Association of the Glutathione S-transferase Omega-1 Ala140Asp Polymorphism With Cerebrovascular Atherosclerosis and Plaque-Associated Interleukin-1α Expression

Abstract

Background and Purpose-Glutathione S-transferase omega-1 is a multifunctional enzyme. The Asp/Asp genotype of the Ala140Asp polymorphism of the GSTO1 gene has been alleged to increase the risk of vascular dementia. The objective of this study is to address the question of whether common vessel disorders known to cause vascular dementia are modified in their severity by this polymorphism. Methods-The severity and expansion of atherosclerosis in the circle of Willis vessels, cerebral small vessel disease, and cerebral amyloid angiopathy were studied in a sample of 79 autopsy cases. Genotyping of the GSTO1 Ala140Asp polymorphism as well as immunohistochemistry for glutathione S-transferase omega-1 was performed. Results-Carriers of the GSTO1 Asp/Asp genotype presented with more severe and widespread atherosclerosis than noncarriers. However, there was no effect on small vessel disease expansion and cerebral amyloid angiopathy severity.Immunohistochemically, we detected interleukin-1␣ expressing macrophages in the lipid core of atherosclerosis plaques exhibiting glutathione S-transferase omega-1-positive material. GSTO1 Asp/Asp carriers showed larger areas of atherosclerosis plaques containing interleukin-1␣-positive material than carriers of the GSTO1 Ala-allele. Key Words: atherosclerosis Ⅲ cerebral arteries Ⅲ GSTO1-1 G lutathione S-transferase omega-1 (GSTO1-1) is a member of the glutathione S-transferases family of phase II enzymes that catalyze the glutathione dependent detoxification of, eg, oxidants. 1 Recently, we have shown that the Asp/Asp genotype of the GSTO1 Ala140Asp polymorphism in exon 4 is associated with an increased risk for vascular dementia. 2 However, the relationship between this GSTO1 polymorphism and common vessel diseases is not clear. Major vessel diseases causing vascular dementia include atherosclerosis (AS) of the arteries of the circle of Willis, small vessel disease, and cerebral amyloid angiopathy. 3 Small vessel disease includes vascular lesions of arteriolosclerosis, arteriohyalinosis, lipohyalinosis, fibrohyalinosis, and arteriosclerotic intimal proliferation and fibrosis of the media in small arteries but no AS plaques. Conclusions-TheThe objective of this study was to investigate whether one of these vessel disorders is influenced by the GSTO1 Ala140Asp polymorphism. Materials and MethodsWe analyzed a sample of 79 formalin-fixed human brains from continuously collected autopsy cases of 60 years of age and older without further selection criteria (Table). We counted the number of vessels with macroscopically detectable AS plaques in relation to the total number of vessels analyzed within the circle of Willis. Vessels included in this quantification were the major branches of the vertebral, basilar, anterior cerebral, middle cerebral, posterior cere- Histopathology confirmed the diagnosis of AS. The histopathological type of AS lesions of the most severely affected artery of the circle of Willis was determined. 4 The extent of small vessel disease was determined in leptomeningeal,...

Stroke Caused by Atherosclerosis of the Major Intracranial Arteries

“…Increased lipoprotein (a), C-reactive protein, and plasminogen activator inhibitor-1 41 are other biomarkers associated with progression of ICAD. In an autopsy study, carriers of the glutathione S-transferase omega-1 Asp/Asp genotype were found to have more severe and widespread intracranial atherosclerosis than noncarriers, while there was no effect of the polymorphism on small vessel disease severity 42 . Among 40 Spanish patients with ischemic stroke secondary to ICAD, a higher endostatin/vascular endothelial growth factor (VEGF) ratio was associated with higher severity of stenosis (OR 15.7;CI 2.2-112.3), as well as a higher risk of recurrent events over a 13 month follow-up (HR 7.24;CI1.…”

A Role for Glutathione Transferase Omega 1 (GSTO1-1) in the Glutathionylation Cycle

“…Since their first description, the Omega class GSTs have been investigated in relation to a number of biologically significant pathways and clinical disorders including drug resistance (21), Alzheimer disease (22)(23)(24), Parkinson disease (25), vascular dementia and stroke (26,27), and amyotrophic lateral sclerosis (28), the action of anti-inflammatory drugs (29), the disposition of arsenic (30), and susceptibility to chronic obstructive pulmonary disease (31)(32)(33) and cancer (34 -40). However, the mechanism by which the Omega GSTs mediate their effects in these diverse settings has not been clear.…”

Epidemiology and Pathophysiology of Intracranial Large Artery Stenosis

“…These include angiotensin converting enzyme polymorphism, plasma to vascular endothelial growth factor ratio, glutathione S-transferase, omega-1 gene polymorphism, and plasma homocysteine level [13,[29][30][31][32]. They exert their action via various mechanisms such as vascular endothelial injury, proliferation of vascular smooth muscle cell, and impairment of angiogenesis.…”