74 results on '"Trégouët, David-Alexandre"'
Search Results
2. High risk of long-term recurrence after a first episode of venous thromboembolism during pregnancy or postpartum: the REcurrence after a PrEgnAncy related Thrombosis (REPEAT) Study
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Ibrahim-Kosta, Manal, El Harake, Sarah, Leclercq, Barbara, De Mari, Céline, Secondi, Jean-François, Paoletti, Emilie, Suchon, Pierre, Benredouane, Yasmine, Brunet, Dominique, Barthet, Marie-Christine, Bruzelius, Maria, Munsch, Gaëlle, Trégouët, David-Alexandre, Morange, Pierre-Emmanuel, Goumidi, Louisa, and Sarlon-Bartoli, Gabrielle
- Abstract
The long-term recurrence risk after a pregnancy-associated venous thromboembolism (VTE) is sparsely assessed.
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- 2025
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3. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles
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Huffman, Jennifer E., Nicholas, Jayna, Hahn, Julie, Heath, Adam S., Raffield, Laura M., Yanek, Lisa R., Brody, Jennifer A., Thibord, Florian, Almasy, Laura, Bartz, Traci M., Bielak, Lawrence F., Bowler, Russell P., Carrasquilla, Germán D., Chasman, Daniel I., Chen, Ming-Huei, Emmert, David B., Ghanbari, Mohsen, Haessler, Jeffrey, Hottenga, Jouke-Jan, Kleber, Marcus E., Le, Ngoc-Quynh, Lee, Jiwon, Lewis, Joshua P., Li-Gao, Ruifang, Luan, Jian'an, Malmberg, Anni, Mangino, Massimo, Marioni, Riccardo E., Martinez-Perez, Angel, Pankratz, Nathan, Polasek, Ozren, Richmond, Anne, Rodriguez, Benjamin A. T., Rotter, Jerome I., Steri, Maristella, Suchon, Pierre, Trompet, Stella, Weiss, Stefan, Zare, Marjan, Auer, Paul, Cho, Michael H., Christofidou, Paraskevi, Davies, Gail, de Geus, Eco, Deleuze, Jean-François, Delgado, Graciela E., Ekunwe, Lynette, Faraday, Nauder, Gögele, Martin, Greinacher, Andreas, Gao, He, Howard, Tom, Joshi, Peter K., Kilpeläinen, Tuomas O., Lahti, Jari, Linneberg, Allan, Naitza, Silvia, Noordam, Raymond, Paüls-Vergés, Ferran, Rich, Stephen S., Rosendaal, Frits R., Rudan, Igor, Ryan, Kathleen A., Souto, Juan Carlos, van Rooij, Frank J. A., Wang, Heming, Zhao, Wei, Becker, Lewis C., Beswick, Andrew, Brown, Michael R., Cade, Brian E., Campbell, Harry, Cho, Kelly, Crapo, James D., Curran, Joanne E., de Maat, Moniek P. M., Doyle, Margaret, Elliott, Paul, Floyd, James S., Fuchsberger, Christian, Grarup, Niels, Guo, Xiuqing, Harris, Sarah E., Hou, Lifang, Kolcic, Ivana, Kooperberg, Charles, Menni, Cristina, Nauck, Matthias, O'Connell, Jeffrey R., Orrù, Valeria, Psaty, Bruce M., Räikkönen, Katri, Smith, Jennifer A., Soria, Jose Manuel, Stott, David J., van Hylckama Vlieg, Astrid, Watkins, Hugh, Willemsen, Gonneke, Wilson, Peter W. F., Ben-Shlomo, Yoav, Blangero, John, Boomsma, Dorret, Cox, Simon R., Dehghan, Abbas, Eriksson, Johan G., Fiorillo, Edoardo, Fornage, Myriam, Hansen, Torben, Hayward, Caroline, Ikram, M. Arfan, Jukema, J. Wouter, Kardia, Sharon L. R., Lange, Leslie A., März, Winfried, Mathias, Rasika A., Mitchell, Braxton D., Mook-Kanamori, Dennis O., Morange, Pierre-Emmanuel, Pedersen, Oluf, Pramstaller, Peter P., Redline, Susan, Reiner, Alexander, Ridker, Paul M., Silverman, Edwin K., Spector, Tim D., Völker, Uwe, Wareham, Nicholas J., Wilson, James F., Yao, Jie, Trégouët, David-Alexandre, Johnson, Andrew D., Wolberg, Alisa S., de Vries, Paul S., Sabater-Lleal, Maria, Morrison, Alanna C., and Smith, Nicholas L.
- Abstract
•Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 distinct variants (20 novel).•Links to (1) liver enzyme, blood cell, and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
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- 2024
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4. Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension
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Hong, Jason, Medzikovic, Lejla, Sun, Wasila, Wong, Brenda, Ruffenach, Grégoire, Rhodes, Christopher J., Brownstein, Adam, Liang, Lloyd L., Aryan, Laila, Li, Min, Vadgama, Arjun, Kurt, Zeyneb, Schwantes-An, Tae-Hwi, Mickler, Elizabeth A., Gräf, Stefan, Eyries, Mélanie, Lutz, Katie A., Pauciulo, Michael W., Trembath, Richard C., Perros, Frédéric, Montani, David, Morrell, Nicholas W., Soubrier, Florent, Wilkins, Martin R., Nichols, William C., Aldred, Micheala A., Desai, Ankit A., Trégouët, David-Alexandre, Umar, Soban, Saggar, Rajan, Channick, Richard, Tuder, Rubin M., Geraci, Mark W., Stearman, Robert S., Yang, Xia, and Eghbali, Mansoureh
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- 2024
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5. Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline.
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Neuffer, Jeanne, Wagner, Maude, Moreno, Elisa, Le Grand, Quentin, Mishra, Aniket, Trégouët, David‐Alexandre, Leffondre, Karen, Proust‐Lima, Cécile, Foubert‐Samier, Alexandra, Berr, Claudine, Tzourio, Christophe, Helmer, Catherine, Debette, Stéphanie, and Samieri, Cécilia
- Abstract
INTRODUCTION: Evaluating whether genetic susceptibility modifies the impact of lifestyle‐related factors on dementia is critical for prevention. METHODS: We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS]). RESULTS: The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non‐carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline. DISCUSSION: Lifestyle‐based prevention may be effective whatever the genetic susceptibility to dementia. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism
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Ward, Joey, Le, Ngoc-Quynh, Suryakant, Suryakant, Brody, Jennifer A., Amouyel, Philippe, Boland, Anne, Bown, Rosemary, Cullen, Breda, Debette, Stéphanie, Deleuze, Jean-François, Emmerich, Joseph, Graham, Nicholas, Germain, Marine, Anderson, Jana J., Pell, Jill P., Lyall, Donald M., Lyall, Laura M., Smith, Daniel J., Wiggins, Kerri L., Soria, José Manuel, Souto, Juan Carlos, Morange, Pierre-Emmanuel, Smith, Nicholas L., Trégouët, David-Alexandre, Sabater-Lleal, Maria, and Strawbridge, Rona J.
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•Genetic regulation of MDD and VTE was correlated.•Genetic predisposition to MDD was associated with an increased risk of VTE.
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- 2023
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7. Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels
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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., and Sabater-Lleal, Maria
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- 2023
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8. Histo-blood group ABO system transferase plasma levels and risk of future venous thromboembolism – The HUNT Study
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Onsaker, Asbjørn L., Arntzen, Anna Y., Trégouët, David-Alexandre, Nøst, Therese H., Tang, Weighing, Guan, Weihua, Jonasson, Christian, Morange, Pierre-Emmanuel, Hinderg, Kristian D., Folsom, Aaron R., Hveem, Kristian, Morelli, Vânia M., and Hansen, John-Bjarne
- Abstract
•Elevated plasma levels of histo-blood group ABO system transferase are associated with increased risk of future venous thromboembolism.•The association is only partly explained by plasma levels of von Willebrand factor or coagulation factor VIII.
