107 results on '"Trégouët, D. A"'
Search Results
2. Clonal hematopoiesis of indeterminate potential do not highly increase the risk of myocardial infarction even when associated with mosaic loss of Y chromosome
- Author
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Fawaz, S., primary, Marti, S., additional, Dufossée, M., additional, Pucheu, Y., additional, Gaufroy, A., additional, Broitman, J., additional, Bidet, A., additional, Soumaré, A., additional, Munsch, G., additional, Tzourio, C., additional, Debette, S., additional, Trégouët, D.-A., additional, James, C., additional, Mansier, O., additional, and Couffinhal, T., additional
- Published
- 2024
- Full Text
- View/download PDF
3. Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes
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de Haan, H.G., van Hylckama Vlieg, A., Lotta, L.A., Gorski, M.M., Bucciarelli, P., Martinelli, I., Baglin, T.P., Peyvandi, F., Rosendaal, F.R., Amouyel, P., de Andrade, M., Basu, S., Berr, C., Brody, J.A., Chasman, D. I, Dartigues, J.‐F., Folsom, A.R., Germain, M., Heit, J., Houwing‐Duitermaat, J., Kabrhel, C., Kraft, P., Le Gal, G., Lindström, S., Monajemi, R., Morange, P.‐E., Psaty, B.M., Reitsma, P.H., Ridker, P.M., Rose, L.M., Saut, N., Slagboom, E., Smadja, D., Smith, N.L., Suchon, P., Tang, W., Taylor, K.D., Trégouët, D.‐A., Tzourio, C., de Visser, M.C.H., Weng, L.‐C., and Wiggins, K.L.
- Published
- 2018
- Full Text
- View/download PDF
4. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.
- Author
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Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, Debette, S, Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, and Debette, S
- 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.
- Published
- 2023
5. Single nucleotide polymorphisms in an intergenic chromosome 2q region associated with tissue factor pathway inhibitor plasma levels and venous thromboembolism
- Author
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Dennis, J., Truong, V., Aïssi, D., Medina‐Rivera, A., Blankenberg, S., Germain, M., Lemire, M., Antounians, L., Civelek, M., Schnabel, R., Wells, P., Wilson, M.D., Morange, P.‐E., Trégouët, D.‐A., and Gagnon, F.
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- 2016
- Full Text
- View/download PDF
6. PB1136 Improving Genetic Testing for Antithrombin Deficiency by Optimizing ACMG/AMP Variant Curation Guidelines for the SERPINC1 Gene
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Lee, K., Mohan, S., Tracey, S., Morales-Rosado, J., Branchford, B., Castoldi, E., Li, A., Orlando, C., Payne, A., Trapp-Stamborski, V., Fergusson, M., Tregouet, D., and Morange, P.
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- 2023
- Full Text
- View/download PDF
7. Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation
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Ibrahim-Kosta, M., Suchon, P., Couturaud, F., Smadja, D., Olaso, R., Germain, M., Saut, N., Goumidi, L., Derbois, C., Thibord, F., Debette, S., Amouyel, P., Deleuze, J. F., van Doorn, P., Castoldi, E., Patin, E., Alessi, M. C., Trégouët, D. A., and Morange, P. E.
- Published
- 2019
- Full Text
- View/download PDF
8. Dilated Cardiomyopathy – Results, Conclusions and Perspectives
- Author
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Garnier, S, Harakalova, M, Weiss, S, Mokry, M, Isnard, R, Duboscq-Bidot, L, Komajda, M, Cambien, F, Deleuze, J-F, Dörr, M, Asselbergs F, W, Villard, E, Trégouët, D-A, Charron, P, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Utrecht University [Utrecht], Universität Greifswald - University of Greifswald, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), University of Medicine Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and GenMed consortuium
- Subjects
[SDV]Life Sciences [q-bio] - Abstract
International audience
- Published
- 2022
9. Current knowledge on the genetics of incident venous thrombosis
- Author
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Morange, P.‐E. and Trégouët, D.‐A.
- Published
- 2013
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10. Clonal hematopoiesis are not associated with an increased systemic inflammation, ATHerosclerosis nor incidence of atherothrombosis: Results from the 3-city study (CHIP-3C)
- Author
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Marti, S., Dufossée, M., Fawaz, S., Tregouet, D.-A., James, C., Couffinhal, T., and Mansier, O.
- Published
- 2022
- Full Text
- View/download PDF
11. Stroke genetics informs drug discovery and risk prediction across ancestries.
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Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Trégouët, D-A, Trompet, S, Tuladhar, AM, Tybjærg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Estonian Biobank, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Kõrv, J, França, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Paré, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernández-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Trégouët, D-A, Trompet, S, Tuladhar, AM, Tybjærg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Estonian Biobank, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Kõrv, J, França, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Paré, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernández-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, and Debette, S
- 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 SH3PXD2A and FURIN) and variants (such as at GRK5 and 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.
- Published
- 2022
12. The Genetic Landscape of Renal Complications in Type 1 Diabetes
- Author
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Sandholm, Niina, Van Zuydam, Natalie, Ahlqvist, Emma, Juliusdottir, Thorhildur, Deshmukh, Harshal A., Rayner, N. William, Di Camillo, Barbara, Forsblom, Carol, Fadista, Joao, Ziemek, Daniel, Salem, Rany M., Hiraki, Linda T., Pezzolesi, Marcus, Trégouët, David, Dahlström, Emma, Valo, Erkka, Oskolkov, Nikolay, Ladenvall, Claes, Marcovecchio, M. Loredana, Cooper, Jason, Sambo, Francesco, Malovini, Alberto, Manfrini, Marco, McKnight, Amy Jayne, Lajer, Maria, Harjutsalo, Valma, Gordin, Daniel, Parkkonen, Maija, Lyssenko, Valeriya, McKeigue, Paul M., Rich, Stephen S., Brosnan, Mary Julia, Fauman, Eric, Bellazzi, Riccardo, Rossing, Peter, Hadjadj, Samy, Krolewski, Andrzej, Paterson, Andrew D., Hirschhorn, Joel N., Maxwell, Alexander P., Cobelli, Claudio, Colhoun, Helen M., Groop, Leif, McCarthy, Mark I., Groop, Per-Henrik, Sandholm, N., Van Zuydam, N., Ahlqvist, E., Juliusdottir, T., Deshmukh, H.A., Di Camillo, B., Forsblom, C., Fadista, J., Ziemek, D., Salem, R.M., Hiraki, L.T., Pezzolesi, M., Trégouët, D., Dahlström, E., Valo, E., Oskolkov, N., Ladenvall, C., Marcovecchio, M.L., Cooper, J., Sambo, F., Malovini, A., Manfrini, M., McKnight, A. J., Lajer, M., V, Gordin, D., Parkkonen, M., Tuomilehto, J., V, McKeigue, P.M., Rich, S.S., Brosnan, M.J., Fauman, E., Bellazzi, R., Rossing, P., Hadjadj, S., Krolewski, A., Paterson, A.D., Florez, J.C., Hirschhorn, J.N., Maxwell, A.P., Dunger, D., Cobelli, C., Colhoun, H.M., Groop, L., McCarthy, M.I., and Groop, P.-H.
