysteine levels increased more in subjects with the TT genotype than in those with the CC genotype. Fasting, post-methionine and delta tHcy were higher in patients with vascular disease than in their healthy siblings, but these levels were less dependent on serum folate levels (P<0.05), whereas the effect of MTHFR genotype was stronger (P=0.01). This study found evidence that post-methionine and delta tHcy levels are not only influenced by factors affecting homocysteine transsulfuration but also by factors that affect remethylation. The explained variances of fasting, post-methionine and delta tHcy were 49%, 62%, and 78%, respectively. We also found evidence, in patients with premature vascular disease but not in their healthy siblings, for a factor that increases tHcy levels but weakens the normal inverse relation between folate and tHcy and amplifies the effect of the MTHFR genotype.

Key Words: homocysteine • methionine loading test • methylenetetrahydrofolate reductase • vitamins • familial hyperhomocysteinemia • premature vascular disease

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