Sex-Specific Association between HO-1 (GT)n Promoter Polymorphism and Large-Artery Atherosclerosis Stroke

Oxidative stress is a central factor in the pathogenesis of atherosclerosis and potentially exhibits sexual dimorphism. The induction of heme oxygenase-1 (HO-1) serves as a crucial mechanism against reactive oxygen species toxicity in the vascular wall, and this induction is regulated by the promoter (GT)n repeat length. We aim to investigate whether or not HO-1 gene (GT)n polymorphism is associated with the occurrence of large-artery atherosclerotic (LAA) stroke.

We consecutively recruited stroke patients, with a control group comprising age- and sex-matched non-stroke individuals. HO-1 (GT)n genotypes were determined using DNA extracted from the peripheral leukocytes. HO-1 (GT)n polymorphism was classified as short [S, ≤ 24 (GT)n], medium [M, 25 ≤ (GT)n ＜31], or long [L, 31 ≤ (GT)n]. Clinical data were collected, and stroke patients were categorized into LAA and non-LAA groups according to the TOAST classification. A multivariable logistic regression analysis was conducted to evaluate the association between HO-1 (GT)n variants and LAA occurrence stratified by sex.

There was no significant difference in the distribution of HO-1 (GT)n genotypes between the stroke and non-stroke populations. However, the proportion of S/S genotype was significantly lower in the LAA stroke patients than in the non-LAA stroke patients (7.08% vs. 21.78%, p＜0.001). A multivariable logistic regression analysis indicated that non-SS genotypes were associated with a significantly increased risk of LAA compared to the S/S genotype patients (odds ratio [OR] 3.35, 95% confidence interval [CI] 1.98-5.67, p＜0.001). After stratification by sex, the protective effect of the HO-1 (GT)n S/S genotype was highly significant in men (OR 5.50, 95% CI 2.67-11.34, p＜0.001), whereas the association was not significant in women (OR 1.60, 95% CI 0.75-3.34, p = 0.228).

Short (GT)n variants in HO-1 may confer significant protection against LAA stroke in men but not in women.