- Published
- 2017
- Full Text
- View/download PDF
13. Identification par étude d’association génome entier (GWAS) de deux nouveaux loci impliqués dans l’insuffisance cardiaque par cardiomyopathie dilatée en 3p25.1 et 22q11.23
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Garnier, S, Harakalova, M, Weiss, S, Mokry, M, Isnard, R, Duboscq-Bidot, L, Komajda, M, Cambien, F, Deleuze, J-F, Dörr, M, Asselbergs F, W, Villard, E, Trégouët, D-A, Charron, P, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Utrecht University [Utrecht], Universität Greifswald - University of Greifswald, Sorbonne Université (SU), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), University of Medicine Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and SFGH
- Subjects
[SDV]Life Sciences [q-bio] - Published
- 2022
14. A multi‐stage multi‐design strategy provides strong evidence that the BAI3 locus is associated with early‐onset venous thromboembolism
- Author
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ANTONI, G., MORANGE, P.‐E., LUO, Y., SAUT, N., BURGOS, G., HEATH, S., GERMAIN, M., BIRON‐ANDREANI, C., SCHVED, J.‐F., PERNOD, G., GALAN, P., ZELENIKA, D., ALESSI, M.‐C., DROUET, L., VISVIKIS‐SIEST, S., WELLS, P.S., LATHROP, M., EMMERICH, J., TREGOUET, D.‐A., and GAGNON, F.
- Published
- 2010
- Full Text
- View/download PDF
15. Detection of two new DNA/chromatin regions increasing DCM risk
- Author
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Garnier, Sophie, Harakalova, M, Weiss, S, Mokry, M, Isnard, R, Duboscq-Bidot, L, Komajda, M, Dörr, M, Asselbergs F, W, Deleuze, J-F, Villard, E, Cambien, F, Trégouët, D-A, Charron, P, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Utrecht University [Utrecht], Universität Greifswald - University of Greifswald, Sorbonne Université (SU), University of Medicine Greifswald, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
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[SDV]Life Sciences [q-bio] - Abstract
International audience
- Published
- 2021
16. Identification of new genetic risk factors for recurrent venous thrombosis: OR148
- Author
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de Haan, H G, Germain, M, Baglin, T P, Deleuze, J-F, Trégouët, D-A, Rosendaal, F R, and van Hylckama Vlieg, A
- Published
- 2015
17. Prise en compte de la confusion non-observée dans les études de cohorte : méthode par variables instrumentales pour exposition transversale et marqueur répété
- Author
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Le Bourdonnec, K., primary, Samieri, C., additional, Trégouët, D., additional, and Proust-Lima, C., additional
- Published
- 2021
- Full Text
- View/download PDF
18. Modélisation rétro-prospective d’évènements récurrents
- Author
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Munsch, G., primary, Ibrahim-Kosta, M., additional, Gouimidi, L., additional, Morange, P., additional, Trégouët, D., additional, and Jacqmin-Gadda, H., additional
- Published
- 2021
- Full Text
- View/download PDF
19. Risk assessment of venous thrombosis in families with known hereditary thrombophilia: the MARseilles-NImes prediction model
- Author
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Cohen, W., Castelli, C., Suchon, P., Bouvet, S., Aillaud, M. F., Brunet, D., Barthet, M. C., Alessi, M. C., Trégouët, D. A., and Morange, P. E.
- Published
- 2014
- Full Text
- View/download PDF
20. Whole-Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome
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Rhodes, CJ, Otero-Núñez, P, Wharton, J, Swietlik, EM, Kariotis, S, Harbaum, L, Dunning, MJ, Elinoff, JM, Errington, N, Thompson, AAR, Iremonger, J, Coghlan, JG, Corris, PA, Howard, LS, Kiely, DG, Church, C, Pepke-Zaba, J, Toshner, M, Wort, SJ, Desai, AA, Humbert, M, Nichols, WC, Southgate, L, Trégouët, D-A, Trembath, RC, Prokopenko, I, Gräf, S, Morrell, NW, Wang, D, Lawrie, A, and Wilkins, MR
- Abstract
Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk.Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis.Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study.Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776; P = 0.012).Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.
- Published
- 2020
21. Association study and subsequent analyses revealed two new key players in DCM
- Author
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Garnier, S, Harakalova, M, Weiss, S, Mokry, M, Isnard, R, Duboscq-Bidot, L, Komajda, M, Cambien, F, Deleuze, J-F, Dörr, M, Asselbergs F, W, Villard, E, Trégouët, D-A, Charron, P, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Utrecht University [Utrecht], Universität Greifswald - University of Greifswald, Sorbonne Université (SU), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), University of Medicine Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
- Subjects
[SDV]Life Sciences [q-bio] - Abstract
International audience
- Published
- 2020
22. Mendelian randomisation analysis of red cell distribution width in pulmonary arterial hypertension
- Author
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Ulrich, A, Wharton, J, Thayer, TE, Swietlik, EM, Assad, TR, Desai, AA, Gräf, S, Harbaum, L, Humbert, M, Morrell, NW, Nichols, WC, Soubrier, F, Southgate, L, Trégouët, D-A, Trembath, RC, Brittain, EL, Wilkins, MR, Prokopenko, I, Rhodes, CJ, NIHR BioResource – Rare Diseases Consortium, UK PAH Cohort Study Consortium, and US PAH Biobank Consortium
- Abstract
Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early stage iron deficiency or iron deficiency anaemia. This study investigated if elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR=1.90, 95% CI=1.80-2.01) in a multi-centre case-control study (N cases=642, N disease controls=15 889). The primary MR analysis was adequately powered to detect a causal effect (OR) from between 1.25 and 1.52 or greater based on estimates reported in the RDW GWAS or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal=1.07, 95% CI=0.92-1.24) or the secondary (ORcausal=1.09, 95% CI=0.77-1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution as any improvements observed may not be mechanistically linked to the development of PAH.