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- 2025
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9. Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction
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Masurkar, Nihar, Bouvet, Marion, Logeart, Damien, Jouve, Charlène, Dramé, Fatou, Claude, Olivier, Roux, Maguelonne, Delacroix, Clément, Bergerot, Damien, Mercadier, Jean-Jacques, Sirol, Marc, Gellen, Barnabas, Livrozet, Marine, Fayol, Antoine, Robidel, Estelle, Trégouët, David-Alexandre, Marazzi, Giovanna, Sassoon, David, Valente, Mariana, and Hulot, Jean-Sébastien
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- 2023
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10. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease
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Duperron, Marie-Gabrielle, Knol, Maria J., Le Grand, Quentin, Evans, Tavia E., Mishra, Aniket, Tsuchida, Ami, Roshchupkin, Gennady, Konuma, Takahiro, Trégouët, David-Alexandre, Romero, Jose Rafael, Frenzel, Stefan, Luciano, Michelle, Hofer, Edith, Bourgey, Mathieu, Dueker, Nicole D., Delgado, Pilar, Hilal, Saima, Tankard, Rick M., Dubost, Florian, Shin, Jean, Saba, Yasaman, Armstrong, Nicola J., Bordes, Constance, Bastin, Mark E., Beiser, Alexa, Brodaty, Henry, Bülow, Robin, Carrera, Caty, Chen, Christopher, Cheng, Ching-Yu, Deary, Ian J., Gampawar, Piyush G., Himali, Jayandra J., Jiang, Jiyang, Kawaguchi, Takahisa, Li, Shuo, Macalli, Melissa, Marquis, Pascale, Morris, Zoe, Muñoz Maniega, Susana, Miyamoto, Susumu, Okawa, Masakazu, Paradise, Matthew, Parva, Pedram, Rundek, Tatjana, Sargurupremraj, Muralidharan, Schilling, Sabrina, Setoh, Kazuya, Soukarieh, Omar, Tabara, Yasuharu, Teumer, Alexander, Thalamuthu, Anbupalam, Trollor, Julian N., Valdés Hernández, Maria C., Vernooij, Meike W., Völker, Uwe, Wittfeld, Katharina, Wong, Tien Yin, Wright, Margaret J., Zhang, Junyi, Zhao, Wanting, Zhu, Yi-Cheng, Schmidt, Helena, Sachdev, Perminder S., Wen, Wei, Yoshida, Kazumichi, Joutel, Anne, Satizabal, Claudia L., Sacco, Ralph L., Bourque, Guillaume, Lathrop, Mark, Paus, Tomas, Fernandez-Cadenas, Israel, Yang, Qiong, Mazoyer, Bernard, Boutinaud, Philippe, Okada, Yukinori, Grabe, Hans J., Mather, Karen A., Schmidt, Reinhold, Joliot, Marc, Ikram, M. Arfan, Matsuda, Fumihiko, Tzourio, Christophe, Wardlaw, Joanna M., Seshadri, Sudha, Adams, Hieab H. H., and Debette, Stéphanie
- Abstract
Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N= 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N= 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.
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- 2023
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11. Stroke genetics informs drug discovery and risk prediction across ancestries
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Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie
- Abstract
Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P< 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2Aand FURIN) and variants (such as at GRK5and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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- 2022
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12. Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors
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Thibord, Florian, Klarin, Derek, Brody, Jennifer A., Chen, Ming-Huei, Levin, Michael G., Chasman, Daniel I., Goode, Ellen L., Hveem, Kristian, Teder-Laving, Maris, Martinez-Perez, Angel, Aïssi, Dylan, Daian-Bacq, Delphine, Ito, Kaoru, Natarajan, Pradeep, Lutsey, Pamela L., Nadkarni, Girish N., de Vries, Paul S., Cuellar-Partida, Gabriel, Wolford, Brooke N., Pattee, Jack W., Kooperberg, Charles, Braekkan, Sigrid K., Li-Gao, Ruifang, Saut, Noemie, Sept, Corriene, Germain, Marine, Judy, Renae L., Wiggins, Kerri L., Ko, Darae, O’Donnell, Christopher J., Taylor, Kent D., Giulianini, Franco, De Andrade, Mariza, Nøst, Therese H., Boland, Anne, Empana, Jean-Philippe, Koyama, Satoshi, Gilliland, Thomas, Do, Ron, Huffman, Jennifer E., Wang, Xin, Zhou, Wei, Manuel Soria, Jose, Carlos Souto, Juan, Pankratz, Nathan, Haessler, Jeffery, Hindberg, Kristian, Rosendaal, Frits R., Turman, Constance, Olaso, Robert, Kember, Rachel L., Bartz, Traci M., Lynch, Julie A., Heckbert, Susan R., Armasu, Sebastian M., Brumpton, Ben, Smadja, David M., Jouven, Xavier, Komuro, Issei, Clapham, Katharine R., Loos, Ruth J.F., Willer, Cristen J., Sabater-Lleal, Maria, Pankow, James S., Reiner, Alexander P., Morelli, Vania M., Ridker, Paul M, Vlieg, Astrid van Hylckama, Deleuze, Jean-François, Kraft, Peter, Rader, Daniel J., Min Lee, Kyung, Psaty, Bruce M., Heidi Skogholt, Anne, Emmerich, Joseph, Suchon, Pierre, Rich, Stephen S., Vy, Ha My T., Tang, Weihong, Jackson, Rebecca D., Hansen, John-Bjarne, Morange, Pierre-Emmanuel, Kabrhel, Christopher, Trégouët, David-Alexandre, Damrauer, Scott M., Johnson, Andrew D., and Smith, Nicholas L.
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- 2022
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13. Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke
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Jaworek, Thomas, Xu, Huichun, Gaynor, Brady J., Cole, John W., Rannikmae, Kristiina, Stanne, Tara M., Tomppo, Liisa, Abedi, Vida, Amouyel, Philippe, Armstrong, Nicole D., Attia, John, Bell, Steven, Benavente, Oscar R., Boncoraglio, Giorgio B., Butterworth, Adam, Carcel-Marquez, Jara, Chen, Zhengming, Chong, Michael, Cruchaga, Carlos, Cushman, Mary, Danesh, John, Debette, Stéphanie, Duggan, David J., Durda, Jon Peter, Engstrom, Gunnar, Enzinger, Chris, Faul, Jessica D., Fecteau, Natalie S., Fernandez-Cadenas, Israel, Gieger, Christian, Giese, Anne-Katrin, Grewal, Raji P., Grittner, Ulrike, Havulinna, Aki S., Heitsch, Laura, Hochberg, Marc C., Holliday, Elizabeth, Hu, Jie, Ilinca, Andreea, Irvin, Marguerite R., Jackson, Rebecca D., Jacob, Mina A., Rabionet, Raquel, Jimenez-Conde, Jordi, Johnson, Julie A., Kamatani, Yoichiro, Kardia, Sharon L.R., Koido, Masaru, Kubo, Michiaki, Lange, Leslie, Lee, Jin-Moo, Lemmens, Robin, Levi, Christopher R., Li, Jiang, Li, Liming, Lin, Kuang, Lopez, Haley, Luke, Sothear, Maguire, Jane, McArdle, Patrick F., McDonough, Caitrin W., Meschia, James F., Metso, Tiina, Müller-Nurasyid, Martina, O'Connor, Timothy D., O'Donnell, Martin, Peddareddygari, Leema R., Pera, Joanna, Perry, James A., Peters, Annette, Putaala, Jukka, Ray, Debashree, Rexrode, Kathryn, Ribases, Marta, Rosand, Jonathan, Rothwell, Peter M., Rundek, Tatjana, Ryan, Kathleen A., Sacco, Ralph L., Salomaa, Veikko, Sanchez-Mora, Cristina, Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Smith, Jennifer A., Smith, Nicholas L., Wassertheil-Smoller, Sylvia, Söderholm, Martin, Stine, O. Colin, Strbian, Daniel, Sudlow, Cathie L.M., Tatlisumak, Turgut, Terao, Chikashi, Thijs, Vincent, Torres-Aguila, Nuria P., Trégouët, David-Alexandre, Tuladhar, Anil M., Veldink, Jan H., Walters, Robin G., Weir, David R., Woo, Daniel, Worrall, Bradford B., Hong, Charles C., Ross, Owen A., Zand, Ramin, Leeuw, Frank-Erik de, Lindgren, Arne G., Pare, Guillaume, Anderson, Christopher D., Markus, Hugh S., Jern, Christina, Malik, Rainer, Dichgans, Martin, Mitchell, Braxton D., and Kittner, Steven J.
