Evidence for a Critical Role of the Modifying Subunit of Glutamatecysteine Ligase in Homocysteine Pathophysiology

Abstract number: OR129

Heil¹ SG, Kluijtmans¹ LAJ, De Vriese² AS, den Heijer^3,4 M, Pfundt⁵ R, Blom¹ HJ

¹¹Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Center, The Netherlands ²²Renal Unit, University Hospital Gent, Belgium ^3,43Department of Endocrinology, Solid squareSolid square, Solid squareSolid square, The Netherlands ⁵⁵Department of Human Genetics, Radboud University Nijmegen Medical Center, The Netherlands

Hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilatation and an increased risk of atherosclerosis and thrombosis. Despite intensive research, the pathophysiology of this association remains conjectural. Here we show by gene-expression profiling using oligonucleotide arrays that the modifying subunit of glutamate-cysteine ligase (GCLM) was up-regulated in the aorta of HHcy rats. Glutamatecysteine ligase is the rate-limiting enzyme of glutathione synthesis. In addition, we show that total glutathione levels were increased in serum of HHcy rats, which corroborates the upregulation of GCLM. A single-nucleotide polymorphism (SNP) in the promoter region of the human GCLM gene (-588 C > T) reduces GCLM mRNA expression under conditions of ambient oxidative stress. In a case-control study including patients with recurrent venous thrombosis, we show that the presence of the -588 C > T SNP increased the risk of venous thrombosis more than 2-fold when also homocysteine levels were elevated [OR 2.5 (1.0–6.2)]. These findings suggest that GCLM is up-regulated to compensate for the adverse oxidative effects of elevated homocysteine on the vascular wall, and thus describe a previously undefined role for GCLM in the pathophysiology of hyperhomocysteinemia.