- Published
- 2020
23. Cerebral small vessel disease genomics and its implications across the lifespan
- Author
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Sargurupremraj, M. (Muralidharan), Suzuki, H. (Hideaki), Jian, X. (Xueqiu), Sarnowski, C., Evans, T.E (Tavia), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Sakaue, S. (Saori), Terzikhan, N. (Natalie), Habes, M. (Mohamad), Zhao, W. (Wei), Armstrong, N.J. (Nicola J.), Hofer, E. (Edith), Yanek, L.R. (Lisa), Hagenaars, S.P. (Saskia P.), Kumar, R.B. (Rajan B.), Akker, E.B. (Erik) van den, McWhirter, R.E. (Rebekah E.), Trompet, S. (Stella), Mishra, A. (Aniket), Saba, Y. (Yasaman), Satizabal, C.L. (Claudia), Beaudet, G. (Gregory), Petit, L. (Laurent), Tsuchida, A. (Ami), Zago, L. (Laure), Schilling, S. (Sabrina), Sigurdsson, S. (Stefan), Gottesman, R.F. (Rebecca), Lewis, C.E. (Cora E.), Aggarwal, N.T. (Neelum T.), Lopez, O.L. (Oscar), Smith, J.A. (Jennifer A), Valdés Hernández, M.C. (Maria C.), van der Grond, J. (Jeroen), Wright, M.J. (Margaret), Knol, M.J. (Maria J.), Dörr, M. (Marcus), Thomson, R. (Russell), Bordes, C. (Constance), Le Grand, Q. (Quentin), Duperron, M.-G. (Marie-Gabrielle), Smith, A.V. (Albert), Knopman, D.S. (David), Schreiner, P.J. (Pamela), Evans, D.A. (Denis A.), Rotter, J.I. (Jerome I.), Beiser, A. (Alexa), Maniega, S.M. (Susana Muñoz), Beekman, M. (Marian), Trollor, J., Stott, D.J. (David. J.), Vernooij, M.W. (Meike), Wittfeld, K. (Katharina), Niessen, W.J. (Wiro), Soumaré, A. (Aicha), Boerwinkle, E.A. (Eric), Sidney, S. (Stephen), Turner, S.T. (Stephen), Davies, G. (Gail), Thalamuthu, A. (Anbupalam), Völker, U. (Uwe), Buchem, M.A. (Mark) van, Bryan, R.N. (R. Nick), Amin, N. (Najaf), Bastin, M.E. (Mark), Ames, D.J. (David), Teumer, A. (Alexander), Amouyel, P. (Philippe), Kwok, J.B. (John B.), Bülow, R. (Robin), Deary, I.J. (Ian), Schofield, P.R. (Peter R.), Brodaty, H. (Henry), Jiang, J. (Jiyang), Tabara, Y. (Yasuharu), Setoh, K. (Kazuya), Miyamoto, S. (Susumu), Yoshida, K. (Kazumichi), Nagata, M. (Manabu), Kamatani, Y. (Yoichiro), Matsuda, F. (Fumihiko), Psaty, B.M. (Bruce), Bennett, D.A. (David), De Jager, P., Mosley, T.H. (Thomas H.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Warren, H. (Helen), Evangelou, E. (Evangelos), Trégouët, D.-A. (David-Alexandre), Andrade, M. (Mariza) de, Basu, S. (Saonli), Berr, C. (Claudine), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel I.), Dartigues, J.-F., Folsom, A.R. (Aaron), Germain, M. (Marine), de Haan, H. (Hugoline), Heit, J.A. (John), Houwing-Duitermaat, J. (Jeanine), Kabrhel, C. (Christopher), Kraft, P. (Peter), Legal, G. (Grégoire), Lindström, S. (Sara), Monajemi, R. (Ramin), Morange, P.-E. (P.), Psaty, B.M. (Bruce M.), Reitsma, P.H. (Pieter H.), Jarvelin, M.-R. (Marjo-Riitta), Rose, L.M. (Lynda M.), Peyvandi, F. (Flora), Saut, N. (Noemie), Slagboom, E. (Eline), Smadja, D. (David), Smith, N.L. (Nicholas L.), Suchon, P. (Pierre), Tang, W. (Weihong), Taylor, K.D. (Kent D.), Tregouet, D.-A. (David-Alexandre), Tzourio, C. (Christophe), Visser, M.C.H. (Marieke) de, Hylckama Vlieg, A. (Astrid) van, Weng, L.-C., Wiggins, K.L. (Kerri L.), Gormley, A.M., Anttila, V. (Verneri), Winsvold, B.S. (Bendik S.), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune H.), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), McMahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela M.), Todt, U. (Unda), Freilinger, T.M. (Tobias M.), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Borck, G. (Guntram), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H. H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie), Schürks, M. (Markus), Ridker, P.M. (Paul M.), Gudlaug Hrafnsdottir, M. (Maria), Stefansson, H. (Hreinn), Ring, S.M. (Susan M.), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Kaunisto, M.A. (Mari), Vepsäläinen, S. (Salli), Malik, R. (Rainer), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela A. F.), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M. (Mitja), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Hämäläinen, E. (Eija), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jie), Stergiakouli, E. (Evie), Lee, P.H. (Phil H.), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Francke Christensen, A. (Anne), Folkmann Hansen, T. (Thomas), Werge, T. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (M. Arfan), Spector, T.D. (Timothy), Järvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Beckmann, J.S. (Jacques), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), van den Maagdenberg, A.M.J.M. (Arn M. J. M.), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Davey Smith, G. (George), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Ikram, M.A. (Arfan), Wen, W. (Wei), DeCarli, C. (Charles), Srikanth, V. (Velandai), Jukema, J.W. (Jan Wouter), Slagboom, P.E. (Eline), Kardia, S.L.R. (Sharon), Okada, Y. (Yukinori), Mazoyer, B. (Bernard), Wardlaw, J.M. (J.), Nyquist, P. (Paul), Mather, R., Grabe, H.J. (Hans Jörgen), Schmidt, H. (Helena), Van Duijn, C.M. (Cornelia M.), Gudnason, V. (Vilmundur), Longstreth Jr, W.T., Launer, L.J. (Lenore), Lathrop, M. (Mark), Seshadri, S. (Sudha), Adams, H.H.H. (Hieab), Matthews, P.M. (P.), Fornage, M. (Myriam), Debette, S. (Stéphanie), Sargurupremraj, M. (Muralidharan), Suzuki, H. (Hideaki), Jian, X. (Xueqiu), Sarnowski, C., Evans, T.E (Tavia), Bis, J.C. (Joshua), Eiriksdottir, G. (Gudny), Sakaue, S. (Saori), Terzikhan, N. (Natalie), Habes, M. (Mohamad), Zhao, W. (Wei), Armstrong, N.J. (Nicola J.), Hofer, E. (Edith), Yanek, L.R. (Lisa), Hagenaars, S.P. (Saskia P.), Kumar, R.B. (Rajan B.), Akker, E.B. (Erik) van den, McWhirter, R.E. (Rebekah E.), Trompet, S. (Stella), Mishra, A. (Aniket), Saba, Y. (Yasaman), Satizabal, C.L. (Claudia), Beaudet, G. (Gregory), Petit, L. (Laurent), Tsuchida, A. (Ami), Zago, L. (Laure), Schilling, S. (Sabrina), Sigurdsson, S. (Stefan), Gottesman, R.F. (Rebecca), Lewis, C.E. (Cora E.), Aggarwal, N.T. (Neelum T.), Lopez, O.L. (Oscar), Smith, J.A. (Jennifer A), Valdés Hernández, M.C. (Maria C.), van der Grond, J. (Jeroen), Wright, M.J. (Margaret), Knol, M.J. (Maria J.), Dörr, M. (Marcus), Thomson, R. (Russell), Bordes, C. (Constance), Le Grand, Q. (Quentin), Duperron, M.-G. (Marie-Gabrielle), Smith, A.V. (Albert), Knopman, D.S. (David), Schreiner, P.J. (Pamela), Evans, D.A. (Denis A.), Rotter, J.I. (Jerome I.), Beiser, A. (Alexa), Maniega, S.M. (Susana Muñoz), Beekman, M. (Marian), Trollor, J., Stott, D.J. (David. J.), Vernooij, M.W. (Meike), Wittfeld, K. (Katharina), Niessen, W.J. (Wiro), Soumaré, A. (Aicha), Boerwinkle, E.A. (Eric), Sidney, S. (Stephen), Turner, S.T. (Stephen), Davies, G. (Gail), Thalamuthu, A. (Anbupalam), Völker, U. (Uwe), Buchem, M.A. (Mark) van, Bryan, R.N. (R. Nick), Amin, N. (Najaf), Bastin, M.E. (Mark), Ames, D.J. (David), Teumer, A. (Alexander), Amouyel, P. (Philippe), Kwok, J.B. (John B.), Bülow, R. (Robin), Deary, I.J. (Ian), Schofield, P.R. (Peter R.), Brodaty, H. (Henry), Jiang, J. (Jiyang), Tabara, Y. (Yasuharu), Setoh, K. (Kazuya), Miyamoto, S. (Susumu), Yoshida, K. (Kazumichi), Nagata, M. (Manabu), Kamatani, Y. (Yoichiro), Matsuda, F. (Fumihiko), Psaty, B.M. (Bruce), Bennett, D.A. (David), De Jager, P., Mosley, T.H. (Thomas H.