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- 2022
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14. Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays
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de la Morena-Barrio, Maria Eugenia, Suchon, Pierre, Jacobsen, Eva Marie, Iversen, Nina, Miñano, Antonia, de la Morena-Barrio, Belén, Bravo-Pérez, Carlos, Padilla, Jose, Cifuentes, Rosa, Asenjo, Susana, Deleuze, Jean François, Trégouët, David Alexandre, Lozano, Maria Luisa, Vicente, Vicente, Sandset, Per Morten, Morange, Pierre Emmanuel, and Corral, Javier
- Abstract
Antithrombin deficiency, the most severe congenital thrombophilia, might be underestimated, as some pathogenic variants are not detected by routine functional methods. We have identified 2 new SERPINC1 variants, p.Glu227Lys and p.Asn224His, in 4 unrelated thrombophilic patients with early and recurrent thrombosis that had normal antithrombin activity. In one case, the mutation was identified by whole genome sequencing, while in the 3 remaining cases, the mutation was identified by sequencing SERPINC1 based on a single functional positive finding supporting deficiency. The 2 variants shared a common functional defect, an impaired or null N-glycosylation of Asn224 according to a eukaryotic expression model. Carriers had normal anti-FXa or anti-FIIa activities but impaired anti-FVIIa activity and a detectable loss of inhibitory function when incubating the plasma for 1 hour at 41°C. Moreover, the β glycoform of the variants, lacking 2 N-glycans, had reduced secretion, increased heparin affinity, no inhibitory activity, and a potential dominant–negative effect. These results explain the increased thrombin generation observed in carriers. Mutation experiments reflected the role that Lysine residues close to the N-glycosylation sequon have in impairing the efficacy of N-glycosylation. Our study shows new elements involved in the regulation of N-glycosylation, a key posttranslational modification that, according to our results, affects folding, secretion, and function, providing new evidence of the pathogenic consequence of an incorrect N-glycosylation of antithrombin. This study supports that antithrombin deficiency is underestimated and encourages the development of new functional and genetic tests to diagnose this severe thrombophilia.
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- 2022
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15. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations
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Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Sabater‐Lleal, Maria, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming‐Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John‐Bjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Smith, Nicholas L, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin
- Abstract
Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.
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- 2022
- Full Text
- View/download PDF
16. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations
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Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Sabater‐Lleal, Maria, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Chen, Ming‐Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Pankratz, Nathan, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John‐Bjarne, Rosendaal, Frits R, Heit, John A, Psaty, Bruce M, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Smith, Nicholas L, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Trompet, Stella, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Wiggins, Kerri L, Yang, Qiong, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin
- Abstract
Multi‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Summary statistics from genome wide‐association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI‐1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi‐trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9obtained after applying Bonferroni correction for the number of multi‐trait combinations performed (n= 27). Across the 27 multi‐trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
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- 2022
- Full Text
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17. GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis
- Author
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Megy, Karyn, Downes, Kate, Morel‐Kopp, Marie‐Christine, Bastida, José M., Brooks, Shannon, Bury, Loredana, Leinoe, Eva, Gomez, Keith, Morgan, Neil V., Othman, Maha, Ouwehand, Willem H., Perez Botero, Juliana, Rivera, José, Schulze, Harald, Trégouët, David‐Alexandre, and Freson, Kathleen
- Abstract
The implementation of high‐throughput sequencing (HTS) technologies in research and diagnostic laboratories has linked many new genes to rare bleeding, thrombotic, and platelet disorders (BTPD), and revealed multiple genetic variants linked to those disorders, many of them being of uncertain pathogenicity when considering the accepted evidence (variant consequence, frequency in control datasets, number of reported patients, prediction models, and functional assays). The sequencing effort has also resulted in resources for gathering disease‐causing variants associated with specific genes, but for BTPD, such well‐curated databases exist only for a few genes. On the other hand, submissions by individuals or diagnostic laboratories to the variant database ClinVar are hampered by the lack of a submission process tailored to capture the specific features of hemostatic diseases. As we move toward the implementation of HTS in the diagnosis of BTPD, the Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis has developed and tested a REDCap‐based interface, aimed at the community, to submit curated genetic variants for diagnostic‐grade BTPD genes. Here, we describe the use of the interface and the initial submission of 821 variants from 30 different centers covering 14 countries. This open‐access variant resource will be shared with the community to improve variant classification and regular bulk data transfer to ClinVar.
- Published
- 2021
- Full Text
- View/download PDF
18. GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis
- Author
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Megy, Karyn, Downes, Kate, Morel‐Kopp, Marie‐Christine, Bastida, José M., Brooks, Shannon, Bury, Loredana, Leinoe, Eva, Gomez, Keith, Morgan, Neil V., Othman, Maha, Ouwehand, Willem H., Perez Botero, Juliana, Rivera, José, Schulze, Harald, Trégouët, David‐Alexandre, and Freson, Kathleen
- Abstract
The implementation of high‐throughput sequencing (HTS) technologies in research and diagnostic laboratories has linked many new genes to rare bleeding, thrombotic, and platelet disorders (BTPD), and revealed multiple genetic variants linked to those disorders, many of them being of uncertain pathogenicity when considering the accepted evidence (variant consequence, frequency in control datasets, number of reported patients, prediction models, and functional assays). The sequencing effort has also resulted in resources for gathering disease‐causing variants associated with specific genes, but for BTPD, such well‐curated databases exist only for a few genes. On the other hand, submissions by individuals or diagnostic laboratories to the variant database ClinVar are hampered by the lack of a submission process tailored to capture the specific features of hemostatic diseases. As we move toward the implementation of HTS in the diagnosis of BTPD, the Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis has developed and tested a REDCap‐based interface, aimed at the community, to submit curated genetic variants for diagnostic‐grade BTPD genes. Here, we describe the use of the interface and the initial submission of 821 variants from 30 different centers covering 14 countries. This open‐access variant resource will be shared with the community to improve variant classification and regular bulk data transfer to ClinVar.
- Published
- 2021
- Full Text
- View/download PDF
19. Whole blood levels of S1PR4 mRNA associated with cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
- Author
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Pulcrano-Nicolas, Anne-Sophie, Jacquens, Alice, Proust, Carole, Clarençon, Frédéric, Perret, Claire, Shotar, Eimad, Puybasset, Louis, Le Goff, Wilfried, Degos, Vincent, Trégouët, David-Alexandre, and Garnier, Sophie
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- 2020
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20. Whole-Blood miRNA Sequencing Profiling for Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage.
