Summary

Total fasting plasma homocysteine (tHcy), homozygosity for theC677T mutation of the methylenetetrahydrofolate reductase (MTHFR)gene and for the A2756G mutation of the methionine synthase (MS)gene, vitamin B₁₂ and folate plasma levels were evaluated in 170 consecutivepatients (89 M, 81 F; mean age 41 ± 12 yrs) with documentedearly-onset thrombosis (89 venous, 69 arterial, 12 both; mean age atfirst episode 36 ± 11 yrs), and in 182 age- and sex-matched healthycontrol subjects. Moderate hyperhomocysteinemia (HHcy, tHcy19.5 M in men and 15 M in women) was detected in 45 patients(26.5%) and in 18 controls (9.9%, Mantel-Haenszel OR and 95% C.I.after stratification for arterial or venous thrombosis: 3.25, 1.78-5.91).The 677TT MTHFR genotype was not significantly more prevalent inpatients (27.6%) than in controls (21.4%, RR = 1.42; 0.84-2.41), andmarkedly contributed to HHcy (Mantel-Haenszel RR after stratificationfor case/control status: 8.29, 4.61-14.9). The 2756GG MS genotype,observed in 4 patients (2.4%) and 8 controls (4.4%), was not associatedto HHcy. tHcy was negatively correlated to folate and vitamin B₁₂ levels,with better correlation found in subjects with the 677TT mutation(r = -0.42 and -0.25) than with the 677CC or CT MTHFR genotype(r = -0.37 and -0.11). However, folate was similar in patients andcontrols and vitamin B₁₂ was higher in patients (460 ± 206 vs. 408 ±185 pg/ml, p = 0.011). In a generalized linear model, 44% of the variationin tHcy levels was explained by folate and vitamin B₁₂ levels, theMTHFR genotype, gender, and by the interaction of the MTHFR genotypewith folate (p 0.028); the interactions of vitamin B₁₂ with theMTHFR genotype, gender and patient/control status also significantlycontributed to the variation in tHcy levels (p 0.028). A 4-week administrationof 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but theresponse to treatment correlated with vitamin B levels (p = 0.023).Subjects carrying the MTHFR 677TT genotype have higher folate andvitamin B₁₂ requirements irrespective of the A2756G polymorphism ofthe MS gene. Yet unidentified abnormalities of MS or of any of theenzymes participating in the synthesis of methylated vitamin B₁₂ mayplay an important role in the phenotypic expression of moderate hyperhomocysteinemia.