scholarly journals Functional rare variant in a C/EBP beta binding site in NINJ2 gene increases the risk of coronary artery disease

Aging ◽  
2021 ◽  
Author(s):  
Pengyun Wang ◽  
Yifan Wang ◽  
Huixin Peng ◽  
Jingjing Wang ◽  
Qian Zheng ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Binding Site ◽  
Rare Variant ◽  
Artery Disease

Rare, Damaging DNA Variants in CORIN and Risk of Coronary Artery Disease: Insights From Functional Genomics and Large-Scale Sequencing Analyses

2021 ◽  
Author(s):  
Minxian Wang ◽  
Vivian S. Lee-Kim ◽  
Deepak S. Atri ◽  
Nadine H. Elowe ◽  
John Yu ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Analysis ◽  
Rare Variant ◽  
Odds Ratio ◽  
Large Scale ◽  
Missense Mutations ◽  
Rare Variant Association ◽  
Missense Variants ◽  
Artery Disease

Background: Corin is a protease expressed in cardiomyocytes that plays a key role in salt handling and intravascular volume homeostasis via activation of natriuretic peptides. It is unknown if Corin loss-of-function (LOF) is causally associated with risk of coronary artery disease (CAD). Methods: We analyzed all coding CORIN variants in an Italian case-control study of CAD. We functionally tested all 64 rare missense mutations in Western Blot and Mass Spectroscopy assays for proatrial natriuretic peptide cleavage. An expanded rare variant association analysis for Corin LOF mutations was conducted in whole exome sequencing data from 37 799 CAD cases and 212 184 controls. Results: We observed LOF variants in CORIN in 8 of 1803 (0.4%) CAD cases versus 0 of 1725 controls ( P , 0.007). Of 64 rare missense variants profiled, 21 (33%) demonstrated <30% of wild-type activity and were deemed damaging in the 2 functional assays for Corin activity. In a rare variant association study that aggregated rare LOF and functionally validated damaging missense variants from the Italian study, we observed no association with CAD—21 of 1803 CAD cases versus 12 of 1725 controls with adjusted odds ratio of 1.61 ([95% CI, 0.79–3.29]; P =0.17). In the expanded sequencing dataset, there was no relationship between rare LOF variants with CAD was also observed (odds ratio, 1.15 [95% CI, 0.89–1.49]; P =0.30). Consistent with the genetic analysis, we observed no relationship between circulating Corin concentrations with incident CAD events among 4744 participants of a prospective cohort study—sex-stratified hazard ratio per SD increment of 0.96 ([95% CI, 0.87–1.07], P =0.48). Conclusions: Functional testing of missense mutations improved the accuracy of rare variant association analysis. Despite compelling pathophysiology and a preliminary observation suggesting association, we observed no relationship between rare damaging variants in CORIN or circulating Corin concentrations with risk of CAD.

Association of γA/γ’ Fibrinogen Levels and Coronary Artery Disease

2002 ◽  
Vol 88 (07) ◽  
pp. 26-31 ◽  
Author(s):  
Rehana Lovely ◽  
Lisa Falls ◽  
Hamid Al-Mondhiry ◽  
Charles Chambers ◽  
Gary Sexton ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Coronary Angiography ◽  
Binding Site ◽  
Factor Xiii ◽  
Blood Donors ◽  
Human Populations ◽  
Total Plasma ◽  
Artery Disease

SummaryγA/γ’ fibrinogen is a fibrinogen isoform that constitutes about 15% of total plasma fibrinogen. This isoform contains an additional binding site for zymogen factor XIII and for active thrombin, and forms fibrin clots that are resistant to fibrinolysis in vitro. Little is known about the variability of γA/γ’ fibrinogen levels in human populations, whereas total fibrinogen levels are known to increase with age and are higher in women than in men. In this report, evidence is presented that, in contrast to total fibrinogen levels, γA/γ’ fibrinogen levels showed no significant association with age or gender in a population of normal blood donors. A study of γA/γ’ fibrinogen levels in patients undergoing coronary angiography also showed that γA/γ’ fibrinogen levels were higher on average in coronary artery disease patients than in patients without coronary artery disease, and that this association was independent of total fibrinogen levels.