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Pulcrano-Nicolas, Anne-Sophie, Proust, Carole, Clarençon, Frédéric, Jacquens, Alice, Perret, Claire, Roux, Maguelonne, Shotar, Eimad, Thibord, Florian, Puybasset, Louis, Garnier, Sophie, Degos, Vincent, Trégouët, David-Alexandre, Clarençon, Frédéric, and Trégouët, David-Alexandre
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- 2018
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21. Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation
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Min, Josine L., Hemani, Gibran, Hannon, Eilis, Dekkers, Koen F., Castillo-Fernandez, Juan, Luijk, René, Carnero-Montoro, Elena, Lawson, Daniel J., Burrows, Kimberley, Suderman, Matthew, Bretherick, Andrew D., Richardson, Tom G., Klughammer, Johanna, Iotchkova, Valentina, Sharp, Gemma, Al Khleifat, Ahmad, Shatunov, Aleksey, Iacoangeli, Alfredo, McArdle, Wendy L., Ho, Karen M., Kumar, Ashish, Söderhäll, Cilla, Soriano-Tárraga, Carolina, Giralt-Steinhauer, Eva, Kazmi, Nabila, Mason, Dan, McRae, Allan F., Corcoran, David L., Sugden, Karen, Kasela, Silva, Cardona, Alexia, Day, Felix R., Cugliari, Giovanni, Viberti, Clara, Guarrera, Simonetta, Lerro, Michael, Gupta, Richa, Bollepalli, Sailalitha, Mandaviya, Pooja, Zeng, Yanni, Clarke, Toni-Kim, Walker, Rosie M., Schmoll, Vanessa, Czamara, Darina, Ruiz-Arenas, Carlos, Rezwan, Faisal I., Marioni, Riccardo E., Lin, Tian, Awaloff, Yvonne, Germain, Marine, Aïssi, Dylan, Zwamborn, Ramona, van Eijk, Kristel, Dekker, Annelot, van Dongen, Jenny, Hottenga, Jouke-Jan, Willemsen, Gonneke, Xu, Cheng-Jian, Barturen, Guillermo, Català-Moll, Francesc, Kerick, Martin, Wang, Carol, Melton, Phillip, Elliott, Hannah R., Shin, Jean, Bernard, Manon, Yet, Idil, Smart, Melissa, Gorrie-Stone, Tyler, Shaw, Chris, Al Chalabi, Ammar, Ring, Susan M., Pershagen, Göran, Melén, Erik, Jiménez-Conde, Jordi, Roquer, Jaume, Lawlor, Deborah A., Wright, John, Martin, Nicholas G., Montgomery, Grant W., Moffitt, Terrie E., Poulton, Richie, Esko, Tõnu, Milani, Lili, Metspalu, Andres, Perry, John R. B., Ong, Ken K., Wareham, Nicholas J., Matullo, Giuseppe, Sacerdote, Carlotta, Panico, Salvatore, Caspi, Avshalom, Arseneault, Louise, Gagnon, France, Ollikainen, Miina, Kaprio, Jaakko, Felix, Janine F., Rivadeneira, Fernando, Tiemeier, Henning, van IJzendoorn, Marinus H., Uitterlinden, André G., Jaddoe, Vincent W. V., Haley, Chris, McIntosh, Andrew M., Evans, Kathryn L., Murray, Alison, Räikkönen, Katri, Lahti, Jari, Nohr, Ellen A., Sørensen, Thorkild I. A., Hansen, Torben, Morgen, Camilla S., Binder, Elisabeth B., Lucae, Susanne, Gonzalez, Juan Ramon, Bustamante, Mariona, Sunyer, Jordi, Holloway, John W., Karmaus, Wilfried, Zhang, Hongmei, Deary, Ian J., Wray, Naomi R., Starr, John M., Beekman, Marian, van Heemst, Diana, Slagboom, P. Eline, Morange, Pierre-Emmanuel, Trégouët, David-Alexandre, Veldink, Jan H., Davies, Gareth E., de Geus, Eco J. C., Boomsma, Dorret I., Vonk, Judith M., Brunekreef, Bert, Koppelman, Gerard H., Alarcón-Riquelme, Marta E., Huang, Rae-Chi, Pennell, Craig E., van Meurs, Joyce, Ikram, M. Arfan, Hughes, Alun D., Tillin, Therese, Chaturvedi, Nish, Pausova, Zdenka, Paus, Tomas, Spector, Timothy D., Kumari, Meena, Schalkwyk, Leonard C., Visscher, Peter M., Davey Smith, George, Bock, Christoph, Gaunt, Tom R., Bell, Jordana T., Heijmans, Bastiaan T., Mill, Jonathan, and Relton, Caroline L.
- Abstract
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.
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- 2021
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22. FGL1 as a modulator of plasma D‐dimer levels: Exome‐wide marker analysis of plasma tPA, PAI‐1, and D‐dimer
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Thibord, Florian, Song, Ci, Pattee, Jack, Rodriguez, Benjamin A.T., Chen, Ming‐Huei, O’Donnell, Christopher J., Kleber, Marcus E., Delgado, Graciela E., Guo, Xiuqing, Yao, Jie, Taylor, Kent D., Ozel, Ayse Bilge, Brody, Jennifer A., McKnight, Barbara, Gyorgy, Beata, Simonsick, Eleanor, Leonard, Hampton L., Carrasquilla, Germán D., Guindo‐Martinez, Marta, Silveira, Angela, Temprano‐Sagrera, Gerard, Yanek, Lisa R., Becker, Diane M., Mathias, Rasika A., Becker, Lewis C., Raffield, Laura M., Kilpeläinen, Tuomas O., Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Hamsten, Anders, Watkins, Hugh, Sabater‐Lleal, Maria, Nalls, Mike A., Trégouët, David‐Alexandre, Morange, Pierre‐Emmanuel, Psaty, Bruce M., Tracy, Russel P., Smith, Nicholas L., Desch, Karl C., Cushman, Mary, Rotter, Jerome I., Vries, Paul S., Pankratz, Nathan D., Folsom, Aaron R., Morrison, Alanna C., März, Winfried, Tang, Weihong, and Johnson, Andrew D.
- Abstract
Use of targeted exome‐arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator‐inhibitor 1 (PAI‐1), tissue plasminogen activator (tPA), and the plasma product D‐dimer are important components of the fibrinolytic system. There have been few large‐scale genome‐wide or exome‐wide studies of PAI‐1, tPA, and D‐dimer. We sought to discover new genetic loci contributing to variation in these traits using an exome‐array approach. Cohort‐level analyses and fixed effects meta‐analyses of PAI‐1 (n= 15 603), tPA (n= 6876,) and D‐dimer (n= 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single‐variant analyses and gene‐based burden testing. Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D‐dimer levels, achieved genome‐wide significance (P< 5 × 10−8). Replication was sought for these 5 variants, as well as 45 well‐imputed variants with P< 1 × 10−4in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1(fibrinogen‐like‐1) with increased plasma D‐dimer levels. Additionally, a candidate‐gene approach revealed a suggestive association for a coding variant (rs143202684‐C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830‐A) in SCARB1associated with increased D‐dimer levels. This work provides new evidence for a role of FGL1in hemostasis.
