A Polymorphism Within the 3′UTR of NLRP3 is Associated with Susceptibility for Ischemic Stroke in Chinese Population

Abstract

Stroke was regarded as a severe disorder with high morbidity and high mortality worldwide, ischemic stroke (IS) accounts for 85 to 90 % of new increased stroke cases. Partial mechanisms were elucidated by genetic factors including genomic instability such as single nucleotide polymorphism (SNP). Previous reports demonstrated that inflammation was involved in IS, NLRP3 [nucleotide-binding domain (NOD)-like receptor protein 3], acting as a specific inflammatory gene, however, its function and influence on IS was not well clarified. In this study, a case-control study including 1102 IS patients and 1610 healthy controls was conducted to investigate the association between IS susceptibility with a SNP (rs10754558) in 3'UTR of NLRP3. Logistic regression analysis showed that the heterozygote and the homozygote GG confer a significantly increased risk of CRC after controlling for other covariates (adjusted OR = 1.52, 95 % C.I. 1.19-1.97, P = 0.002; adjusted OR = 2.22, 95 % C.I. 2.18-3.67, P< 0.001, respectively). Carriage of G allele was associated with a greatly increased risk of developing the disease (OR = 1.69, 95 % C.I. 1.31-1.83, P < 0.001). Stratification analysis found that hypertension had interaction with rs10754558 to modulate IS risk. Further in vitro assay revealed that rs10754558 can affect mRNA level of NLRP3, suggesting its possible functional significance. Our data suggested that genetic polymorphisms in NLRP3 may influence IS risk in Chinese population. Replication of our studies in other populations and further functional studies are required for complete comprehension of the roles of NLRP3 polymorphisms in IS risk.

Rs4612666 Polymorphism of the NLRP3 Gene Is Associated with the Occurrence of Large Artery Atherosclerotic Ischemic Strokes and Microembolic Signals

“…Previous studies have shown that there is an association between NLRP3 gene polymorphisms and susceptibilities to certain diseases, including Crohn's disease [ 14 ], abdominal aortic aneurysms [ 15 ], and late-onset Alzheimer's disease [ 20 ]. The influence of an NLRP3 gene polymorphism on ischemic strokes was also shown in Zhu et al's study [ 16 ]. LAA ischemic stroke is the most common type of ischemic stroke and is primarily caused by atherosclerosis.…”

“…NLRP3 gene mutations are also observed to be associated with rheumatoid arthritis [ 13 ], Crohn's disease [ 14 ], and abdominal aortic aneurysms [ 15 ]. One study from China suggested that genetic polymorphisms in NLRP3 may influence the risk of ischemic stroke in the Chinese population [ 16 ]. To the best of our knowledge, there are limited studies regarding the relationship between NLRP3 polymorphisms and susceptibility for LAA stroke and MES in the Chinese Han population.…”

Inflammasomes link vascular disease with neuroinflammation and brain disorders

“…IL-1b and/or NLRP3 polymorphisms and changes in gene expression are associated with depression, migraine, MS, AD, PD and ischaemic stroke in patients. 28,[57][58][59][60][61][62][63] Similarly, NLRP3 polymorphisms are associated with risk of hypertension and age-related increase of blood pressure, type 2 diabetes, coronary heart disease and acute vascular events. [64][65][66][67] Increased caspase-1 activation is seen in the brain of AD patients and the NLRP3 inflammasome was found to contribute to disease progression and changes in cognitive function in rodents.…”

Minocycline Suppresses NLRP3 Inflammasome Activation in Experimental Ischemic Stroke

“…The NOD (nucleotide-binding oligomerization domain)-like receptor (NLR) pyrin-domain-containing 3 (NLRP3) inflammasomes are abundantly expressed in the brain and immune cells. Recent findings demonstrate the participation of NLRP3 in ischemic stroke [6][7][8][9] . These findings indicate that NLRP3 inflammasomes may play an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke.…”