Polymorphisms in human apolipoprotein(a) kringle IV-10 and coronary artery disease: relationship to allele size, plasma lipoprotein(a) concentration, and lysine binding site activity

2001 ◽  
Vol 79 (5-6) ◽  
pp. 294-299 ◽  
Author(s):  
Josep M. Simó ◽  
Jorge Joven ◽  
Elisabet Vilella ◽  
Montserrat Ribas ◽  
Lídia Figuera ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Binding Site ◽  
Plasma Lipoprotein ◽  
Allele Size ◽  
Lipoprotein A ◽  
Human Apolipoprotein ◽  
Apolipoprotein A ◽  
Artery Disease

scholarly journals The apolipoprotein B3304–3317 peptide as an inhibitor of the lipoprotein (a):apolipoprotein B-containing lipoprotein interaction

1995 ◽  
Vol 307 (1) ◽  
pp. 17-22 ◽  
Author(s):  
V N Trieu ◽  
U Olsson ◽  
W J McConathy
Keyword(s):  
Coronary Artery Disease ◽  
Risk Factor ◽  
Coronary Artery ◽  
Binding Site ◽  
Apolipoprotein B ◽  
Proline Residue ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Artery Disease ◽  
Competitive Nature

Lipoprotein (a) [Lp(a)] is a risk factor for coronary artery disease. It is characterized by apolipoprotein (a) [apo(a)] disulphide linked to apolipoprotein B (apoB), by Cys4057 of apo(a) and possibly Cys3734 of apoB. We call this the covalent apo(a):apoB-Lp interaction, to distinguish it from the non-covalent Lp(a):apoB-Lp interaction, mediated by the proline-binding kringle-4-like domain(s) of Lp(a). The Lp(a):apoB-Lp interaction was inhibited by an apoB peptide spanning residues 3304-3317. This peptide was found by a computerized search for sites on apoB similar to the plasminogen's kringle-4-binding site of alpha 2-antiplasmin. It probably constitutes part of the Lp(a)-binding site on apoB because: (1) it corresponds to the alpha 2-antiplasmin minimum binding domain for plasminogen's kringle-4; (2) the competitive nature of inhibition [KI = (1.5 +/- 0.7) x 10(-4) M, n = 5] suggested that it and apoB-Lp bound to Lp(a) by the same mechanism at the same site; and (3) it specifically bound Lp(a) and not apoB-Lp, and the bound Lp(a) was dissociated by inhibitors of the Lp(a):apoB-Lp interaction, 6-aminohexanoic acid and L-proline. Inhibition was independent of its proline residue, suggesting that proline in the context of a peptide is not a ligand for the kringle(s) which mediated the binding of Lp(a) to apoB-Lp.

scholarly journals Common and Rare Variant Association Study for Plasma Lipids and Coronary Artery Disease

2016 ◽  
Vol 23 (3) ◽  
pp. 241-256 ◽  
Author(s):  
Hayato Tada ◽  
Masa-aki Kawashiri ◽  
Tetsuo Konno ◽  
Masakazu Yamagishi ◽  
Kenshi Hayashi
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Study ◽  
Rare Variant ◽  
Plasma Lipids ◽  
Rare Variant Association ◽  
Artery Disease

scholarly journals A Polymorphism in Thrombospondin-1 Associated with Familial Premature Coronary Artery Disease Alters Ca2+ Binding

2004 ◽  
Vol 279 (50) ◽  
pp. 51915-51922 ◽  
Author(s):  
Blue-leaf A. Hannah ◽  
Tina M. Misenheimer ◽  
Michelle M. Pranghofer ◽  
Deane F. Mosher
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Binding Site ◽  
Equilibrium Dialysis ◽  
Consensus Sequence ◽  
Binding Motif ◽  
Premature Coronary Artery Disease ◽  
Binding Motifs ◽  
Thrombospondin 1 ◽  
Artery Disease