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- 2021
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23. FGL1 as a modulator of plasma D‐dimer levels: Exome‐wide marker analysis of plasma tPA, PAI‐1, and D‐dimer
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Thibord, Florian, Song, Ci, Pattee, Jack, Rodriguez, Benjamin A.T., Chen, Ming‐Huei, O’Donnell, Christopher J., Kleber, Marcus E., Delgado, Graciela E., Guo, Xiuqing, Yao, Jie, Taylor, Kent D., Ozel, Ayse Bilge, Brody, Jennifer A., McKnight, Barbara, Gyorgy, Beata, Simonsick, Eleanor, Leonard, Hampton L., Carrasquilla, Germán D., Guindo‐Martinez, Marta, Silveira, Angela, Temprano‐Sagrera, Gerard, Yanek, Lisa R., Becker, Diane M., Mathias, Rasika A., Becker, Lewis C., Raffield, Laura M., Kilpeläinen, Tuomas O., Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Hamsten, Anders, Watkins, Hugh, Sabater‐Lleal, Maria, Nalls, Mike A., Trégouët, David‐Alexandre, Morange, Pierre‐Emmanuel, Psaty, Bruce M., Tracy, Russel P., Smith, Nicholas L., Desch, Karl C., Cushman, Mary, Rotter, Jerome I., de Vries, Paul S., Pankratz, Nathan D., Folsom, Aaron R., Morrison, Alanna C., März, Winfried, Tang, Weihong, and Johnson, Andrew D.
- Abstract
Use of targeted exome‐arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator‐inhibitor 1 (PAI‐1), tissue plasminogen activator (tPA), and the plasma product D‐dimer are important components of the fibrinolytic system. There have been few large‐scale genome‐wide or exome‐wide studies of PAI‐1, tPA, and D‐dimer.
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- 2021
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24. Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation
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Goumidi, Louisa, Thibord, Florian, Wiggins, Kerri L., Li-Gao, Ruifang, Brown, Mickael R., van Hylckama Vlieg, Astrid, Souto, Joan-Carles, Soria, José-Manuel, Ibrahim-Kosta, Manal, Saut, Noémie, Daian, Delphine, Olaso, Robert, Amouyel, Philippe, Debette, Stéphanie, Boland, Anne, Bailly, Pascal, Morrison, Alanna C., Mook-Kanamori, Denis O., Deleuze, Jean-François, Johnson, Andrew, de Vries, Paul S., Sabater-Lleal, Maria, Chiaroni, Jacques, Smith, Nicholas L., Rosendaal, Frits R., Chasman, Daniel I., Trégouët, David-Alexandre, and Morange, Pierre-Emmanuel
- Abstract
Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.
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- 2021
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25. Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation
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Goumidi, Louisa, Thibord, Florian, Wiggins, Kerri L., Li-Gao, Ruifang, Brown, Mickael R., van Hylckama Vlieg, Astrid, Souto, Joan-Carles, Soria, José-Manuel, Ibrahim-Kosta, Manal, Saut, Noémie, Daian, Delphine, Olaso, Robert, Amouyel, Philippe, Debette, Stéphanie, Boland, Anne, Bailly, Pascal, Morrison, Alanna C., Mook-Kanamori, Denis O., Deleuze, Jean-François, Johnson, Andrew, de Vries, Paul S., Sabater-Lleal, Maria, Chiaroni, Jacques, Smith, Nicholas L., Rosendaal, Frits R., Chasman, Daniel I., Trégouët, David-Alexandre, and Morange, Pierre-Emmanuel
- Abstract
Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABOlocus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABOlocus on VT risk to avoid any risk misestimation. Compared with the O1haplotype, the A2haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1and Bhaplotypes are associated with an ∼1.8-fold increased risk, whereas the O2haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.
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- 2021
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26. Plasma Biomarkers and Identification of Resilient Metabolic Disruptions in Patients With Venous Thromboembolism Using a Metabolic Systems Approach
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Fraser, Karl, Roy, Nicole C., Goumidi, Louisa, Verdu, Alexandre, Suchon, Pierre, Leal-Valentim, Felipe, Trégouët, David-Alexandre, Morange, Pierre-Emmanuel, and Martin, Jean-Charles
- Abstract
Supplemental Digital Content is available in the text.
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- 2020
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27. Bayesian network analysis of plasma microRNA sequencing data in patients with venous thrombosis
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Thibord, Florian, Munsch, Gaëlle, Perret, Claire, Suchon, Pierre, Roux, Maguelonne, Ibrahim-Kosta, Manal, Goumidi, Louisa, Deleuze, Jean-François, Morange, Pierre-Emmanuel, and Trégouët, David-Alexandre
- Abstract
MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P= 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P= 0.019), hsa-miR-27b-3p (P= 0.016) and hsa-miR-222-3p (P= 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P< 5 × 10−8, some of these associations pertaining to thrombosis associated mechanisms. In conclusion, this study provides novel data about the impact of miRNAs’ variability in haemostasis and new arguments supporting the association of few miRNAs with the risk of recurrence in patients with venous thrombosis.
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- 2020
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28. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
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Lindström, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rebecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Damrauer, Scott M., Natarajan, Pradeep, Klarin, Derek, de Vries, Paul S., Sabater-Lleal, Maria, Huffman, Jennifer E., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, Trégouët, David-Alexandre, and Smith, Nicholas L.
- Abstract
Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30?234 VTE cases and 172?122 controls and assessed the association between 12?923?718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
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- 2019
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29. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
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Lindström, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rebecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Damrauer, Scott M., Natarajan, Pradeep, Klarin, Derek, de Vries, Paul S., Sabater-Lleal, Maria, Huffman, Jennifer E., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, Trégouët, David-Alexandre, and Smith, Nicholas L.
- Abstract
Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
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- 2019
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30. Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease
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Klarin, Derek, Busenkell, Emma, Judy, Renae, Lynch, Julie, Levin, Michael, Haessler, Jeffery, Aragam, Krishna, Chaffin, Mark, Haas, Mary, Lindström, Sara, Assimes, Themistocles L., Huang, Jie, Min Lee, Kyung, Shao, Qing, Huffman, Jennifer E., Kabrhel, Christopher, Huang, Yunfeng, Sun, Yan V., Vujkovic, Marijana, Saleheen, Danish, Miller, Donald R., Reaven, Peter, DuVall, Scott, Boden, William E., Pyarajan, Saiju, Reiner, Alex P., Trégouët, David-Alexandre, Henke, Peter, Kooperberg, Charles, Gaziano, J. Michael, Concato, John, Rader, Daniel J., Cho, Kelly, Chang, Kyong-Mi, Wilson, Peter W. F., Smith, Nicholas L., O’Donnell, Christopher J., Tsao, Philip S., Kathiresan, Sekar, Obi, Andrea, Damrauer, Scott M., and Natarajan, Pradeep
- Abstract
Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.
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- 2019
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31. A Genome Wide Association Study on plasma FV levels identified PLXDC2as a new modifier of the coagulation process
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Thibord, Florian, Hardy, Lise, Ibrahim‐Kosta, Manal, Saut, Noémie, Pulcrano‐Nicolas, Anne‐Sophie, Goumidi, Louisa, Civelek, Mete, Eriksson, Per, Deleuze, Jean‐François, Le Goff, Wilfried, Trégouët, David‐Alexandre, and Morange, Pierre‐Emmanuel
- Abstract
Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process.
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- 2019
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32. A gain of function variant in RGS18candidate for a familial mild bleeding syndrome
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Vayne, Caroline, Roux, Maguelonne, Gruel, Yves, Poggi, Marjorie, Pouplard, Claire, Peiretti, Franck, Trégouët, David-Alexandre, Nurden, Paquita, and Alessi, Marie-Christine
- Abstract
Inherited platelet diseases are bleeding disorders characterized by either defects in platelet count or platelet function, the latter being less common and very heterogeneous. Numerous gene variants associated with abnormal receptors, granules, and signaling pathways have been reported. Despite significant advancements in our understanding, many patients still lack a precise diagnosis.
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- 2024
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33. Next-generation sequencing strategies in venous thromboembolism: in whom and for what purpose?
