The transcription factor GATA-2 does not associate with angiographic coronary artery disease in the Ottawa Heart Genomics and Cleveland Clinic GeneBank Studies

Dandona, Sonny; Chen, Li; Fan, Meng; Alam, Mohammad Afaque; Assogba, Olivia; Belanger, Melanie; Williams, Kathryn; Wells, George A.; Tang, W.H. Wilson; Ellis, Stephen G.; Hazen, Stanley L.; McPherson, Ruth; Roberts, Robert; Stewart, Alexandre F.R.

doi:10.1007/s00439-009-0761-3

Cited by 13 publications

(12 citation statements)

References 20 publications

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“…We observed that rs3803 was a CAD-protective factor. rs2713604 was not significantly correlated with CAD, consistent with observations by Dandona et al (2010) indicating that rs2713604 does not contribute to the development of CAD.…”

Section: Discussionsupporting

confidence: 86%

Gene polymorphisms associated with susceptibility to coronary artery disease in Han Chinese people

et al. 2014

Genet. Mol. Res.

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ABSTRACT. This study investigated 5 single nucleotide polymorphism (SNP) haplotypes in susceptibility genes for coronary artery disease (CAD) and the putative involvement of these SNPs in CAD in the Chinese Han population. From March 2008 to June 2009, we selected 119 CAD patients and 115 subjects not related to the CAD of Chinese Han origin as controls. The SNP genotypes were performed by multiplex SNaPshot technology. The HNRPUL1 gene rs11881940T and GATA2 gene rs3803T loci were highly correlated with CAD (P < 0.05). rs10757278G increased the risk of CAD in patients indicated by an odds ratio (OR) = 1.242 [95% confidence interval (CI) = 1.04-1.49]; rs11881940T and rs3803T were protective factors for CAD with ORs = 0.767 (95%CI = 0.61-0.97) and 0.53 (95%CI = 0.40-0.72), respectively. Analysis of the rs10757278, rs11881940 and rs3803 loci showed that haplotypes ATC (OR = 4.26; 95%CI = 2.85-6.40, P < 0.01), GAC (OR = 1.50; 95%CI = 1.25-1.81, P < 0.01) and GAT (OR = 1.53; 95%CI = 1.12-2.09, P < 0.01) were CAD risk factors, whereas GTC was protective (OR = 0.48; 95%CI = 0.32-0.72, P < 0.01). ATC and glucose were positively correlated (OR = 1.91; 95%CI = 1.01-3.61, P < 0.05). GAT was a risk factor for hypertension (OR = 2.86; 95%CI = 1.40-5.83, P < 0.01). In conclusion, polymorphisms and haplotype analysis of susceptibility genes for CAD can improve predicting this disease and will enable early diagnosis of CAD.

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Section: Discussionsupporting

confidence: 86%

Gene polymorphisms associated with susceptibility to coronary artery disease in Han Chinese people

et al. 2014

Genet. Mol. Res.

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“…The webappendix (pp 2–4, 8, and 9) shows additional studies, including case-control subsets from the Wellcome Trust Case-Control Consortium (WTCCC) Study, 3,4 the Ottawa Heart Genomics Study (OHGS), 2,9 the Atherosclerotic Disease Vascular Function and Genetic Epidemiology study (ADVANCE), 10 the Cadomics study, 6,11 the Emory Genebank study, 1 the Intermountain Heart Collaborative Study (IHCS), 12 the Verona Heart Study (VHS), 5,13 the Cleveland Clinic GeneBank Study, 9 the Myocardial Infarction Genetics Consortium (MI-GEN), 5 and the German myocardial infarction Family Studies. 6 …”

Section: Methodsmentioning

confidence: 99%

Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies

et al. 2011

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Summary Background We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. Methods We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12 393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). Findings In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10−13). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10−9). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. Interpretation Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. Funding The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

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“…We exploited a BsrI restriction site that is interrupted by the 9-nucleotide deletion to genotype a random sample of 1066 angiographically documented CAD cases and 1011 controls from the Ottawa Heart Genomics Study. 15 Homozygous carriers of this deletion variant had a higher incidence of CAD, odds ratio (95% confidence interval) =1.560 (1.179-2.065), P=1.73E-03 in a recessive model ( Figure 7B). By comparison, the 9p21.3 locus (tagged by rs1333049) was associated with CAD risk with an odds ratio 1.45 (1.28-1.64), P=3.00E-09.…”

Section: Deletion Polymorphism (Rs3045215) In the 3′utr Of Irf2bp2 Inmentioning

confidence: 95%

“…Details of the phenotypic characteristics and inclusion and exclusion criteria are in Methods in the Online Data Supplement and as described previously. 15 …”

Section: Study Participantsmentioning

confidence: 99%

IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis

Chen

Keyhanian

Zhou

et al. 2015

Circulation Research

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Rationale: Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2–binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans. Objectives: To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans. Methods and Results: We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3′ untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179–2.065], P =1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies. Conclusion: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.

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The transcription factor GATA-2 does not associate with angiographic coronary artery disease in the Ottawa Heart Genomics and Cleveland Clinic GeneBank Studies

Cited by 13 publications

References 20 publications

Gene polymorphisms associated with susceptibility to coronary artery disease in Han Chinese people

Gene polymorphisms associated with susceptibility to coronary artery disease in Han Chinese people

Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies

IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis

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