Polymorphisms of homocysteine metabolism are associated with intracranial aneurysms

Background: Impaired homocysteine metabolism is associated with a number of vasculopathies including extracranial aneurysms. We analyzed the possible association of nine genetic variants of homocysteine metabolism with the occurrence of intracranial aneurysms. Methods: Caucasian patients (n = 255) treated at two German hospitals for intracranial aneurysms and local controls (n = 348) were genotyped for the following polymorphisms: methionine synthase (MTR) c.2756A→G, methylenetetrahydrofolate reductase (MTHFR) c.677C→T, MTHFR c.1298A→C, cystathionine β-synthase (CBS) c.844_855ins68, CBS c.833T→C, dihydrofolate reductase (DHFR) c.594 + 59del19bp, glutathione S-transferase Ω-1 (GSTO1) c.428C→A, reduced folate carrier 1 (RFC1) c.80G→A and transcobalamin 2 (Tc2) c.776C→G. Results: The G-allele of the missense polymorphism Tc2 c.777C→G was found to be underrepresented in patients, suggesting that this variant may protect from the formation of cerebral aneurysms [odds ratio per two risk alleles (OR) 0.48; 95% confidence interval (CI) 0.30-0.77; p = 0.002]. We obtained borderline results for the G-allele of RFC1 c.80G→A (OR 1.64; 95% CI 1.01-2.65; p = 0.051) and the insertion allele of DHFR c.594 + 59del19bp (OR 1.61; 95% CI 1.00-2.60; p = 0.059), which were found to be overrepresented in patients. Conclusion: Polymorphisms of homocysteine metabolism are possible risk factors for the formation of intracranial aneurysms.