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Trégouët, David-Alexandre and Pierre-Emmanuel, Morange
- Abstract
This invited review follows the oral presentation “To Sequence or Not to Sequence, That Is Not the Question; But ‘When, Who, Which and What For?’ Is” given during the State of the Art session “Translational Genomics in Thrombosis: From OMICs to Clinics” of the International Society on Thrombosis and Haemostasis 2023 Congress. Emphasizing the power of next-generation sequencing technologies and the diverse strategies associated with DNA variant analysis, this review highlights the unresolved questions and challenges in their implementation both for the clinical diagnosis of venous thromboembolism and in translational research.
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- 2024
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34. Genome-Wide Investigation of Exogenous Female Hormones, Genetic Variation, and Venous Thromboembolism Risk
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Hasser, Emily K., Brody, Jennifer A., Bartz, Traci M., Thibord, Florian, Li-Gao, Ruifang, Kauko, Anni, Wiggins, Kerri L., Teder-Laving, Maris, Kim, Jihye, Munsch, Gaëlle, Haile, Helen G., Deleuze, Jean-Francois, van Hylckama Vlieg, Astrid, Wolberg, Alisa S., Boland, Anne, Morange, Pierre-Emmanuel, Kraft, Peter, Lowenstein, Charles J., Emmerich, Joseph, Sitlani, Colleen M., Suchon, Pierre, Rosendaal, Frits R., Niiranen, Teemu, Kabrhel, Christopher, Trégouët, David-Alexandre, and Smith, Nicholas L.
- Abstract
Increased risk of venous thromboembolism (VTE) is a life-threatening side effect for users of oral contraceptives (OCs) or hormone therapy (HT).
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- 2024
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35. A genetic-association study of circulating coagulation factor VIII and von Willebrand factor levels
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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, Benjmain 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., Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas 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., and Morrison, Alanna C.
- Abstract
•We identified 7 new genetic regions for factor VIII levels, 1 for von Willebrand factor levels, and 3 in a combined analysis.•Silencing B3GNT2and CD36reduced factor VIII release in vitro.Silencing B3GNT2, CD36, and PDIA3reduced von Willebrand factor release.
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- 2024
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36. Genome-Wide Association Study Identifies a Novel Genetic Risk Factor for Recurrent Venous Thrombosis.
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de Haan, Hugoline G., van Hylckama Vlieg, Astrid, Germain, Marine, Baglin, Trevor P., Deleuze, Jean-François, Trégouët, David-Alexandre, and Rosendaal, Frits R.
- Abstract
BACKGROUND: Genetic risk factors for a first venous thrombosis (VT) seem to have little effect on recurrence risk. Therefore, we aimed specifically to identify novel genetic determinants of recurrent VT. To date, genome-wide association studies are lacking. METHODS AND RESULTS: We performed a genome-wide association scan in 1279 patients from the MEGA (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) follow-up study; 832 patients who remained recurrence free during a median follow-up time of 6.1 years and 447 recurrent VT patients with a median time-to-recurrence of 2.6 years. We analyzed genotype probabilities of ≈8.6 million variants, imputed to the Genome of the Netherlands project reference panel, with a minor allele frequency ≥1% for an association with recurrent VT. One region exceeded genome-wide significance (P≤5×10
−8 ), mapping to the well-known factor V Leiden locus. Conditional association analyses on factor V Leiden did not yield any secondary association signals. We also identified 52 suggestive association signals (P<1×10−5 ) at 17 additional loci. None of these loci were previously implicated in VT risk. Replication analyses for 17 lead variants were performed in 350 patients with recurrent VT and 1866 patients with a single VT event from the MEGA follow-up study, THE-VTE (Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism) study, and LETS (Leiden Thrombophilia Study). We observed an association with recurrence for an intergenic variant at 18q22.1 with an odds ratio of 1.7 (95% confidence interval, 1.2–2.6) per copy of the minor allele. CONCLUSIONS: We confirmed the association of factor V Leiden and identified a novel risk locus at 18q22.1 in the first large genetic study on recurrent VT. [ABSTRACT FROM AUTHOR]- Published
- 2018
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37. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
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Rhodes, Christopher J, Batai, Ken, Bleda, Marta, Haimel, Matthias, Southgate, Laura, Germain, Marine, Pauciulo, Michael W, Hadinnapola, Charaka, Aman, Jurjan, Girerd, Barbara, Arora, Amit, Knight, Jo, Hanscombe, Ken B, Karnes, Jason H, Kaakinen, Marika, Gall, Henning, Ulrich, Anna, Harbaum, Lars, Cebola, Inês, Ferrer, Jorge, Lutz, Katie, Swietlik, Emilia M, Ahmad, Ferhaan, Amouyel, Philippe, Archer, Stephen L, Argula, Rahul, Austin, Eric D, Badesch, David, Bakshi, Sahil, Barnett, Christopher, Benza, Raymond, Bhatt, Nitin, Bogaard, Harm J, Burger, Charles D, Chakinala, Murali, Church, Colin, Coghlan, John G, Condliffe, Robin, Corris, Paul A, Danesino, Cesare, Debette, Stéphanie, Elliott, C Gregory, Elwing, Jean, Eyries, Melanie, Fortin, Terry, Franke, Andre, Frantz, Robert P, Frost, Adaani, Garcia, Joe G N, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, J Simon R, Harley, John, He, Hua, Hill, Nicholas S, Hirsch, Russel, Houweling, Arjan C, Howard, Luke S, Ivy, Dunbar, Kiely, David G, Klinger, James, Kovacs, Gabor, Lahm, Tim, Laudes, Matthias, Machado, Rajiv D, MacKenzie Ross, Robert V, Marsolo, Keith, Martin, Lisa J, Moledina, Shahin, Montani, David, Nathan, Steven D, Newnham, Michael, Olschewski, Andrea, Olschewski, Horst, Oudiz, Ronald J, Ouwehand, Willem H, Peacock, Andrew J, Pepke-Zaba, Joanna, Rehman, Zia, Robbins, Ivan, Roden, Dan M, Rosenzweig, Erika B, Saydain, Ghulam, Scelsi, Laura, Schilz, Robert, Seeger, Werner, Shaffer, Christian M, Simms, Robert W, Simon, Marc, Sitbon, Olivier, Suntharalingam, Jay, Tang, Haiyang, Tchourbanov, Alexander Y, Thenappan, Thenappan, Torres, Fernando, Toshner, Mark R, Treacy, Carmen M, Vonk Noordegraaf, Anton, Waisfisz, Quinten, Walsworth, Anna K, Walter, Robert E, Wharton, John, White, R James, Wilt, Jeffrey, Wort, Stephen J, Yung, Delphine, Lawrie, Allan, Humbert, Marc, Soubrier, Florent, Trégouët, David-Alexandre, Prokopenko, Inga, Kittles, Richard, Gräf, Stefan, Nichols, William C, Trembath, Richard C, Desai, Ankit A, Morrell, Nicholas W, and Wilkins, Martin R
- Abstract
Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
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- 2019
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38. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis
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Ward-Caviness, Cavin K., Huffman, Jennifer E., Everett, Karl, Germain, Marine, van Dongen, Jenny, Hill, W. David, Jhun, Min A., Brody, Jennifer A., Ghanbari, Mohsen, Du, Lei, Roetker, Nicholas S., de Vries, Paul S., Waldenberger, Melanie, Gieger, Christian, Wolf, Petra, Prokisch, Holger, Koenig, Wolfgang, O’Donnell, Christopher J., Levy, Daniel, Liu, Chunyu, Truong, Vinh, Wells, Philip S., Trégouët, David-Alexandre, Tang, Weihong, Morrison, Alanna C., Boerwinkle, Eric, Wiggins, Kerri L., McKnight, Barbara, Guo, Xiuqing, Psaty, Bruce M., Sotoodehnia, Nona, Boomsma, Dorret I., Willemsen, Gonneke, Ligthart, Lannie, Deary, Ian J., Zhao, Wei, Ware, Erin B., Kardia, Sharon L. R., Van Meurs, Joyce B. J., Uitterlinden, Andre G., Franco, Oscar H., Eriksson, Per, Franco-Cereceda, Anders, Pankow, James S., Johnson, Andrew D., Gagnon, France, Morange, Pierre-Emmanuel, de Geus, Eco J. C., Starr, John M., Smith, Jennifer A., Dehghan, Abbas, Björck, Hanna M., Smith, Nicholas L., and Peters, Annette
- Abstract
Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10−5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
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- 2018
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39. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis
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Ward-Caviness, Cavin K., Huffman, Jennifer E., Everett, Karl, Germain, Marine, van Dongen, Jenny, Hill, W. David, Jhun, Min A., Brody, Jennifer A., Ghanbari, Mohsen, Du, Lei, Roetker, Nicholas S., de Vries, Paul S., Waldenberger, Melanie, Gieger, Christian, Wolf, Petra, Prokisch, Holger, Koenig, Wolfgang, O'Donnell, Christopher J., Levy, Daniel, Liu, Chunyu, Truong, Vinh, Wells, Philip S., Trégouët, David-Alexandre, Tang, Weihong, Morrison, Alanna C., Boerwinkle, Eric, Wiggins, Kerri L., McKnight, Barbara, Guo, Xiuqing, Psaty, Bruce M., Sotoodenia, Nona, Boomsma, Dorret I., Willemsen, Gonneke, Ligthart, Lannie, Deary, Ian J., Zhao, Wei, Ware, Erin B., Kardia, Sharon L.R., Van Meurs, Joyce B.J., Uitterlinden, Andre G., Franco, Oscar H., Eriksson, Per, Franco-Cereceda, Anders, Pankow, James S., Johnson, Andrew D., Gagnon, France, Morange, Pierre-Emmanuel, de Geus, Eco J.C., Starr, John M., Smith, Jennifer A., Dehghan, Abbas, Björck, Hanna M., Smith, Nicholas L., and Peters, Annette
- Abstract
Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry–specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P= .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P= 6.6 ×10−5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGGin both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.
