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  • Online Resource  (6)
  • Ovid Technologies (Wolters Kluwer Health)  (6)
  • Uitterlinden, Andre G.  (6)
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  • Online Resource  (6)
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  • Ovid Technologies (Wolters Kluwer Health)  (6)
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  • 1
    Online Resource
    Online Resource
    Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of the American Heart Association Vol. 6, No. 6 ( 2017-11-06)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 6 ( 2017-11-06)
    Abstract: Plasminogen activator inhibitor type 1 ( PAI ‐1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI ‐1 levels are associated with increased risk of coronary heart disease ( CHD ). However, it is unclear whether the association reflects a causal influence of PAI ‐1 on CHD risk. Methods and Results To evaluate the association between PAI ‐1 and CHD , we applied a 3‐step strategy. First, we investigated the observational association between PAI ‐1 and CHD incidence using a systematic review based on a literature search for PAI ‐1 and CHD studies. Second, we explored the causal association between PAI ‐1 and CHD using a Mendelian randomization approach using summary statistics from large genome‐wide association studies. Finally, we explored the causal effect of PAI ‐1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta‐analysis, the highest quantile of blood PAI ‐1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age‐ and sex‐adjusted model. The effect size was reduced in studies using a multivariable‐adjusted model (odds ratio=1.46; 95% CI : 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI ‐1 level on CHD risk (odds ratio=1.22 per unit increase of log‐transformed PAI ‐1; 95% CI : 1.01, 1.47). In addition, we also detected a causal effect of PAI ‐1 on elevating blood glucose and high‐density lipoprotein cholesterol. Conclusions Our study indicates a causal effect of elevated PAI ‐1 level on CHD risk, which may be mediated by glucose dysfunction.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.116.004918
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2653953-6
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  • 2
    Online Resource
    Online Resource
    Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Vol. 123, No. 17 ( 2011-05-03), p. 1864-1872
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 123, No. 17 ( 2011-05-03), p. 1864-1872
    Abstract: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search. Methods and Results— A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 ( P =6.4×10 −52 ) was 46.0 kb upstream from F3 , coagulation factor III (tissue factor). At 1q24, rs6687813 ( P =2.4×10 −14 ) was 79.7 kb downstream of F5 , coagulation factor V. At 4q32, rs13109457 ( P =2.9×10 −18 ) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA . Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus. Conclusions— Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.110.009480
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1466401-X
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  • 3
    Online Resource
    Online Resource
    Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Journal of the American Society of Nephrology Vol. 24, No. 12 ( 2013-12), p. 2105-2117
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 24, No. 12 ( 2013-12), p. 2105-2117
    Type of Medium: Online Resource
    ISSN: 1046-6673
    URL: Article
    DOI: 10.1681/ASN.2012100983
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 2029124-3
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  • 4
    Online Resource
    Online Resource
    Multiethnic Meta-Analysis of Genome-Wide Association Studies in 〉100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Circulation Vol. 128, No. 12 ( 2013-09-17), p. 1310-1324
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 128, No. 12 ( 2013-09-17), p. 1310-1324
    Abstract: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion ( 〈 2%) of its variation. Methods and Results— We conducted a meta-analysis of 28 genome-wide association studies including 〉 90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant ( P 〈 5×10 −8 ) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions— We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.113.002251
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1466401-X
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  • 5
    Online Resource
    Online Resource
    Meta-Analysis of Genome-Wide Association Studies in 〉80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Vol. 123, No. 7 ( 2011-02-22), p. 731-738
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 123, No. 7 ( 2011-02-22), p. 731-738
    Abstract: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results— We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome ( APOC1 , HNF1A , LEPR , GCKR , HNF4A , and PTPN2 ) or the immune system ( CRP , IL6R , NLRP3 , IL1F10 , and IRF1 ) or that reside in regions previously not known to play a role in chronic inflammation ( PPP1R3B , SALL1 , PABPC4 , ASCL1 , RORA , and BCL7B ). We found a significant interaction of body mass index with LEPR ( P 〈 2.9×10 −6 ). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusions— We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.110.948570
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1466401-X
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  • 6
    Online Resource
    Online Resource
    Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. 5 ( 2014-05), p. 1093-1101
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 5 ( 2014-05), p. 1093-1101
    Abstract: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA. Approach and Results— Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels ( P 〈 5.0×10 −8 ). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P =2.9×10 −14 ) within STXBP5 . The second locus is on 8p11.21. The lead SNP (rs3136739; P =1.3×10 −9 ) is intronic to POLB and 〈 200 kb away from the tPA encoding the gene PLAT . We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 ( r 2 =0.50) within exon 5 of PLAT ( P =2.0×10 −8 ). The third locus is on 12q24.33, with the lead SNP (rs7301826; P =1.0×10 −9 ) within intron 7 of STX2 . We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke. Conclusions— We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5 , and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.113.302088
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1494427-3
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