Heme Oxygenase‐1 Gene (GT)n Polymorphism Linked to Deep White Matter Hyperintensities, Not Periventricular Hyperintensities

Abstract

Background Oxidative stress plays a principal role in the pathogenesis of white matter hyperintensities (WMHs). The induction of heme oxygenase‐1 (HO‐1) gene in the brain represents 1 of the pivotal mechanisms to counteract the noxious effects of reactive oxygen species, and the transcriptional modulation of HO‐1 induction depends on the length of a GT‐repeat (GT)n in the promoter region. We investigated whether the HO‐1 gene (GT)n polymorphism is associated with the risk of WMHs. Methods and Results A total of 849 subjects from the memory clinic were consecutively enrolled, and the HO‐1 (GT)n genotype was determined. WMHs were assessed with the Fazekas scale and further divided into periventricular WMHs and deep WMHs (DWMHs). Allelic HO‐1 (GT)n polymorphisms were classified as short (≤24 (GT)n), median (25≤[GT]n<31), or long (31≤[GT]n). Multivariate logistic regression analysis was used to evaluate the effect of the HO‐1 (GT)n variants on WMHs. The number of repetitions of the HO‐1 gene (GT)n ranged from 15 to 39 with a bimodal distribution at lengths 23 and 30. The proportion of S/S genotypes was higher for moderate/severe DWMHs than none/mild DWMHs (22.22% versus 12.44%; P=0.001), but the association for periventricular WMHs was not statistically significant. Logistic regression suggested that the S/S genotype was significantly associated with moderate/severe DWMHs (S/S versus non‐S/S: odds ratio, 2.001 [95% CI, 1.323–3.027]; P<0.001). The HO‐1 gene (GT)n S/S genotype and aging synergistically contributed to the progression of DWMHs (relative excess risk attributable to interaction, 6.032 [95% CI, 0.149–11.915]). Conclusions Short (GT)n variants in the HO‐1 gene may confer susceptibility to rather than protection from DWMHs, but not periventricular WMHs. Registration URL: https://www.chictr.org.cn; Unique identifier: ChiCTR2100045869.

Keywords

• cognitive impairment
• HO‐1 gene
• oxidative stress
• polymorphism
• white matter hyperintensity