- Published
- 2018
- Full Text
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40. Association of Oral Contraceptives With Drug-Induced QT Interval Prolongation in Healthy Nonmenopausal Women
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Salem, Joe-Elie, Dureau, Pauline, Bachelot, Anne, Germain, Marine, Voiriot, Pascal, Lebourgeois, Bruno, Trégouët, David-Alexandre, Hulot, Jean-Sébastien, and Funck-Brentano, Christian
- Abstract
IMPORTANCE: Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. OBJECTIVE: To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018. MAIN OUTCOMES AND MEASURES: Electrocardiographic changes 3 hours after sotalol administration. RESULTS: A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P = .005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P = .005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n = 13 of 61 [21.0%]) than those taking levonorgestrel (n = 20 of 137 [14.6%]) or women taking no OCs (n = 24 of 207 [11.6%]; P = .01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P = .01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P < .001). CONCLUSIONS AND RELEVANCE: Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.
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- 2018
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41. Whole-Blood miRNA Sequencing Profiling for Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage
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Pulcrano-Nicolas, Anne-Sophie, Proust, Carole, Clarençon, Frédéric, Jacquens, Alice, Perret, Claire, Roux, Maguelonne, Shotar, Eimad, Thibord, Florian, Puybasset, Louis, Garnier, Sophie, Degos, Vincent, and Trégouët, David-Alexandre
- Abstract
Supplemental Digital Content is available in the text.
- Published
- 2018
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42. Corrigendum to GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis[J Thromb Haemost. 2021 Oct;19(10):2612-2617]
- Author
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Megy, Karyn, Downes, Kate, Morel-Kopp, Marie-Christine, Bastida, José M., Brooks, Shannon, Bury, Loredana, Leinoe, Eva, Gomez, Keith, Morgan, Neil V., Othman, Maha, Ouwehand, Willem H., Botero, Juliana Perez, Rivera, José, Schulze, Harald, Trégouët, David-Alexandre, and Freson, Kathleen
- Published
- 2023
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43. PDGFB, a new candidate plasma biomarker for venous thromboembolism: results from the VEREMA affinity proteomics study
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Bruzelius, Maria, Iglesias, Maria Jesus, Hong, Mun-Gwan, Sanchez-Rivera, Laura, Gyorgy, Beata, Souto, Juan Carlos, Frånberg, Mattias, Fredolini, Claudia, Strawbridge, Rona J., Holmström, Margareta, Hamsten, Anders, Uhlén, Mathias, Silveira, Angela, Soria, Jose Manuel, Smadja, David M., Butler, Lynn M., Schwenk, Jochen M., Morange, Pierre-Emmanuel, Trégouët, David-Alexandre, and Odeberg, Jacob
- Abstract
There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish “Venous Thromboembolism Biomarker Study,” using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor β (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (ρ ∼ 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P = .002). PDGFΒ was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.
- Published
- 2016
- Full Text
- View/download PDF
44. PDGFB, a new candidate plasma biomarker for venous thromboembolism: results from the VEREMA affinity proteomics study
- Author
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Bruzelius, Maria, Iglesias, Maria Jesus, Hong, Mun-Gwan, Sanchez-Rivera, Laura, Gyorgy, Beata, Souto, Juan Carlos, Frånberg, Mattias, Fredolini, Claudia, Strawbridge, Rona J., Holmström, Margareta, Hamsten, Anders, Uhlén, Mathias, Silveira, Angela, Soria, Jose Manuel, Smadja, David M., Butler, Lynn M., Schwenk, Jochen M., Morange, Pierre-Emmanuel, Trégouët, David-Alexandre, and Odeberg, Jacob
- Abstract
There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish “Venous Thromboembolism Biomarker Study,” using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor β (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (ρ ∼ 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P< .001; PDGFB P= .002). PDGFΒ was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.
- Published
- 2016
- Full Text
- View/download PDF
45. Comparison of Cox Model Methods in a Low-Dimensional Setting with Few Events
- Author
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Ojeda, Francisco M., Müller, Christian, Börnigen, Daniela, Trégouët, David-Alexandre, Schillert, Arne, Heinig, Matthias, Zeller, Tanja, and Schnabel, Renate B.
- Abstract
Prognostic models based on survival data frequently make use of the Cox proportional hazards model. Developing reliable Cox models with few events relative to the number of predictors can be challenging, even in low-dimensional datasets, with a much larger number of observations than variables. In such a setting we examined the performance of methods used to estimate a Cox model, including (i) full model using all available predictors and estimated by standard techniques, (ii) backward elimination (BE), (iii) ridge regression, (iv) least absolute shrinkage and selection operator (lasso), and (v) elastic net. Based on a prospective cohort of patients with manifest coronary artery disease(CAD), we performed a simulation study to compare the predictive accuracy, calibration, and discrimination of these approaches. Candidate predictors for incident cardiovascular events we used included clinical variables, biomarkers, and a selection of genetic variants associated with CAD. The penalized methods, i.e., ridge, lasso, and elastic net, showed a comparable performance, in terms of predictive accuracy, calibration, and discrimination, and outperformed BE and the full model. Excessive shrinkage was observed in some cases for the penalized methods, mostly on the simulation scenarios having the lowest ratio of a number of events to the number of variables. We conclude that in similar settings, these three penalized methods can be used interchangeably. The full model and backward elimination are not recommended in rare event scenarios.
