Association between ADAM17 Promoter Polymorphisms and Ischemic Stroke in a Chinese Population

Abstract

Aim: Stroke is a leading cause of death and disability worldwide. Most ischemic strokes (IS) are caused by atherosclerosis. Recently, the pivotal role of ADAM17 in atherosclerosis has been thoroughly addressed. However, the association between ADAM17 and IS has not yet been thoroughly explored. The present study therefore aimed to investigate the association between disintegrin and metalloproteinase 17 (ADAM17) gene polymorphisms and the risk of ischemic stroke (IS). Methods: The associations between five ADAM17 promoter polymorphisms and the risk of IS were assessed in 342 patients with IS and 296 age-matched healthy individuals in a case-control study. Results: The allele and genotype frequencies of the ADAM17 polymorphisms (rs11684747, rs11689958, rs12692386, rs55790676 and rs1524668) did not differ significantly between the IS patients and healthy control group subjects. In addition, no significant associations were detected between the ADAM17 haplotypes and IS. The mean intima-media thickness in the IS patients was not associated with the ADAM17 polymorphisms. When the IS patients were stratified according to their OCSP classification, the genotype frequencies of the ADAM17-rs1524668 polymorphism exhibited a significant association with the PACI subtype of IS. Moreover, the ADAM17-rs12692386 A＞G polymorphism was found to be associated with a higher ADAM17 mRNA expression. Conclusions: The SNPs in the ADAM17 promoter region do not appear to be major contributors to the pathogenesis of IS. However, the rs12692386 G ADAM17 allele is correlated with a higher expression of ADAM17 mRNA, which may play a role in increasing inflammation in IS patients. Furthermore, the ADAM17-rs1524668 polymorphism is linked to a higher risk of PACI-type stroke, confirming the role of ADAM17 in the pathophysiology of PACI, with potentially important therapeutic implications. and the third most common cause of death in many developed and developing countries. Approximately 80% of stroke cases involve ischemic stroke (IS) 1) , which is primarily caused by atherosclerosis, a chronic inflammatory disease of the vessel wall 2) . ADAM (a disintegrin and metalloproteinase) genes, which are characterized by their metalloproteinase domain and disintegrin-cysteine rich region, are essential for a number of biological processes, including inflammation, cell proliferation and migration, immunity and You Li and Li-Li Cui contributed equally to this work. 879 ADAM17 Polymorphisms and Ischemic Stroke Materials and Methods SubjectsA total of 342 ischemic stroke patients (mean age, 70.30±10.75 years) were recruited from the First Affiliated Hospital of Guangdong Medical College between 2012 and 2013. An IS diagnosis was established based on the patient's clinical signs and symptoms. All patients underwent computed tomography (CT) scans and/or magnetic resonance imaging (MRI) as well as standardized blood tests. Based on the clinical manifestations and neuroimaging data, two neurologists classified the ischemic strokes into four subtypes using eithe...

Association Study Between Promoter Polymorphisms of ADAM17 and Progression of Sepsis

“…A recent study has revealed that the rs11684747 polymorphism has a potential allele-specific binding site for the hepatocyte nuclear factor-1 alpha (HNF1A/B) transcription factor, which is associated with the insulin sensitivity and progression of diabetes [26,39]. Our previous studies have shown that the ADAM17 rs1524668 A>C increases the susceptibility to PACI-type stroke and that the rs12692386 GA/GG genotypes of ADAM17 are linked to high ADAM17 mRNA expression and increase susceptibility to human abdominal aortic aneurysm [28,31]. We speculate that transcriptional enhancers and other regulatory elements in the promoter regions may play various regulatory roles in the gene transcription.…”

“…Five SNPs (rs55790676, rs12692386, rs11684747, rs1524668 and rs11689958) within the promoter region of ADAM17 were selected according to our previous reports [28,31]. The five ADAM17 genetic variants were genotyped by using the SNaPshot Multiplex Kit (Genesky Biotechnologies, Inc., Shanghai, China).…”

“…Several genetic variations of ADAM17 have been demonstrated to be involved in various inflammation-related diseases, such as Kawasaki disease, obesity, Alzheimer's disease and ischemic stroke [25][26][27][28]. A recent study has demonstrated that two functional genetic variations of ADAM17, C-154A and Ser747Leu, contribute to high serum concentration of TNF-α and increased susceptibility to cardiovascular death [29].…”

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and The Risk of SARS-CoV-2 Infection: A Systematic Review and Meta-analysis 

“…The OR for ARB use in the study by Yan et al was only adjusted for age, sex and BMI and therefore, could have been affected by residual confounding. On the other hand, it has been shown in a, Chinese population that rs12692386 G promotor polymorphism was associated with higher ADMA17 expression 32 .Moreover, several ACE2 polymorphisms have been reported in different populations including the Chinese. These polymorphisms have been shown to be associated with HTN, DM and CVD as well as with ACE2 activity, and serum ACE2 and angiotensin-(1-7) peptide levels 33 .It remains to be determined whether increased circulating ACE2 levels are due to increased shedding or due to both increased shedding and expression.…”

The -172A>G Polymorphism in ADAM17 Promoter Region Enhances Its Binding to EGR1 and Confers Susceptibility to Sepsis Progression

“…The human ADAM17 gene is located on chromosome 2 and contains 19 exons. Accumulating evidence demonstrates that single-nucleotide polymorphisms (SNPs) in the ADAM17 gene are associated with risk for various in ammation-related diseases, such as ischemic stroke, Kawasaki disease and cardiovascular death [17][18][19]. Our previous study revealed, for the rst time that ADAM17 -172A>G may act as a functional SNP involved in sepsis progression [13].…”