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Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals
Örebro universitet, Institutionen för hälsovetenskap och medicin.ORCID-id: 0000-0002-4589-6440
Örebro universitet, Institutionen för hälsovetenskap och medicin.ORCID-id: 0000-0002-9826-0462
Örebro universitet, Institutionen för hälsovetenskap och medicin.ORCID-id: 0000-0003-1067-8627
Örebro universitet, Institutionen för hälsovetenskap och medicin.
Vise andre og tillknytning
2013 (engelsk)Inngår i: Biomedical Reports, ISSN 2049-9434, Vol. 1, nr 6, s. 879-882Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Inflammation is a multifaceted process that underlies the pathophysiology of acute myocardial infarction (MI). Variations in the inflammasome‑related NLRP3 gene have been associated with risk for a number of different inflammatory diseases. Therefore, Q705K polymorphism in NLRP3 gene likely confers susceptibility to risk for MI. A First‑ever myocardial Infarction study in Ac‑county (FIA) cohort comprising 555 MI patients and 1,016 controls was used to genotype rs35829419 in the NLRP3 gene by TaqMan single‑nucleotide polymorphism assay. C‑reactive protein (CRP) was measured in the study participants by ELISA. The results showed no significant association between the variant rs35829419 and MI. However, the minor A allele of the rs35829419 polymorphism conferred a protective effect against the risk of developing MI in females. The minor A allele of rs35829419 polymorphism was also associated with increased CRP levels in males. Results of the study suggested a gender‑specific deregulation of NLRP3 gene mediated by rs35829419 polymorphism that confers protection against MI in females but has no effect on MI susceptibility in males. However, the rs35829419 polymorphism was associated with increased CRP levels among the male subjects, thereby demonstrating the possible effect of the Q705K polymorphism in elevating the basal active state of innate immune response.

sted, utgiver, år, opplag, sider
2013. Vol. 1, nr 6, s. 879-882
HSV kategori
Identifikatorer
URN: urn:nbn:se:oru:diva-35448DOI: 10.3892/br.2013.155OAI: oai:DiVA.org:oru-35448DiVA, id: diva2:726904
Tilgjengelig fra: 2014-06-19 Laget: 2014-06-19 Sist oppdatert: 2017-10-18bibliografisk kontrollert
Inngår i avhandling
1. Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
Åpne denne publikasjonen i ny fane eller vindu >>Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Atherosclerosis is complex inflammatory disease of the arterial wall with progressive accumulation of lipids and narrowing of the vessel. Increasing evidence suggest that inflammation plays an important role in plaque stability and often accelerate cardiovascular events such as myocardial infarction (MI). Among the vast number of inflammatory cytokines, IL-1β is known to be a key modulator in vessel wall inflammation and acceleration of the atherosclerotic process. The biologically active IL-1β is regulated by a multiprotein complex known as the NLRP3 inflammasome complex. In this thesis, we have focused on polymorphisms in the NLRP3 and CARD8 genes and their possible association to atherosclerosis and/or MI. We have also investigated the expression of inflammasome components NLRP3 and CARD8 in atherosclerosis and the role of genetic variants for the expression of these genes. The expression of NLRP3, CARD8, ASC, caspase-1, IL-1β, and IL-18 were found significantly upregulated in atherosclerotic lesions compared to normal arteries. Human carotid plaques not only express the NLRP3 inflammasome, but also release IL-1β upon exposure to lipopolysaccharide (LPS), adenosine triphosphate (ATP) and cholesterol crystals, which suggest NLRP3 inflammasome activation in human atherosclerotic lesions. Also, CARD8 was found to be important in the regulation of several inflammatory markers in endothelial cells, like RANTES, IP10 and ICAM-1. We further assessed the potential association of a CARD8 polymorphism and polymorphisms located downstream of the NLRP3 gene to the risk of MI in two independent Swedish cohorts. The CARD8 variant exhibited no association to risk of MI in either of the two cohorts. Some of the minor alleles of NLRP3 variants were associated with increased IL-1β levels and to NLRP3 mRNA levels in peripheral blood monocytic cells (PBMC). Taken together, the present thesis shows that NLRP3 inflammasome activation and increased expression of CARD8 in the atherosclerotic plaque might be possible contributors to the enhanced inflammatory response and leukocyte infiltration in the pathophysiology of atherosclerosis.

sted, utgiver, år, opplag, sider
Örebro: Örebro University, 2017. s. 77
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 154
Emneord
Atherosclerosis, Inflammasome, NLRP3, CARD8, Myocardial infarction, Endothelial cells, Polymorphism, IL-1β, Cytokines, Innate immunity
HSV kategori
Forskningsprogram
Biomedicin
Identifikatorer
urn:nbn:se:oru:diva-53482 (URN)978-91-7529-173-4 (ISBN)
Disputas
2017-01-27, Campus USÖ, hörsal C1, Södra Grev Rosengatan 30, Örebro, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2016-11-14 Laget: 2016-11-14 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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