Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease

Elevated plasma total homocysteine (tHcy) levels, either measured in the fa sting state or after oral methionine loading, are associated with an increa sed risk of atherothrombotic disease. Fasting and post-methionine hyperhomo cysteinemia (HHC) overlap to a limited extent; both can occur as familial t raits. We investigated determinants of fasting; postmethionine and delta (i e, post-methionine minus fasting levels) tHcy levels in 510 subjects of 192 HHC-prone families including 161 patients with clinical vascular disease a nd 349 without vascular disease. We focused on tHcy levels in relation to l evels of vitamin B-12, B-6 and folate and the methylenetetrahydrofolate red uctase (MTHFR) C677T mutation. Multivariate linear analyses adjusted for th e presence of vascular disease showed that fasting tHcy was significantly r elated to folate and vitamin B-12, and the presence of the MTHFR TT genotyp e and the T allele, and to age, smoking habits, and serum levels of creatin ine. Both post-methionine and delta tHcy levels were related to serum;folat e levels, and the presence of the MTHFR TT genotype and the T allele, and t o postmenopausal status, and body mass index. An interaction was found betw een MTHFR TT genotype and serum folate levels for both fasting and post-met hionine 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 w ith vascular disease than in their healthy siblings, but these levels were less dependent on serum folate levels (P < 0.05), whereas the effect of MTH FR genotype was stronger (P = 0.01). This-study found evidence that post-me thionine and delta tHcy levels are not only influenced by factors affecting homocysteine transsulfuration but also by factors that affect: remethylati on. explained variances of fasting, post-methionine and delta tHcy were 49% , 62%, and 78%, respectively. We also found evidence, in patients with prem ature vascular disease but not in their healthy siblings, for a factor that increases tHcy levels but weakens the normal inverse relation between fola te and tHcy and amplifies the effect of the MTHFR genotype.