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  1. Article ; Online: Coronary heart disease and ischemic stroke polygenic risk scores and atherosclerotic cardiovascular disease in a diverse, population-based cohort study.

    Bebo, Allison / Jarmul, Jamie A / Pletcher, Mark J / Hasbani, Natalie R / Couper, David / Nambi, Vijay / Ballantyne, Christie M / Fornage, Myriam / Morrison, Alanna C / Avery, Christy L / de Vries, Paul S

    PloS one

    2023  Volume 18, Issue 6, Page(s) e0285259

    Abstract: The predictive ability of coronary heart disease (CHD) and ischemic stroke (IS) polygenic risk scores (PRS) have been evaluated individually, but whether they predict the combined outcome of atherosclerotic cardiovascular disease (ASCVD) remains ... ...

    Abstract The predictive ability of coronary heart disease (CHD) and ischemic stroke (IS) polygenic risk scores (PRS) have been evaluated individually, but whether they predict the combined outcome of atherosclerotic cardiovascular disease (ASCVD) remains insufficiently researched. It is also unclear whether associations of the CHD and IS PRS with ASCVD are independent of subclinical atherosclerosis measures. 7,286 White and 2,016 Black participants from the population-based Atherosclerosis Risk in Communities study who were free of cardiovascular disease and type 2 diabetes at baseline were included. We computed previously validated CHD and IS PRS consisting of 1,745,179 and 3,225,583 genetic variants, respectively. Cox proportional hazards models were used to test the association between each PRS and ASCVD, adjusting for traditional risk factors, ankle-brachial index, carotid intima media thickness, and carotid plaque. The hazard ratios (HR) for the CHD and IS PRS were significant with HR of 1.50 (95% CI: 1.36-1.66) and 1.31 (95% CI: 1.18-1.45) respectively for the risk of incident ASCVD per standard deviation increase in CHD and IS PRS among White participants after adjusting for traditional risk factors. The HR for the CHD PRS was not significant with an HR of 0.95 (95% CI: 0.79-1.13) for the risk of incident ASCVD in Black participants. The HR for the IS PRS was significant with an HR of 1.26 (95%CI: 1.05-1.51) for the risk of incident ASCVD in Black participants. The association of the CHD and IS PRS with ASCVD was not attenuated in White participants after adjustment for ankle-brachial index, carotid intima media thickness, and carotid plaque. The CHD and IS PRS do not cross-predict well, and predict better the outcome for which they were created than the composite ASCVD outcome. Thus, the use of the composite outcome of ASCVD may not be ideal for genetic risk prediction.
    MeSH term(s) Humans ; Cardiovascular Diseases/genetics ; Ischemic Stroke ; Cohort Studies ; Diabetes Mellitus, Type 2 ; Carotid Intima-Media Thickness ; Coronary Disease/epidemiology ; Coronary Disease/genetics ; Atherosclerosis/complications ; Atherosclerosis/genetics ; Risk Factors ; Plaque, Atherosclerotic ; Risk Assessment
    Language English
    Publishing date 2023-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0285259
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: American Heart Association's Life's Simple 7: Lifestyle Recommendations, Polygenic Risk, and Lifetime Risk of Coronary Heart Disease.

    Hasbani, Natalie R / Ligthart, Symen / Brown, Michael R / Heath, Adam S / Bebo, Allison / Ashley, Kellan E / Boerwinkle, Eric / Morrison, Alanna C / Folsom, Aaron R / Aguilar, David / de Vries, Paul S

    Circulation

    2022  Volume 145, Issue 11, Page(s) 808–818

    Abstract: Background: Understanding the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease (CHD) is important to improving public health initiatives. Our objective was to quantify remaining lifetime risk and years free of CHD ... ...

