The clinical impact of MTHFR polymorphism on the vascular complications of sickle cell disease

Abstract

Sickle cell disease (SCD) is one of the most common inherited diseases in the world and the patients present notorious clinical heterogeneity. It is known that patients with SCD present activation of the blood coagulation and fibrinolytic systems, especially during vaso-occlusive crises, but also during the steady state of the disease. We determined if the presence of the factor V gene G1691A mutation (factor V Leiden), the prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may be risk factors for vascular complications in individuals with SCD. We studied 53 patients with SCD (60% being women), 29 with SS (sickle cell anemia; 28 years, range: 13-52 years) and 24 with SC (sicklehemoglobin C disease; 38.5 years, range: 17-72 years) hemoglobinopathy. Factor V Leiden, MTHFR C677T polymorphism, and prothrombin G20210A variant were identified by PCR followed by further digestion of the PCR product with specific endonucleases. The following vascular complications were recorded: stroke, retinopathy, acute thoracic syndrome, and X-ray-documented avascular necrosis. Only one patient was heterozygous for factor V Leiden (1.8%) and there was no prothrombin G20210A variant. MTHFR 677TT polymorphism was detected in 1 patient (1.8%) and the heterozygous form 677TC was observed in 18 patients (34%, 9 with SS and 9 with SC disease), a prevalence similar to that reported by others. No association was detected between the presence of the MTHFR 677T allele and other genetic modulation factors, such as α-thalassemia, ß-globin gene haplotype and fetal hemoglobin. The presence of the MTHFR 677T allele was associated with the occurrence of vascular complications in SCD, although this association was not significant when each complication was considered separately. In conclusion, MTHFR C677T polymorphism might be a risk factor for vascular complications in SCD.

Clinical impact of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations among sickle cell disease patients of Central India

“…Considerable evidence suggests that endothelial damage and thrombosis play important contributory roles in the vaso‐occlusive complications such as stroke, avascular necrosis of bone joints, pulmonary embolism in SCD . The significant association of FVL mutation with SCD in the present study is consistent with the earlier study of Iranian patients with SCD but inconsistent with the findings of other workers from Africa, Saudi Arabia, Brazil, and Jamaica . Similarly, significant incidence of MTHFR C677T polymorphism among patients with SCD in present series supports to that of the earlier Brazilian studies of patients with SCD .…”

Role of the Hemostatic System on Sickle Cell Disease Pathophysiology and Potential Therapeutics

“…However, despite the moderate prevalence of Factor V Leiden (FVL) mutation (2.97-5.5%) among the general population of Iran 128 , the prevalence of FVL mutation is higher (14.3%) among Iranian SCD patients 129 with a significant association between this mutation and SCD (OR=6.5). Also, a study from Brazil suggests that MTHFR C677T might be a risk factor for vascular complications in SCD 123 . Also, three studies of inherited risk factors of venous thromboembolism in SCD patients from Southern Mediterranean countries 130-132 , report high prevalence of thrombophilic mutations in SCD patients and their association with thromboembolic events.…”