Associations between Toll-like receptor 4 Asp299Gly polymorphism and susceptibility to intracranial aneurysm among male and female patients within the North Indian population

Abstract

ABSTRACT Objectives Intracranial aneurysms (IA), often remain asymptomatic until they get ruptured, invariably leads to subarachnoid hemorrhage (SAH), and is influenced by both genetic and environmental factors. Recent studies indicated inflammation as a key player in IA development. This study delves into genetic variations within inflammatory pathways, focusing on TLR4-mediated cytokine release as potential IA biomarkers. Methods Eighty IA patients and eighty healthy controls from North India participated, and demographic and clinical data were analyzed, including gender-stratified comparisons of TLR4 Asp299Gly genotype and TLR4 expression. Histological and molecular analyses of blood and brain tissue were done using SEM imaging, qPCR, and western blot. Results Our result revealed elevated TLR4 expression in IA patients, with SEM imaging indicating intracerebral damage. TLR4 Asp299Gly heterozygote genotype was less prevalent in IA patients, suggesting a protective effect against IA development. Moreover, TNF-α levels were significantly higher in IA patients, indicating an inflammatory response. Further, TNF-α expression was downregulated in heterozygous patients, suggesting TLR4 Asp299Gly gene polymorphism affects the activation of TNF-α expression. Gender-based analysis between control and aneurysm cases showed a decrease in TLR4 Asp299Gly heterozygote genotype with heightened TLR4 expression and neurological deficits in IA female patients compared to males. Conclusions This study highlights the association between TLR4 Asp299Gly genotype and IA susceptibility in North Indian populations, linking increased TLR4 expression to IA pathogenesis. Gender-specific disparities in TLR4 genotype and expression underscore the need for personalized treatment strategies, with TLR4 signaling modulation emerging as a promising therapeutic avenue warranting further investigation.