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Warren, H. (Helen), Evangelou, E. (Evangelos), Trégouët, D.-A. (David-Alexandre), Andrade, M. (Mariza) de, Basu, S. (Saonli), Berr, C. (Claudine), Brody, J.A. (Jennifer A.), Chasman, D.I. (Daniel I.), Dartigues, J.-F., Folsom, A.R. (Aaron), Germain, M. (Marine), de Haan, H. (Hugoline), Heit, J.A. (John), Houwing-Duitermaat, J. (Jeanine), Kabrhel, C. (Christopher), Kraft, P. (Peter), Legal, G. (Grégoire), Lindström, S. (Sara), Monajemi, R. (Ramin), Morange, P.-E. (P.), Psaty, B.M. (Bruce M.), Reitsma, P.H. (Pieter H.), Jarvelin, M.-R. (Marjo-Riitta), Rose, L.M. (Lynda M.), Peyvandi, F. (Flora), Saut, N. (Noemie), Slagboom, E. (Eline), Smadja, D. (David), Smith, N.L. (Nicholas L.), Suchon, P. (Pierre), Tang, W. (Weihong), Taylor, K.D. (Kent D.), Tregouet, D.-A. (David-Alexandre), Tzourio, C. (Christophe), Visser, M.C.H. (Marieke) de, Hylckama Vlieg, A. (Astrid) van, Weng, L.-C., Wiggins, K.L. (Kerri L.), Gormley, A.M., Anttila, V. (Verneri), Winsvold, B.S. (Bendik S.), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune H.), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), McMahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela M.), Todt, U. (Unda), Freilinger, T.M. (Tobias M.), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Borck, G. (Guntram), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H. H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie), Schürks, M. (Markus), Ridker, P.M. (Paul M.), Gudlaug Hrafnsdottir, M. (Maria), Stefansson, H. (Hreinn), Ring, S.M. (Susan M.), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Kaunisto, M.A. (Mari), Vepsäläinen, S. (Salli), Malik, R. (Rainer), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela A. F.), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M. (Mitja), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Hämäläinen, E. (Eija), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jie), Stergiakouli, E. (Evie), Lee, P.H. (Phil H.), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Francke Christensen, A. (Anne), Folkmann Hansen, T. (Thomas), Werge, T. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (M. Arfan), Spector, T.D. (Timothy), Järvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Beckmann, J.S. (Jacques), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), van den Maagdenberg, A.M.J.M. (Arn M. J. M.), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Davey Smith, G. (George), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Ikram, M.A. (Arfan), Wen, W. (Wei), DeCarli, C. (Charles), Srikanth, V. (Velandai), Jukema, J.W. (Jan Wouter), Slagboom, P.E. (Eline), Kardia, S.L.R. (Sharon), Okada, Y. (Yukinori), Mazoyer, B. (Bernard), Wardlaw, J.M. (J.), Nyquist, P. (Paul), Mather, R., Grabe, H.J. (Hans Jörgen), Schmidt, H. (Helena), Van Duijn, C.M. (Cornelia M.), Gudnason, V. (Vilmundur), Longstreth Jr, W.T., Launer, L.J. (Lenore), Lathrop, M. (Mark), Seshadri, S. (Sudha), Adams, H.H.H. (Hieab), Matthews, P.M. (P.), Fornage, M. (Myriam), and Debette, S. (Stéphanie)
- Abstract
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
- Published
- 2020
- Full Text
- View/download PDF
24. Cerebral small vessel disease genomics and its implications across the lifespan
- Author
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Sargurupremraj, M., Suzuki, H., Jian, X., Sarnowski, C., Evans, T.E., Bis, J.C., Eiriksdottir, G., Sakaue, S., Terzikhan, N., Habes, M., Zhao, W., Armstrong, N.J., Hofer, E., Yanek, L.R., Hagenaars, S.P., Kumar, R.B., van den Akker, E.B., McWhirter, R.E., Trompet, S., Mishra, A., Saba, Y., Satizabal, C.L., Beaudet, G., Petit, L., Tsuchida, A., Zago, L., Schilling, S., Sigurdsson, S., Gottesman, R.F., Lewis, C.E., Aggarwal, N.T., Lopez, O.L., Smith, J.A., Valdés Hernández, M.C., Van der Grond, J., Wright, M.J., Knol, M.J., Dörr, M., Thomson, R.J., Bordes, C., Le Grand, Q., Duperron, M-G, Smith, A.V., Knopman, D.S., Schreiner, P.J., Evans, D.A., Rotter, J.I., Beiser, A.S., Maniega, S.M., Beekman, M., Trollor, J., Stott, D.J., Vernooij, M.W., Wittfeld, K., Niessen, W.J., Soumaré, A., Boerwinkle, E., Sidney, S., Turner, S.T., Davies, G., Thalamuthu, A., Völker, U., van Buchem, M.A., Bryan, R.N., Dupuis, J., Bastin, M.E., Ames, D., Teumer, A., Amouyel, P., Kwok, J.B., Bülow, R., Deary, I.J., Schofield, P.R., Brodaty, H., Jiang, J., Tabara, Y., Setoh, K., Miyamoto, S., Yoshida, K., Nagata, M., Kamatani, Y., Matsuda, F., Psaty, B.M., Bennett, D.A., De Jager, P.L., Mosley, T.H., Sachdev, P.S., Schmidt, R., Warren, H.R., Evangelou, E., Trégouët, D-A, Ikram, M.A., Wen, W., DeCarli, C., Srikanth, V.K., Jukema, J.W., Slagboom, E.P., Kardia, S.L.R., Okada, Y., Mazoyer, B., Wardlaw, J.M., Nyquist, P.A., Mather, K.A., Grabe, H.J., Schmidt, H., van Duijn, C.M., Gudnason, V., Longstreth, W.T., Launer, L. J., Lathrop, M., Seshadri, S., Tzourio, C., Adams, H.H., Matthews, P.M., Fornage, M., Debette, S., Sargurupremraj, M., Suzuki, H., Jian, X., Sarnowski, C., Evans, T.E., Bis, J.C., Eiriksdottir, G., Sakaue, S., Terzikhan, N., Habes, M., Zhao, W., Armstrong, N.J., Hofer, E., Yanek, L.R., Hagenaars, S.P., Kumar, R.B., van den Akker, E.B., McWhirter, R.E., Trompet, S., Mishra, A., Saba, Y., Satizabal, C.L., Beaudet, G., Petit, L., Tsuchida, A., Zago, L., Schilling, S., Sigurdsson, S., Gottesman, R.F., Lewis, C.E., Aggarwal, N.T., Lopez, O.L., Smith, J.A., Valdés Hernández, M.C., Van der Grond, J., Wright, M.J., Knol, M.J., Dörr, M., Thomson, R.J., Bordes, C., Le Grand, Q., Duperron, M-G, Smith, A.V., Knopman, D.S., Schreiner, P.J., Evans, D.A., Rotter, J.I., Beiser, A.S., Maniega, S.M., Beekman, M., Trollor, J., Stott, D.J., Vernooij, M.W., Wittfeld, K., Niessen, W.J., Soumaré, A., Boerwinkle, E., Sidney, S., Turner, S.T., Davies, G., Thalamuthu, A., Völker, U., van Buchem, M.A., Bryan, R.N., Dupuis, J., Bastin, M.E., Ames, D., Teumer, A., Amouyel, P., Kwok, J.B., Bülow, R., Deary, I.J., Schofield, P.R., Brodaty, H., Jiang, J., Tabara, Y., Setoh, K., Miyamoto, S., Yoshida, K., Nagata, M., Kamatani, Y., Matsuda, F., Psaty, B.M., Bennett, D.A., De Jager, P.L., Mosley, T.H., Sachdev, P.S., Schmidt, R., Warren, H.R., Evangelou, E., Trégouët, D-A, Ikram, M.A., Wen, W., DeCarli, C., Srikanth, V.K., Jukema, J.W., Slagboom, E.P., Kardia, S.L.R., Okada, Y., Mazoyer, B., Wardlaw, J.M., Nyquist, P.A., Mather, K.A., Grabe, H.J., Schmidt, H., van Duijn, C.M., Gudnason, V., Longstreth, W.T., Launer, L. J., Lathrop, M., Seshadri, S., Tzourio, C., Adams, H.H., Matthews, P.M., Fornage, M., and Debette, S.
