A susceptibility putative haplotype within NLRP3 inflammasome gene influences ischaemic stroke risk in the population of Punjab, India

Abstract

Despite strong genetic implications of NLRP3 inflammasome, its examination as genetic determinant of ischaemic stroke (IS) remains to be done in Punjab, which has been investigated in this study. In this case control study, 400 subjects (200 IS patients, 200 stroke free controls) were included. Contributions of 5 single nucleotide polymorphisms (SNPs) including a functional SNP within NLRP3 gene (rs10754558, rs4612666, rs2027432, rs3738488 and rs1539019) for the risk of IS were investigated through genetic models after correcting the effect of significant variables.Plasma levels of three pro-inflammatory markers, that is, C-reactive protein (CRP), interleukin-1beta (IL-1β) and interleukin-18 (IL-18) were measured by enzyme-linked immunosorbent assays (ELISA). Minor alleles of 3 out of 5 SNPs (rs10754558, rs4612666 and rs1539019) exhibited association with IS risk in additive, recessive and multiplicative models. Multivariable regression analysis confirmed that higher levels of systolic blood pressure (β ± SE: 1.42 ± 0.57, p = .013), CRP (β ± SE: 1.22 ± 0.41, p = .003), IL-1β (β ± SE: 1.78 ± 0.88, p = .043) and IL-18 (β ± SE: 1.13 ± 0.49, p = .021) were independent risk predictors for IS. Haplotype analysis revealed a susceptibility putative haplotype GTGTA, which approximately doubled the IS risk (OR: 1.98, 95% CI:1.12-3.78, p = .04) in dominant mode after adjusting the effect with confounding variables. This susceptibility putative haplotype GTGTA was significantly associated with increased concentrations of CRP (β = 1.21, p = .014) and IL-1β (β = 1.53, p = .034) in dose-dependent manner (less in carriers of 1 copy than those who had 2 copies of GTGTA).The present study has revealed a susceptibility putative haplotype GTGTA within NLRP3 gene, carriers of which have double the risk of IS by having increased plasma levels of CRP and IL-1β in a dose-dependent manner.

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“…CPN1 may be involved in acute phase response signaling and the development of hypercoagulable and hypofibrinolytic states, and its activation impairs the clearance of impaired mitochondria, leading to mitochondrial dysfunction ( 21 , 22 ). Elevated plasma CRP, which may increase the risk of ischemic stroke, is closely associated with cryptogenic stroke with systemic inflammatory features and also increases asymptomatic intracranial or extracranial arterial stenosis in patients with AIS or TIA at 1-year risk of ischemic stroke and risk of ischemic stroke recurrence ( 23 – 25 ). VWF interacts with the circulatory system and platelets in hemostasis and thrombosis by sensing and responding to changes in hemodynamics, which have been associated with atherosclerosis, stroke, and more recently, COVID-19 thrombotic symptoms ( 26 ).…”