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

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.