- Abstract
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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- 2020
25. Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
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Garnier, S., primary, Harakalova, M., additional, Weiss, S., additional, Mokry, M., additional, Isnard, R., additional, Jouven, X., additional, Dubourg, O., additional, Dorent, R., additional, De Groote, P., additional, Fauchier, L., additional, Trochu, J., additional, Duboscq-Bidot, L., additional, Komajda, M., additional, Cambien, F., additional, Deleuze, J., additional, Dörr, M., additional, Asselbergs, F., additional, Villard, E., additional, Trégouët, D., additional, and Charron, P., additional
- Published
- 2021
- Full Text
- View/download PDF
26. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimerʼs disease
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Lambert, J-C, Grenier-Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M A, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz-Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J-F, Tzourio, C, Berr, C, Schrijvers, E MC, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C A, Lannfelt, L, Ingelsson, M, Prince, J A, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez-Garcia, F, Del Zompo, M, Coto, E, Owen, M, OʼDonovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D-A, Williams, J, Amouyel, P, consortium, E ADI, and consortium, G ERAD
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- 2013
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27. No prognostic role of a GWAS-derived genetic risk score in renal outcomes for patients from French cohorts with type 1 and type 2 diabetes
- Author
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Barbieux, P., György, B., Gand, E., Saulnier, P.-J., Ducrocq, G., Halimi, J.-M., Feigerlova, E., Hulin-Delmotte, C., Llaty, P., Montaigne, D., Rigalleau, V., Roussel, R., Sosner, P., Zaoui, P., Ragot, S., Marre, M., Tregouët, D.-A., and Hadjadj, S.
- Published
- 2019
- Full Text
- View/download PDF
28. Impact on venous thrombosis risk of newly discovered gene variants associated with FVIII and VWF plasma levels
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MORANGE, P.-E., SAUT, N., ANTONI, G., EMMERICH, J., and TRÉGOUËT, D.-A.
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- 2011
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29. Dissection of familial correlations in hepatitis C virus (HCV) seroprevalence suggests intrafamilial viral transmission and genetic predisposition to infection
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Plancoulaine, S, Mohamed, M K, Arafa, N, Bakr, I, Rekacewicz, C, Trégouët, D-A, Obach, D, Daly, M El, Thiers, V, Féray, C, Abdel-Hamid, M, Abel, L, and Fontanet, A
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- 2008
- Full Text
- View/download PDF
30. Effects of Genetically Determined Iron Status on Risk of Venous Thromboembolism and Carotid Atherosclerotic Disease: A Mendelian Randomization Study
- Author
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Gill, D, Brewer, CF, Monori, G, Trégouët, D-A, Franceschini, N, Giambartolomei, C, INVENT Consortium, Tzoulaki, I, and Dehghan, A
- Abstract
Background Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this study was to investigate the effect of genetically determined iron status on carotid intima-media thickness, carotid plaque, and venous thromboembolism using Mendelian randomization. Methods and Results Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48 972 subjects. Genetic association estimates for carotid intima-media thickness and carotid plaque were obtained using data from 71 128 and 48 434 participants, respectively, and estimates for venous thromboembolism were obtained using data from a study incorporating 7507 cases and 52 632 controls. Conventional 2-sample summary data Mendelian randomization was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of venous thromboembolism. Odds ratios per SD increase in biomarker levels were 1.37 (95% CI 1.14-1.66) for serum iron, 1.25 (1.09-1.43) for transferrin saturation, 1.92 (1.28-2.88) for ferritin, and 0.76 (0.63-0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding odds ratios were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80-1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no Mendelian randomization evidence of an effect of iron status on carotid intima-media thickness. Conclusions These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease but increases the risk of thrombosis related to stasis of blood.
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- 2019
31. The effect of genetically determined iron status on risk of venous thromboembolism and carotid atherosclerotic disease: A Mendelian randomization study
- Author
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Gill, D, Brewer, CF, Monori, G, Trégouët, D-A, Franceschini, N, Giambartolomei, C, Consortium, INVENT, Tzoulaki, I, and Dehghan, A
- Subjects
Mendelian randomization ,INVENT Consortium ,atherosclerosis ,thrombosis - Abstract
Background: Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this work was to investigate the effect of genetically determined iron status on carotid intima-media thickness (cIMT), carotid plaque and venous thromboembolism (VTE) using Mendelian randomization (MR). Methods and Results: Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48,972 subjects. Genetic association estimates for cIMT and carotid plaque were obtained using data from 71,128 and 48,434 participants respectively, whilst estimates for VTE were obtained using data from a study incorporating 7,507 cases and 52,632 controls. Conventional two-sample summary data MR was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of VTE. Odds ratios (ORs) per standard deviation increase in biomarker levels were 1.37 (95% confidence interval 1.14–1.66) for serum iron, 1.25 (1.09–1.43) for transferrin saturation, 1.92 (1.28–2.88) for ferritin, and 0.76 (0.63–0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding ORs were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80–1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no MR evidence of an effect of iron status on cIMT. Conclusions: These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease, but increases risk of thrombosis related to stasis of blood.