    Abstract Background: Understanding the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease (CHD) is important to improving public health initiatives. Our objective was to quantify remaining lifetime risk and years free of CHD according to polygenic risk and the American Heart Association's Life's Simple 7 (LS7) guidelines in a population-based cohort study.
    Methods: Our analysis included data from participants of the ARIC (Atherosclerosis Risk in Communities) study: 8372 White and 2314 Black participants; 45 years of age and older; and free of CHD at baseline examination. A polygenic risk score (PRS) comprised more than 6 million genetic variants was categorized into low (<20th percentile), intermediate, and high (>80th percentile). An overall LS7 score was calculated at baseline and categorized into "poor," "intermediate," and "ideal" cardiovascular health. Lifetime risk and CHD-free years were computed according to polygenic risk and LS7 categories.
    Results: The overall remaining lifetime risk was 27%, ranging from 16.6% in individuals with an ideal LS7 score to 43.1% for individuals with a poor LS7 score. The association of PRS with lifetime risk differed according to ancestry. In White participants, remaining lifetime risk ranged from 19.8% to 39.3% according to increasing PRS categories. Individuals with a high PRS and poor LS7 had a remaining lifetime risk of 67.1% and 15.9 fewer CHD-free years than did those with intermediate polygenic risk and LS7 scores. In the high-PRS group, ideal LS7 was associated with 20.2 more CHD-free years compared with poor LS7. In Black participants, remaining lifetime risk ranged from 19.1% to 28.6% according to increasing PRS category. Similar lifetime risk estimates were observed for individuals of poor LS7 regardless of PRS category. In the high-PRS group, an ideal LS7 score was associated with only 4.5 more CHD-free years compared with a poor LS7 score.
    Conclusions: Ideal adherence to LS7 recommendations was associated with lower lifetime risk of CHD for all individuals, especially in those with high genetic susceptibility. In Black participants, adherence to LS7 guidelines contributed to lifetime risk of CHD more so than current PRSs. Improved PRSs are needed to properly evaluate genetic susceptibility for CHD in diverse populations.
    MeSH term(s) American Heart Association ; Cardiovascular Diseases/diagnosis ; Cohort Studies ; Coronary Disease/diagnosis ; Coronary Disease/epidemiology ; Coronary Disease/genetics ; Genetic Predisposition to Disease ; Humans ; Life Style ; Risk Factors ; United States/epidemiology
    Language English
    Publishing date 2022-01-31
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80099-5
    ISSN 1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
    ISSN (online) 1524-4539
    ISSN 0009-7322 ; 0069-4193 ; 0065-8499
    DOI 10.1161/CIRCULATIONAHA.121.053730
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

    Ji, Yuekai / Temprano-Sagrera, Gerard / Holle, Lori A / Bebo, Allison / Brody, Jennifer A / Le, Ngoc-Quynh / Kangro, Kadri / Brown, Michael R / Martinez-Perez, Angel / Sitlani, Colleen M / Suchon, Pierre / Kleber, Marcus E / Emmert, David B / Bilge Ozel, Ayse / Dobson, Dre'Von A / Tang, Weihong / Llobet, Dolors / Tracy, Russell P / Deleuze, Jean-François /
    Delgado, Graciela E / Gögele, Martin / Wiggins, Kerri L / Souto, Juan Carlos / Pankow, James S / Taylor, Kent D / Trégouët, David-Alexandre / Moissl, Angela P / Fuchsberger, Christian / Rosendaal, Frits R / Morrison, Alanna C / Soria, Jose Manuel / Cushman, Mary / Morange, Pierre-Emmanuel / März, Winfried / Hicks, Andrew A / Desch, Karl C / Johnson, Andrew D / de Vries, Paul S / Wolberg, Alisa S / Smith, Nicholas L / Sabater-Lleal, Maria

    Arteriosclerosis, thrombosis, and vascular biology

    2023  Volume 43, Issue 7, Page(s) e254–e269

    Abstract: Background: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving ... ...

