A genetic basis for coronary artery disease

Roberts, Robert

doi:10.1016/j.tcm.2014.10.008

Cited by 37 publications

(25 citation statements)

References 68 publications

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“…GWAS also revealed another significant CAD risk variant, SNP rs17465637 in an intron of the MIA3/TANGO1 gene encoding ARNT or TANGO1[9]. We replicated the finding in an American Gene Bank Caucasian population [10] and a Chinese GeneID population [11].…”

Section: Introductionsupporting

confidence: 65%

“…We performed a global gene expression analysis using microarrays with knockdown of ADTRP expression in HepG2 cells using siRNA [16] and found that one of the candidate downstream genes of ADTRP is MIA3/TANGO1 , a CAD susceptibility gene identified by GWAS [9, 11]. Using an independent set of HepG2 cells transfected with ADTRP siRNA and negative control siRNA (NC siRNA), we confirmed that siRNA knockdown of ADTRP expression by 80% reduced the expression level of MIA3/TANGO1 by 75% ( P <0.0001; Fig.…”

Section: Resultsmentioning

confidence: 99%

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Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease

Luo

Wang

Ren

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Coronary artery disease (CAD) is the leading cause of death worldwide. GWAS have identified >50 genomic loci for CAD, including ADTRP and MIA3/TANGO1. However, it is important to determine whether the GWAS genes form a molecular network. In this study, we have uncovered a novel molecular network between ADTRP and MIA3/TANGO1 for the pathogenesis of CAD. We showed that knockdown of ADTRP expression markedly down-regulated expression of MIA3/TANGO1. Mechanistically, ADTRP positively regulates expression of PIK3R3 encoding the regulatory subunit 3 of PI3K, which leads to activation of AKT, resulting in up-regulation of MIA3/TANGO1. Both ADTRP and MIA3/TANGO1 are involved in endothelial cell (EC) functions relevant to atherosclerosis. Knockdown of ADTRP expression by siRNA promoted oxidized-LDL-mediated monocyte adhesion to ECs and transendothelial migration of monocytes, inhibited EC proliferation and migration, and increased apoptosis, which was reversed by expression of constitutively active AKT1 and MIA3/TANGO1 overexpression, while the over-expression of ADTRP in ECs blunted these processes. Knockdown of MIA3/TANGO1 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes, and vice versa for overexpression of MIA3/TANGO1. We found that ADTRP negatively regulates the levels of collagen VII and ApoB in HepG2 and endothelial cells, which are downstream regulatory targets of MIA3/TANGOI. In conclusion, we have uncovered a novel molecular signaling pathway for the pathogenesis of CAD, which involves a novel gene-gene regulatory network. We show that ADTRP positively regulates PIK3R3 expression, which leads to activation of AKT and up-regulation of MIA3/TANGO1, thereby regulating endothelial cell functions directly relevant to atherosclerosis.

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Section: Introductionsupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease

Luo

Wang

Ren

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In recent decades, the studies have been directed at introducing statins as drugs lowering the serum LDL-C level. Moreover, a new approach following in clinical trials is suggested to target the circulating PCSK9 in order to diminish the LDLR internalization and serum LDL-C level (13, 14). In this study, we investigated the correlations between LDL-C and sdLDL-C values and some lipid parameters.…”

Section: Discussionmentioning

confidence: 99%

Serum sdLDL-C and Cellular SREBP2-Dependent Cholesterol Levels; Is there a Challenge on Targeting PCSK9?

Soltanmohammadi

Piran

Mohammadi

et al. 2016

Journal of Medical Biochemistry

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SummaryBackgroundSerum small dense LDL-cholesterol (sdLDL-C) value is suggested to bean important risk factor for atherosclerosis. Since sdLDL-C changes may be related to PCSK9 and SREBP-2 functions, the aim of this study was to investigate correlations between sdLDL-C, circulating PCSK9, SREBP-2 expression and some lipid parameters in serum and butty coat fraction of healthy subjects.MethodsOne hundred and twenty-four subjects were randomly included in the study. The lipid profile was measured using routine laboratory methods. The serum sdLDL-C level was calculated by a heparin-related precipitation technique. The cellular LDL-C/protein and cholesterol/protein values were measured after lysing of cells with methanol/chloroform binary solvent. The circulating PCSK9 level was measured using ELISA technique. The SREBP-2 expression level was estimated using theRT-qPCR technique.ResultsData showed significant correlations between LDL-C, TG and sdLDL-C levels (r=0.34, p=0.001; r=0.2, p=0.04). The circulating PCSK9 level was correlated to LDL-C (r=0.29, p=0.04), but not to sdLDL-C (r=-0.08, p=0.57). Also, cellular LDL-C value was not related to serum LDL-C level (r=-0.12, p=0.39). Furthermore, there was an inverse correlation between cellular LDL-C/protein value and estimated de novo cholesterol/protein value (r= -0.5, p=0.001). Similar results were observed for cellular LDL-C/protein value and SREBP-2 expression level (r= -0.52, p=0.004).ConclusionsWe concluded that the serum sdLDL-C value is not related to circulating PCSK9. Furthermore, SREBP-2 regulatory system was able to elevate the cellular cholesterol level after reducing LDL influx. We suggest to investigate the cellular sdLDL fate and lipid synthesis pathways in PCSK9-targeting studies.

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“…A study exceeding 23,000 subjects showed a significant genetic variant located on the short arm of chromosome (9p21) [38,39]. This was validated by various other studies, and it was shown that there is 25 and 50 % CAD risk increase in heterozygous and homozygous carriers, respectively [38]. 9p21 was shown to be an individual risk factor for coronary artery disease independent of other factors [38,39].…”

Section: Genetics Of Intermediate Phenotypes For Sudden Cardiac Deathmentioning

confidence: 67%

Genetics of Sudden Cardiac Death

2015

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Sudden cardiac death (SCD) is defined by the World Health Organization (WHO) as death within 1 h of symptom onset (witnessed) or within 24 h of being observed alive and symptom free (unwitnessed). It affects more than 3 million people annually worldwide and affects approximately 1/1000 people each year in the USA. Familial studies of syndromes with Mendelian inheritance, candidate genes analyses, and genome-wide association studies (GWAS) have helped our understanding of the genetics of SCD. We will review the genetics of arrhythmogenic hereditary syndromes with Mendelian inheritance from familial studies with structural heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) as well as primary electrical causes (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome). In addition, we will review the genetics of intermediate phenotypes for SCD such as coronary artery disease and electrocardiographic variables (QT interval, QRS duration, and RR interval). Finally, we will review rare and common variants that are associated with SCD in the general population and were identified from candidate gene analyses and GWAS. Our understanding of the genetics of SCD will improve by the use of next-generation sequencing/whole-exome sequencing as well as whole-genome sequencing which have the potential to discover unsuspected common and rare genetic variants that might be associated with SCD.

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A genetic basis for coronary artery disease

Cited by 37 publications

References 68 publications

Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease

Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease

Serum sdLDL-C and Cellular SREBP2-Dependent Cholesterol Levels; Is there a Challenge on Targeting PCSK9?

Genetics of Sudden Cardiac Death

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