- Published
- 2019
32. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis
- Author
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Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Knight, J, Hanscombe, KB, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RV, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, A, Waisfisz, Q, Walsworth, AK, Walter, RE, Wharton, J, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, Consortium, UK NIHR Bioresource Rare Diseases, Consortium, UK PAH Cohort Study, Consortium, US PAH Biobank, McCarthy, M, Sorbonne Université (SU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, APH - Quality of Care, and ACS - Microcirculation
- Subjects
Male ,Pulmonary Arterial Hypertension ,Genotyping Techniques ,[SDV]Life Sciences [q-bio] ,Genetic Variation ,HLA-DP alpha-Chains ,Middle Aged ,Polymorphism, Single Nucleotide ,Risk Assessment ,Survival Analysis ,Article ,SOXF Transcription Factors ,Humans ,Female ,Genetic Predisposition to Disease ,HLA-DP beta-Chains ,Genome-Wide Association Study ,Signal Transduction - Abstract
Background Raregenetic variantscause pulmonary arterial hypertension, but the contribution of commongenetic variationto 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. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS usedgenotypesfrom 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals.Cross-validationof loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration ofsurvival.All-cause mortalitywas the primary endpoint in survival analyses. Findings A locus nearSOX17(rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus inHLA-DPA1andHLA-DPB1(collectively referred to asHLA-DPA1/DPB1here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. TheSOX17locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional andepigenomicdata indicate that the risk variants nearSOX17altergene regulationvia anenhanceractive inendothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reducedSOX17expression. TheHLA-DPA1/DPB1rs2856830 genotype was strongly associated with survival. Median survival fromdiagnosisin patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baselinedisease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer nearSOX17and inHLA-DPA1/DPB1is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by raremutationsinSOX17. Further studies are needed to confirm the association betweenHLA typingor rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improvesrisk stratificationin clinical practice or trials.
- Published
- 2019
33. Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis
- Author
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Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Walter, RE, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Walsworth, AK, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Knight, J, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, Hanscombe, KB, US PAH Biobank Consortium, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RVM, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, British Heart Foundation, Wellcome Trust, and Medical Research Council (MRC)
- Subjects
ALPHA ,Science & Technology ,US PAH Biobank Consortium ,Critical Care Medicine ,ENDODERM FORMATION ,General & Internal Medicine ,UK NIHR BioResource Rare Diseases Consortium ,Respiratory System ,UK PAH Cohort Study Consortium ,SUSCEPTIBILITY ,SOX17 ,Life Sciences & Biomedicine ,DISEASE - Abstract
Background 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. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
- Published
- 2018
34. Dilated Cardiomyopathy - Results and Perspectives
- Author
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Garnier, Sophie, Harakalova, M, Weiss, S, Mokry, M, van Setten, J, Proust, C, Duboscq-Bidot, L, Boland, A, Cambien, F, Deleuze, J-F, Dörr, M, Asselbergs F, W, Villard, E, Trégouët, D-A, Charron, Philippe, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Utrecht University [Utrecht], Universität Greifswald - University of Greifswald, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), University of Medicine Greifswald, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Référence des Cardiomyopathies et des Troubles du Rythme Cardiaque Héréditaires ou Rares [Boulogne-Billancourt], Hôpital Ambroise Paré [AP-HP], and Sorbonne Université (SU)
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[SDV]Life Sciences [q-bio] - Abstract
International audience
- Published
- 2018
35. A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein
- Author
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Dusart, Philip, Fagerberg, Linn, Perisic, L., Civelek, M., Struck, Eike, Hedin, U., Uhlén, Mathias, Trégouët, D. -A, Renné, T., Odeberg, Jacob, Butler, Lynn M., Dusart, Philip, Fagerberg, Linn, Perisic, L., Civelek, M., Struck, Eike, Hedin, U., Uhlén, Mathias, Trégouët, D. -A, Renné, T., Odeberg, Jacob, and Butler, Lynn M.
- Abstract
The intermediate filament protein nestin is expressed during embryonic development, but considered largely restricted to areas of regeneration in the adult. Here, we perform a body-wide transcriptome and protein-profiling analysis to reveal that nestin is constitutively, and highly-selectively, expressed in adult human endothelial cells (EC), independent of proliferative status. Correspondingly, we demonstrate that it is not a marker for tumour EC in multiple malignancy types. Imaging of EC from different vascular beds reveals nestin subcellular distribution is shear-modulated. siRNA inhibition of nestin increases EC proliferation, and nestin expression is reduced in atherosclerotic plaque neovessels. eQTL analysis reveals an association between SNPs linked to cardiovascular disease and reduced aortic EC nestin mRNA expression. Our study challenges the dogma that nestin is a marker of proliferation, and provides insight into its regulation and function in EC. Furthermore, our systems-based approach can be applied to investigate body-wide expression profiles of any candidate protein., Export Date: 22 October 2018; Article; Correspondence Address: Butler, L.M.; Science for Life Laboratory, School of Biotechnology, Kungliga Tekniska Högskolan (KTH) Royal Institute of TechnologySweden; email: Lynn.Butler@ki.se. QC 20181127
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- 2018
- Full Text
- View/download PDF
36. Fourth European stroke science workshop
- Author
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Debette, S., Strbian, D., Wardlaw, J. M., van der Worp, H. B., Rinkel, G. J.E., Caso, V., Dichgans, M., Tournier-Lasserve, E., Grefkes, C., Kelly, P. J., Muir, K., Berge, E., Trégouët, D. A., Roffe, C., Brainin, M., Beck, J., Steiner, T., de Lau, L. M., Jouvent, E., Veltkamp, R., Baron, J. C., Nedeltchev, K., Bath, P. M., Quinn, T. J., Richard, E., Ziemann, U., Liesz, A., Ntaios, G., Iadecola, C., Lees, K. R., Christensen, H. Krarup, van Veluw, S. J., Endres, M., Anderson, C. S., Molina, C. A., Düring, M., Dufouil, C., Ostergaard, L., Samani, N. J., Fischer, U., de Leeuw, F. E., Norrving, B., Biessels, G. J., Cordonnier, C., Mas, J. L., Mattle, H., Debette, S., Strbian, D., Wardlaw, J. M., van der Worp, H. B., Rinkel, G. J.E., Caso, V., Dichgans, M., Tournier-Lasserve, E., Grefkes, C., Kelly, P. J., Muir, K., Berge, E., Trégouët, D. A., Roffe, C., Brainin, M., Beck, J., Steiner, T., de Lau, L. M., Jouvent, E., Veltkamp, R., Baron, J. C., Nedeltchev, K., Bath, P. M., Quinn, T. J., Richard, E., Ziemann, U., Liesz, A., Ntaios, G., Iadecola, C., Lees, K. R., Christensen, H. Krarup, van Veluw, S. J., Endres, M., Anderson, C. S., Molina, C. A., Düring, M., Dufouil, C., Ostergaard, L., Samani, N. J., Fischer, U., de Leeuw, F. E., Norrving, B., Biessels, G. J., Cordonnier, C., Mas, J. L., and Mattle, H.