- Published
- 2016
- Full Text
- View/download PDF
46. Comparison of Cox Model Methods in A Low-dimensional Setting with Few Events
- Author
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Ojeda, Francisco M., Müller, Christian, Börnigen, Daniela, Trégouët, David-Alexandre, Schillert, Arne, Heinig, Matthias, Zeller, Tanja, and Schnabel, Renate B.
- Abstract
Prognostic models based on survival data frequently make use of the Cox proportional hazards model. Developing reliable Cox models with few events relative to the number of predictors can be challenging, even in low-dimensional datasets, with a much larger number of observations than variables. In such a setting we examined the performance of methods used to estimate a Cox model, including (i) full model using all available predictors and estimated by standard techniques, (ii) backward elimination (BE), (iii) ridge regression, (iv) least absolute shrinkage and selection operator (lasso), and (v) elastic net. Based on a prospective cohort of patients with manifest coronary artery disease(CAD), we performed a simulation study to compare the predictive accuracy, calibration, and discrimination of these approaches. Candidate predictors for incident cardiovascular events we used included clinical variables, biomarkers, and a selection of genetic variants associated with CAD. The penalized methods, i.e., ridge, lasso, and elastic net, showed a comparable performance, in terms of predictive accuracy, calibration, and discrimination, and outperformed BE and the full model. Excessive shrinkage was observed in some cases for the penalized methods, mostly on the simulation scenarios having the lowest ratio of a number of events to the number of variables. We conclude that in similar settings, these three penalized methods can be used interchangeably. The full model and backward elimination are not recommended in rare event scenarios.
- Published
- 2016
- Full Text
- View/download PDF
47. Risk factors for venous thromboembolism in women under combined oral contraceptive
- Author
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Suchon, Pierre, Frouh, Fadi Al, Henneuse, Agathe, Ibrahim, Manal, Brunet, Dominique, Barthet, Marie-Christine, Aillaud, Marie-Françoise, Venton, Geoffroy, Alessi, Marie-Christine, Trégouët, David-Alexandre, and Morange, Pierre-Emmanuel
- Published
- 2016
- Full Text
- View/download PDF
48. Adrenomedullin and Arterial Stiffness.
- Author
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Beygui, Farzin, Wild, Philipp S., Zeller, Tanja, Germain, Marine, Castagné, Raphaele, Lackner, Karl J., Münzel, Thomas, Montalescot, Gilles, Mitchell, Gary F., Verwoert, Germaine C., Tarasov, Kirill V., Trégouët, David-Alexandre, Cambien, François, Blankenberg, Stefan, and Tiret, Laurence
- Abstract
Adrenomedullin (ADM) is a circulating vasoactive peptide involved in vascular homeostasis and endothelial function. Single nucleotide polymorphisms of the ADM gene are associated with blood pressure variability, and elevated levels of plasma midregional proadrenomedullin (MR-pro-ADM) are associated with cardiovascular diseases.We investigated the sources of variability of ADM gene expression and plasma MR-pro-ADM concentrations in the general population, and their relationship with markers of atherosclerosis. MR-pro-ADM levels were assessed in 4155 individuals who underwent evaluation of carotid intima-media thickness and arterial rigidity (reflection index and stiffness index). In a subsample of 1372 individuals, ADM gene expression was assessed as part of a transcriptomic study of circulating monocytes. Nongenetic factors explained 45.8% and 7.5% of MR-pro-ADM and ADM expression variability, respectively. ADM expression correlated with plasma C-reactive protein, interleukin-receptor 1A, and myeloperoxidase, whereas MR-pro-ADM levels correlated with C-terminal proendothelin-1, creatinine, and N-terminal pro-B-type natriuretic peptide. Genome-wide association study of ADM expression and MR-pro-ADM levels both identified a single locus encompassing the ADM gene. ADM expression was associated with 1 single nucleotide polymorphism rs11042717 (P=2.36×10
-12 ), whereas MR-pro-ADM was associated with 2 single nucleotide polymorphisms with additive effects, rs2957692 (P=1.54×10-13 ) and rs2957717 (P=4.24×10-8 ). Reflection index was independently associated with rs11042717 (P<10-4 ) and ADM expression (P=0.0002) but not with MR-pro-ADM. Weaker associations were observed for stiffness index. Intima-media thickness was not related to ADM single nucleotide polymorphisms or expression.These results support an involvement of the ADM gene in the modulation of peripheral vascular tone. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
49. Familial resemblance of physical activity levels in the Portuguese population.
- Author
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Maia, José, Gomes, Thayse N., Trégouët, David-Alexandre, and Katzmarzyk, Peter T.
- Abstract
Abstract: Objectives: Moderate to high levels of physical activity are related to positive health status. Parents share with their children important cultural aspects and beliefs related to healthy living. However, family studies show contradictory results for familial aggregation of physical activity. The purposes of this study were to assess whether physical activity shows familial aggregation in the Portuguese population and to disentangle the exact pattern of familial resemblance. Design: Cross-sectional family study. Methods: We sampled 2661 Portuguese nuclear families (10,644 subjects) and assessed their physical activity using the Baecke questionnaire, including components for physical activity work/school, leisure-time activity, sports participation, and a total index of physical activity. Generalized estimating equations were used to compute spousal, parent–offspring and sibling correlations. Results: For leisure-time activity and total index of physical activity, the patterns were characterized with spouse correlations higher than parent–offspring correlations (0.20 vs 0.12, p =0.001 and 0.22 vs 0.12, p =10
−4 , respectively) but lower than those in offspring (0.20 vs 0.51, p <10−4 and 0.22 vs 0.35, p <10−4 , respectively). For sports participation, the spouse correlation was higher than parent–offspring correlations (0.30 vs 0.18, p <10−4 ), but also higher than sibling correlations (0.30 vs 0.22, p <10−4 ). Finally, the physical activity work/school spouse correlation was higher than the sibling correlations (0.22 vs 0.12, p <10−4 ). Conclusions: The results support the hypothesis of familial aggregation in physical activity. Further, fathers and mothers had a similar influence on their offspring's physical activity levels irrespective of their sex, and equal sibling correlations point toward shared physical activity habits. [Copyright &y& Elsevier]- Published
- 2014
- Full Text
- View/download PDF
50. DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood
- Author
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Hahn, Julie, Bressler, Jan, Domingo-Relloso, Arce, Chen, Ming-Huei, McCartney, Daniel L., Teumer, Alexander, van Dongen, Jenny, Kleber, Marcus E., Aïssi, Dylan, Swenson, Brenton R., Yao, Jie, Zhao, Wei, Huang, Jian, Xia, Yujing, Brown, Michael R., Costeira, Ricardo, de Geus, Eco J.C., Delgado, Graciela E., Dobson, Dre'Von A., Elliott, Paul, Grabe, Hans J., Guo, Xiuqing, Harris, Sarah E., Huffman, Jennifer E., Kardia, Sharon L.R., Liu, Yongmei, Lorkowski, Stefan, Marioni, Riccardo E., Nauck, Matthias, Ratliff, Scott M., Sabater-Lleal, Maria, Spector, Tim D., Suchon, Pierre, Taylor, Kent D., Thibord, Florian, Trégouët, David-Alexandre, Wiggins, Kerri L., Willemsen, Gonneke, Bell, Jordana T., Boomsma, Dorret I., Cole, Shelley A., Cox, Simon R., Dehghan, Abbas, Greinacher, Andreas, Haack, Karin, März, Winfried, Morange, Pierre-Emmanuel, Rotter, Jerome I., Sotoodehnia, Nona, Tellez-Plaza, Maria, Navas-Acien, Ana, Smith, Jennifer A., Johnson, Andrew D., Fornage, Myriam, Smith, Nicholas L., Wolberg, Alisa S., Morrison, Alanna C., and de Vries, Paul S.
- Abstract
Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa.
- Published
- 2023
- Full Text
- View/download PDF
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