    Abstract Background: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total.
    Methods: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes.
    Results: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (
    Conclusions: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
    MeSH term(s) Protein C/genetics ; Protein S/genetics ; Genome-Wide Association Study ; Antithrombins ; Transcriptome ; Anticoagulants ; Antithrombin III/genetics ; Polymorphism, Single Nucleotide
    Chemical Substances Protein C ; Protein S ; Antithrombins ; Anticoagulants ; Antithrombin III (9000-94-6)
    Language English
    Publishing date 2023-04-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1221433-4
    ISSN 1524-4636 ; 1079-5642
    ISSN (online) 1524-4636
    ISSN 1079-5642
    DOI 10.1161/ATVBAHA.122.318213
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

    de Vries, Paul S / Reventun, Paula / Brown, Michael R / Heath, Adam S / Huffman, Jennifer E / Le, Ngoc-Quynh / Bebo, Allison / Brody, Jennifer A / Temprano-Sagrera, Gerard / Raffield, Laura M / Ozel, Ayse Bilge / Thibord, Florian / Jain, Deepti / Lewis, Joshua P / Rodriguez, Benjamin A T / Pankratz, Nathan / Taylor, Kent D / Polasek, Ozren / Chen, Ming-Huei /
    Yanek, Lisa R / Carrasquilla, German D / Marioni, Riccardo E / Kleber, Marcus E / Trégouët, David-Alexandre / Yao, Jie / Li-Gao, Ruifang / Joshi, Peter K / Trompet, Stella / Martinez-Perez, Angel / Ghanbari, Mohsen / Howard, Tom E / Reiner, Alex P / Arvanitis, Marios / Ryan, Kathleen A / Bartz, Traci M / Rudan, Igor / Faraday, Nauder / Linneberg, Allan / Ekunwe, Lynette / Davies, Gail / Delgado, Graciela E / Suchon, Pierre / Guo, Xiuqing / Rosendaal, Frits R / Klaric, Lucija / Noordam, Raymond / van Rooij, Frank / Curran, Joanne E / Wheeler, Marsha M / Osburn, William O / O'Connell, Jeffrey R / Boerwinkle, Eric / Beswick, Andrew / Psaty, Bruce M / Kolcic, Ivana / Souto, Juan Carlos / Becker, Lewis C / Hansen, Torben / Doyle, Margaret F / Harris, Sarah E / Moissl, Angela P / Deleuze, Jean-François / Rich, Stephen S / van Hylckama Vlieg, Astrid / Campbell, Harry / Stott, David J / Soria, Jose Manuel / de Maat, Moniek P M / Almasy, Laura / Brody, Lawrence C / Auer, Paul L / Mitchell, Braxton D / Ben-Shlomo, Yoav / Fornage, Myriam / Hayward, Caroline / Mathias, Rasika A / Kilpeläinen, Tuomas O / Lange, Leslie A / Cox, Simon R / März, Winfried / Morange, Pierre-Emmanuel / Rotter, Jerome I / Mook-Kanamori, Dennis O / Wilson, James F / van der Harst, Pim / Jukema, J Wouter / Ikram, M Arfan / Blangero, John / Kooperberg, Charles / Desch, Karl C / Johnson, Andrew D / Sabater-Lleal, Maria / Lowenstein, Charles J / Smith, Nicholas L / Morrison, Alanna C

    Blood

    2024  Volume 143, Issue 18, Page(s) 1845–1855

    Abstract: Abstract: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program ... ...

    Abstract Abstract: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
    MeSH term(s) Humans ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism ; Factor VIII/genetics ; Factor VIII/metabolism ; Polymorphism, Single Nucleotide ; Human Umbilical Vein Endothelial Cells/metabolism ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Thrombosis/genetics ; Thrombosis/blood ; Genetic Association Studies ; Male ; Endothelial Cells/metabolism ; Female ; Kininogens ; Receptors, Cell Surface ; Cell Adhesion Molecules ; Lectins, C-Type
    Chemical Substances von Willebrand Factor ; Factor VIII (9001-27-8) ; F8 protein, human (839MOZ74GK) ; CLEC4M protein, human ; KNG1 protein, human ; Kininogens ; Receptors, Cell Surface ; Cell Adhesion Molecules ; Lectins, C-Type
    Language English
    Publishing date 2024-02-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2023021452
    Database MEDical Literature Analysis and Retrieval System OnLINE

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