- Abstract
Lake Eibsee, Garmisch-Partenkirchen, 16 to 18 November, 2017: The European Stroke Organisation convened >120 stroke experts from 21 countries to discuss latest results and hot topics in clinical, translational and basic stroke research. Since its inception in 2011, the European Stroke Science Workshop has become a cornerstone of European Stroke Organisation’s academic activities and a major highlight for researchers in the field. Participants include stroke researchers at all career stages and with different backgrounds, who convene for plenary lectures and discussions. The workshop was organised in seven scientific sessions focusing on the following topics: (1) acute stroke treatment and endovascular therapy; (2) small vessel disease; (3) opportunities for stroke research in the omics era; (4) vascular cognitive impairment; (5) intracerebral and subarachnoid haemorrhage; (6) alternative treatment concepts and (7) neural circuits, recovery and rehabilitation. All sessions started with a keynote lecture providing an overview on current developments, followed by focused talks on a timely topic with the most recent findings, including unpublished data. In the following, we summarise the key contents of the meeting. The program is provided in the online only Data Supplement. The workshop started with a key note lecture on how to improve the efficiency of clinical trial endpoints in stroke, which was delivered by Craig Anderson (Sydney, Australia) and set the scene for the following discussions.
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- 2018
37. Genetic risk factors for venous thrombosis in women using combined oral contraceptives: update of the PILGRIM study
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Suchon, P., Al Frouh, F., Ibrahim, Marwa, Sarlon, G, Venton, G, Alessi, Marie-Christine, Trégouët, D-A, Morange, Pierre-Emmanuel, Goletto, Marie-Hélène, Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]
- Subjects
Adult ,Genotype ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,Polymorphism, Single Nucleotide ,Young Adult ,Gene Frequency ,genetic polymorphisms ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Risk Factors ,Odds Ratio ,Humans ,Genetic Predisposition to Disease ,Alleles ,Factor XI ,oral contraceptives ,risk assessment ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Contraceptives, Oral, Combined ,case control studies ,[SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Female ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,venous thrombosis ,Drug Monitoring - Abstract
International audience; Identifying women at risk of venous thrombosis (VT) under combined oral contraceptives (COC) is a major public health issue. The aim of this study was to investigate in COC users the impact on disease of genetic polymorphisms recently identified to associate with VT risk in the general population. Nine polymorphisms located on KNG1, F11, F5, F2, PROCR, FGG, TSPAN and SLC44A2 genes were genotyped in a sample of 766 patients and 464 controls as part of the PILGRIM (PILl Genetic Risk Monitoring) study. Cases were women who experienced an episode of documented VT during COC use, while controls were women with no history of VT using COC at the time of inclusion. Among the studied polymorphisms, only F11 rs2289252 was significantly associated with VT. The F11 rs2289252‐A allele was associated with a 1.6‐fold increased risk of VT (p < 0.0001). Besides, the combination of the rs2289252‐A allele with non‐O blood group, present in 52% of the cohort, was associated with an odds ratio of 4.00 (2.49–6.47; p < 10 −4). The consideration of this genetic risk factor could help to better assess the risk of VT in COC users. In women, the overall incidence of venous thrombosis (VT) is about 1.2 per 1000 person‐ years 1; this incidence being lower in women of reproductive age, with an estimate ranging between 0.4 and 0.6 per 1000 person‐years 1. The use of combined oral contraceptive (COC) is a major established risk factor for VT in women of reproductive age. The relative risk for COC use is about 3–6. It is well known that this risk depends on two major factors: the progestogen and the ethinyl estradiol dosage 2. It is estimated that more than 100 million women worldwide are using COC, making the impact of COC use on VT risk and public health of major importance 3. In France, 20 young women die annually of pulmonary embolism (PE) as a consequence of COC use 4. Furthermore, young and middle‐aged women with a personal history of VT have a 2.3‐fold increased risk of mortality 5. Besides, among survivors, 25–50% will have lasting debilitating health problems such as post‐thrombotic syndrome, severely hampering mobility and quality of life 6. Chronic thromboembolic pulmonary hypertension occurs in about 3% PE patients 7. Oral contraceptives and inherited thrombophilic defects (i.e. factor V Leiden and prothrombin mutations, deficiencies of protein C, protein S or antithrombin) are known to interact synergistically to increase the risk of VT 8. Very recently, we have found that the ABO blood group, an increasingly recognized risk factor for VT in the general population, was also associated with the risk of VT in COC users. In the PILGRIM (Pill Genetic Risk Monitoring) study, we observed that, under COC use, women of non‐O blood group displayed a 1.85‐fold increased risk of VT compared with O blood group carriers 9. Last year, the International VENous Thrombosis (INVENT) consortium presented the results of the first international meta‐analysis of genome‐wide association studies for VT in the general population 10. This project led to the identification of two unsuspected susceptibility
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- 2017
38. Erratum: Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
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Lambert, J-C, Grenier-Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M A, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz-Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J-F, Tzourio, C, Berr, C, Schrijvers, E M C, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C A, Lannfelt, L, Ingelsson, M, Prince, J A, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez-Garcia, F, Zompo, M Del, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D-A, Williams, J, and Amouyel, P
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- 2013
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- View/download PDF
39. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk
