The Role of Vitamin B12 in Fasting Hyperhomocysteinemia and Its Interaction with the Homozygous C677T Mutation of the Methylenetetrahydrofolate Reductase (MTHFR) Gene

Abstract

SummaryTotal fasting plasma homocysteine (tHcy), homozygosity for the C677T 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 consecutive patients (89 M, 81 F; mean age 41 ± 12 yrs) with documented early-onset thrombosis (89 venous, 69 arterial, 12 both; mean age at first episode 36 ± 11 yrs), and in 182 age- and sex-matched healthy control subjects. Moderate hyperhomocysteinemia (HHcy, tHcy >19.5 µM in men and >15 µM 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 in patients (27.6%) than in controls (21.4%, RR = 1.42; 0.84–2.41), and markedly contributed to HHcy (Mantel-Haenszel RR after stratification for 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 associated to 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 and controls 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 variation in tHcy levels was explained by folate and vitamin B12 levels, the MTHFR genotype, gender, and by the interaction of the MTHFR genotype with folate (p ≤0.028); the interactions of vitamin B12 with the MTHFR genotype, gender and patient/control status also significantly contributed to the variation in tHcy levels (p ≤0.028). A 4-week administration of 5-methyltetrahydrofolate (15 mg/day) markedly lowered plasma tHcy in 24 patients with MTHFR 677TT genotype, but the response to treatment correlated with vitamin B12 levels (p = 0.023). Subjects carrying the MTHFR 677TT genotype have higher folate and vitamin B12 requirements irrespective of the A2756G polymorphism of the MS gene. Yet unidentified abnormalities of MS or of any of the enzymes participating in the synthesis of methylated vitamin B12 may play an important role in the phenotypic expression of moderate hyperhomocysteinemia.

Plasma Folate, Vitamin B₁₂, and Total Homocysteine and Homozygosity for the C677T Mutation of the 5,10-Methylene Tetrahydrofolate Reductase Gene in Patients with Alzheimer’s Dementia

“…This is in agreement with results of other studies which showed that MTHFR C677T genotype was not associated with an increased risk of either AD or vascular dementia [17]. In both groups, the prevalence of homozygosity was higher than in other populations [8,18], but coincident with that usually observed in northern and southern Italy [14,17,19]. The normal upper limit of the normal range for plasma tHcy was also high, but consistent with results of other studies performed in southern Italy [19].…”

“…In recent studies the C677T MTHFR mutation was not considered an independent risk factor for cardiovascular disease [20] and may explain only a fraction of the elevated tHcy levels contributing to the risk of thrombosis [18]. We also observed [19] that the status of carriers of the homozygous C677T MTHFR mutation contributed to an increased risk of hyperhomocysteinemia in both patients with early-onset thrombotic events and in normal controls, but its prevalence was similar in both groups. In this study, patients with early-onset thrombotic events and normal controls had similar plasma folate levels, while the plasma vitamin B 12 levels were higher among the patients.…”

Dietary and genetic determinants of homocysteine levels among Mexican women of reproductive age

“…In one study, healthy subjects were given a multivitamin supplement containing 0.4 mg/day of hydroxicobalamin, 5 mg of folic acid, and 50 mg of pyridoxine (den Heijer et al, 1998); the results demonstrated a 49% reduction in the basal median value of Hcy, among individuals with the 677TT genotype. In another study, a similar response could only be detected among subjects with hyperhomocysteinemia, who were carriers of the polymorphism 677C4T, who had taken the supplements over 4 weeks, and these had either normal or elevated levels of vitamin B 12 (D'Angelo et al, 2000).…”

Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke

“…Recently, the homocysteine-lowering effects of folate and vitamins B 6 and B 12 have been extensively described, 46,47 and the possibility of vitamin supplementation as a therapeutic strategy for vascular diseases has received attention. At this time, the beneficial effects of lowering plasma homocysteine by vitamins, in relation to the risk of vascular disease, have not yet been established.…”