Contribution of the cystathionine beta-synthase gene (844ins68) polymorphism to the risk of early-onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia

The frequency of the heterozygous 844ins68 mutation of the cystathionine be ta-synthase (CBS) gene and of its association with the homozygous C677T tra nsition of the methylenetetrahydrofolate reductase (MTHFR) gene, plasma fas ting tHcy, folate and vitamin B-12 levels were evaluated in 309 consecutive patients with objectively diagnosed early-onset venous (n = 200) or arteri al thromboembolic disease (n = 109) recruited over 25 months in Milan (Nort h Italy! and Naples (South Italy). The above gene polymorphisms were also e valuated in a population of 787 unmatched controls, 204 of whom - similar t o patients for age- and sex-distribution - had fasting tHcy, vitamins and a ctivated protein C resistance measured in their plasma. Moderate fasting hyperhomocysteinemia was detected in 15.5% of patients and in 5.9% of 204 controls (Mantel-Haenszel OR after stratification for type of occlusive disease and gender: 2.88; 1.48-5.32). The frequencies of the 6 77TT mutation of the MTHFR gene and of the heterozygous 844ins68 insertion of the CBS gene were not significantly different in the patient (19.4% and 6.9%) and the control population (16.5% and 7.8%), but the association of t he two gene polymorphisms found in 3.9% of patients and in 1.1% of controls - was significantly associated with an increased risk of venous or arteria l occlusive diseases (RR = 3.63; 1.48-8.91). The MTHFR 677TT mutation (RR: 6.92; 3.86-12.4) and its association with the 844ins68 insertion (RR: 21.9; 8.35-57.4), but not the isolated insertion (RR: 0.71), were more frequent in patients and controls with fasting hyperhomocysteinemia than in normohom ocysteinemic subjects, irrespective of the type of occlusive disease (venou s or arterial). When adjusted for determinants of hyperhomocysteinemia in t he patient and the control populations (generalized linear model), fasting tHcy levels were significantly higher in subjects with association of the t wo gene abnormalities (24.2 +/- 3.8 mu mol/L) than in subjects with the MTH FR 677TT mutation only (14.0 +/- 5.8 mu mol/L, p = 0.004). Activated protei n C resistance was significantly more prevalent in venous patients (9.9%) t han in controls (3.9%,. OR = 2.69: 1.08-6.88). Six of 21 venous patients wi th APC-resistance also had hyperhomocysteinemia (RR = 5.04; 0.68-37.6), but isolated fasting hyperhomocysteinemia retained statistical significance fo r the association with venous occlusive disease (RR = 2.84; 1.34-6.01). Heterozygosity for the 844ins68 mutation of the CBS gene is not per se a ri sk factor for premature arterial and/or venous occlusive diseases. However, when detected in combination with thermolabile MTHFR, it increases by almo st 4-fold the risk of occlusive diseases (arterial and/or venous), by incre asing the risk and the degree of fasting hyperhomocysteinemia.