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Thromb Haemost 2000; 83(04): 563-570
DOI: 10.1055/s-0037-1613864
Commentary
Schattauer GmbH

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

A Case-control Study of Patients with Early-onset Thrombotic Events
Armando D’Angelo
1   From the Coagulation Service and Thrombosis Research Unit, Milan, Italy
,
Antonio Coppola
2   Department of Clinical and Experimental Medicine, University of Naples “Federico II”, Naples, Italy
,
Pasquale Madonna
2   Department of Clinical and Experimental Medicine, University of Naples “Federico II”, Naples, Italy
,
Isabella Fermo
3   Department of Laboratory Medicine, Milan, Italy
,
Anna Pagano
2   Department of Clinical and Experimental Medicine, University of Naples “Federico II”, Naples, Italy
,
Giuseppina Mazzola
1   From the Coagulation Service and Thrombosis Research Unit, Milan, Italy
,
Laura Galli
4   Epidemiology Unit, I.R.C.C.S. H. S. Raffaele, Milan, Italy
,
Anna Maria Cerbone
2   Department of Clinical and Experimental Medicine, University of Naples “Federico II”, Naples, Italy
› Author AffiliationsThis work was partly supported by CNR grants (97.00472.CT04) and from Telethon-Italy (no. E.C.804).
Further Information

Publication History

Received 11 August 1999

Accepted after resubmission 14 December 1999

Publication Date:
08 December 2017 (online)

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Summary

Total 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.

Keywords

Hyperhomocysteinemia - folate - Vitamin B12 5,10-methylenetetrahydrofolate reductase - methionine synthase - juvenile thrombosis
 

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