A single nucleotide polymorphism that results in substitution at residue 700 of a serine (Ser-700) for an asparagine (Asn-700) in thrombospondin-1 is associated with familial premature coronary artery disease. The polymorphism is located in the first of 13 Ca2+-binding motifs, within a consensus sequence in which Asn-700 likely coordinates Ca2+. Equilibrium dialysis of constructs comprised of the adjoining epidermal growth factor-like module and the Ca2+-binding region (E3Ca) demonstrated that E3Ca Ser-700 binds significantly less Ca2+than E3Ca Asn-700 at low [Ca2+]. The hypothesis that this difference is due to loss of a binding site in Ser-700 protein was tested with truncations of E3Ca containing four (Tr4), three (Tr3), two (Tr2), or one (Tr1) N-terminal Ca2+-binding motifs. The Ser-700 truncation constructs bound 1 fewer Ca2+than matching Asn-700 constructs and exhibited decreased binding affinities. Intrinsic fluorescence of a tryptophan at residue 698 (Trp-698) in the most N-terminal motif was cooperatively quenched by the addition of Ca2+to Asn-700 Tr2, Tr3, and Tr4 constructs. In Ser-700 constructs, quenching of Trp-698 was incomplete in the Tr2 and Tr3 constructs and complete only in the Tr4 construct. Ca2+-induced quenching of Ser-700 constructs required higher [Ca2+] and was slower as shown in stopped-flow experiments than quenching of Asn-700 constructs. Such differences were not found with Tb3+, which quenched the fluorescence of Asn-700 and Ser-700 constructs equivalently. Thus, the Ser-700 polymorphism alters a rapidly filled, high affinity Ca2+-binding site in the first Ca2+-binding motif. Slower Ca2+binding to adjoining motifs partly compensates for the change.

A 3′ Untranslated Region Polymorphism of CTNNB1 (Rs2953) Alters MiR-3161 Binding and Affects the Risk of Ischemic Stroke and Coronary Artery Disease in Chinese Han Population

2021 ◽  
pp. 1-11
Author(s):  
Xin-Yi Zhao ◽  
Shu-Yan Hu ◽  
Jia-Lei Yang ◽  
Xing-Mei Chen ◽  
Xian-Li Huang ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Ischemic Stroke ◽  
Coronary Artery ◽  
Mrna Expression ◽  
Binding Site ◽  
Untranslated Region ◽  
Luciferase Activity ◽  
Expression Level ◽  
Mrna Expression Level ◽  
Artery Disease

<b><i>Background:</i></b> <i>CTNNB1</i> is reported to be related to the pathological process of ischemic stroke (IS) and coronary artery disease (CAD). Polymorphism located in the 3′ untranslated region (3′UTR) of a gene might affect gene expression by modifying binding sites for microRNAs (miRNAs). This study aimed to analyze the association between polymorphism rs2953, which locates in the 3′UTR of <i>CTNNB1,</i> and the risk of IS and CAD. <b><i>Methods:</i></b> The <i>CTNNB1</i> messenger RNA (mRNA) expression level in peripheral venous blood was measured. In total, 533 patients with IS, 500 patients with CAD, and 531 healthy individuals were genotyped by Sequenom Mass­Array technology. The binding of miR-3161 to <i>CTNNB1</i> was determined by dual-luciferase reporter assay. <b><i>Results:</i></b> The <i>CTNNB1</i> mRNA expression level for the IS group was significantly lower than that for the control group. Rs2953 was significantly associated with both IS risk and CAD risk. Significant association was also found between polymorphism rs2953 and many conventional factors, such as serum lipid level, blood coagulation markers, blood glucose level, and homocysteine level in patients. Rs2953 T allele introduced a binding site to miRNA-3161 and thus decreased luciferase activity. <b><i>Conclusion:</i></b> Polymorphism rs2953 is associated with the risk of both IS and CAD. Moreover, polymorphism rs2953 (T) introduces a binding site to miRNA-3161 and thus decreases luciferase activity in cell lines.

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

2019 ◽  
Vol 133 (22) ◽  
pp. 2283-2299
Author(s):  
Apabrita Ayan Das ◽  
Devasmita Chakravarty ◽  
Debmalya Bhunia ◽  
Surajit Ghosh ◽  
Prakash C. Mandal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chronic Inflammation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Critical Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tnf Α ◽  
Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

The clinical basis for the management of coronary artery disease

2002 ◽  
Vol 32 (3) ◽  
pp. 110-113
Author(s):  
M. Jelinek
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Artery Disease
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