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Brænne, I, Zeng, L, Willenborg, C, Tragante, V, Kessler, T, Willer, C, Laakso, M, Wallentin, L, Franks, P, Salomaa, V, Dehghan, A, Meitinger, T, Samani, N, Asselbergs, F, Erdmann, J, Schunkert, H, Deloukas, P, Kanoni, S, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Goldstein, B, Absher, D, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shun, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Zieg, A, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi-Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco-Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Ehunt, S, Kang, H, Illig, T, Knowles, J, Kolovou, G, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller-Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, Van Der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, De Faire, U, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wareham, N, Zimmermann, M, Nieminen, M, Hengsten, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Oboehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Hengstenberg, C, Mcpherson, R, Ziegler, A, Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W., Erdmann, Jeanette, Schunkert, Heribert, Deloukas, Panos, Kanoni, Stavroula, Farrall, Martin, Assimes, Themistocles L., Thompson, John R., Ingelsson, Erik, Saleheen, Danish, Goldstein, Benjamin A., Absher, Devin, König, Inke R., Cazier, Jean-Baptiste, Johansson, Åsa, Hall, Alistair S., Lee, Jong-Young, Chambers, John C., Esko, Tõnu, Folkersen, Lasse, Goel, Anuj, Grundberg, Elin, Havulinna, Aki S., Ho, Weang K., Hopewell, Jemma C., Eriksson, Niclas, Kleber, Marcus E., Kristiansson, Kati, Lundmark, Per, Lyytikäinen, Leo-Pekka, Rafelt, Suzanne, Shun, Dmitry, Strawbridge, Rona J., Thorleifsson, Gudmar, Tikkanen, Emmi, Van Zuydam, Natalie, Voight, Benjamin F., Waite, Lindsay L., Zhang, Weihua, Zieg, Andreas, Altshuler, David, Balmforth, Anthony J., Barroso, Inês, Braund, Peter S., Burgdorf, Christof, Claudi-Boehm, Simone, Cox, David, Dimitriou, Maria, Do, Ron, Doney, Alex S. F., El Mokhtari, Nour Eddine, Eriksson, Per, Fischer, Krista, Fontanillas, Pierre, Franco-Cereceda, Anders, Gigante, Bruna, Groop, Leif, Gustafsson, Stefan, Hager, Jörg, Hallmans, Göran, Han, Bok-Ghee, Ehunt, Sarah, Kang, Hyun M., Illig, Thomas, Knowles, Joshua W., Kolovou, Genovefa, Kuusisto, Johanna, Langenberg, Claudia, Langford, Cordelia, Leander, Karin, Lokki, Marja-Liisa, Lundmark, Anders, McCarthy, Mark I., Meisinger, Christa, Melander, Olle, Mihailov, Evelin, Maouche, Seraya, Morris, Andrew D., Müller-Nurasyid, Martina, Nikus, Kjell, Peden, John F., Rayner, N. William, Rasheed, Asif, Rosinger, Silke, Rubin, Diana, Rumpf, Moritz P., Schäfer, Arne, Sivananthan, Mohan, Song, Ci, Stewart, Alexandre F. R., Tan, Sian-Tsung, Thorgeirsson, Gudmundur, Van Der Schoot, C. Ellen, Wagner, Peter J., Wells, George A., Wild, Philipp S., Yang, Tsun-Po, Amouyel, Philippe, Arveiler, Dominique, Basart, Hanneke, Boehnke, Michael, Boerwinkle, Eric, Brambilla, Paolo, Cambien, Francois, Cupples, Adrienne L., De Faire, Ulf, Diemert, Patrick, Epstein, Stephen E., Evans, Alun, Ferrario, Marco M., Ferrières, Jean, Gauguier, Dominique, Go, Alan S., Goodall, Alison H., Gudnason, Villi, Hazen, Stanley L., Holm, Hilma, Iribarren, Carlos, Jang, Yangsoo, Kähönen, Mika, Kee, Frank, Kim, Hyo-Soo, Klopp, Norman, Koenig, Wolfgang, Kratzer, Wolfgang, Kuulasmaa, Kari, Laaksonen, Reijo, Lee, Ji-Young, Lind, Lars, Ouwehand, Willem H., Parish, Sarah, Park, Jeong E., Pedersen, Nancy L., Peters, Annette, Quertermous, Thomas, Rader, Daniel J., Schadt, Eric, Shah, Svati H., Sinisalo, Juha, Stark, Klaus, Stefansson, Kari, Trégouët, David-Alexandre, Virtamo, Jarmo, Wareham, Nicholas, Zimmermann, Martina E., Nieminen, Markku S., Hengsten, Christian, Sandhu, Manjinder S., Pastinen, Tomi, Syvänen, Ann-Christine, Hovingh, G. Kees, Dedoussis, George, Lehtimäki, Terho, Metspalu, Andres, Zalloua, Pierre A., Siegbahn, Agneta, Schreiber, Stefan, Ripatti, Samuli, Blankenberg, Stefan S., Perola, Markus, Clarke, Robert, Oboehm, Bernhard, O’Donnell, Christopher, Reilly, Muredach P., März, Winfried, Collins, Rory, Kathiresan, Sekar, Hamsten, Anders, Kooner, Jaspal S., Thorsteinsdottir, Unnur, Danesh, John, Palmer, Colin N. A., Roberts, Robert, Watkins, Hugh, Hall, Alistair, Hengstenberg, Christian, McPherson, Ruth, Ziegler, Andreas, Brænne, I, Zeng, L, Willenborg, C, Tragante, V, Kessler, T, Willer, C, Laakso, M, Wallentin, L, Franks, P, Salomaa, V, Dehghan, A, Meitinger, T, Samani, N, Asselbergs, F, Erdmann, J, Schunkert, H, Deloukas, P, Kanoni, S, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Goldstein, B, Absher, D, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shun, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Zieg, A, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi-Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco-Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Ehunt, S, Kang, H, Illig, T, Knowles, J, Kolovou, G, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller-Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, Van Der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, De Faire, U, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wareham, N, Zimmermann, M, Nieminen, M, Hengsten, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Oboehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Hengstenberg, C, Mcpherson, R, Ziegler, A, Brænne, Ingrid, Zeng, Lingyao, Willenborg, Christina, Tragante, Vinicius, Kessler, Thorsten, Willer, Cristen J., Laakso, Markku, Wallentin, Lars, Franks, Paul W., Salomaa, Veikko, Dehghan, Abbas, Meitinger, Thomas, Samani, Nilesh J., Asselbergs, Folkert W., Erdmann, Jeanette, Schunkert, Heribert, Deloukas, Panos, Kanoni, Stavroula, Farrall, Martin, Assimes, Themistocles L., Thompson, John R., Ingelsson, Erik, Saleheen, Danish, Goldstein, Benjamin A., Absher, Devin, König, Inke R., Cazier, Jean-Baptiste, Johansson, Åsa, Hall, Alistair S., Lee, Jong-Young, Chambers, John C., Esko, Tõnu, Folkersen, Lasse, Goel, Anuj, Grundberg, Elin, Havulinna, Aki S., Ho, Weang K., Hopewell, Jemma C., Eriksson, Niclas, Kleber, Marcus E., Kristiansson, Kati, Lundmark, Per, Lyytikäinen, Leo-Pekka, Rafelt, Suzanne, Shun, Dmitry, Strawbridge, Rona J., Thorleifsson, Gudmar, Tikkanen, Emmi, Van Zuydam, Natalie, Voight, Benjamin F., Waite, Lindsay L., Zhang, Weihua, Zieg, Andreas, Altshuler, David, Balmforth, Anthony J., Barroso, Inês, Braund, Peter S., Burgdorf, Christof, Claudi-Boehm, Simone, Cox, David, Dimitriou, Maria, Do, Ron, Doney, Alex S. F., El Mokhtari, Nour Eddine, Eriksson, Per, Fischer, Krista, Fontanillas, Pierre, Franco-Cereceda, Anders, Gigante, Bruna, Groop, Leif, Gustafsson, Stefan, Hager, Jörg, Hallmans, Göran, Han, Bok-Ghee, Ehunt, Sarah, Kang, Hyun M., Illig, Thomas, Knowles, Joshua W., Kolovou, Genovefa, Kuusisto, Johanna, Langenberg, Claudia, Langford, Cordelia, Leander, Karin, Lokki, Marja-Liisa, Lundmark, Anders, McCarthy, Mark I., Meisinger, Christa, Melander, Olle, Mihailov, Evelin, Maouche, Seraya, Morris, Andrew D., Müller-Nurasyid, Martina, Nikus, Kjell, Peden, John F., Rayner, N. William, Rasheed, Asif, Rosinger, Silke, Rubin, Diana, Rumpf, Moritz P., Schäfer, Arne, Sivananthan, Mohan, Song, Ci, Stewart, Alexandre F. R., Tan, Sian-Tsung, Thorgeirsson, Gudmundur, Van Der Schoot, C. Ellen, Wagner, Peter J., Wells, George A., Wild, Philipp S., Yang, Tsun-Po, Amouyel, Philippe, Arveiler, Dominique, Basart, Hanneke, Boehnke, Michael, Boerwinkle, Eric, Brambilla, Paolo, Cambien, Francois, Cupples, Adrienne L., De Faire, Ulf, Diemert, Patrick, Epstein, Stephen E., Evans, Alun, Ferrario, Marco M., Ferrières, Jean, Gauguier, Dominique, Go, Alan S., Goodall, Alison H., Gudnason, Villi, Hazen, Stanley L., Holm, Hilma, Iribarren, Carlos, Jang, Yangsoo, Kähönen, Mika, Kee, Frank, Kim, Hyo-Soo, Klopp, Norman, Koenig, Wolfgang, Kratzer, Wolfgang, Kuulasmaa, Kari, Laaksonen, Reijo, Lee, Ji-Young, Lind, Lars, Ouwehand, Willem H., Parish, Sarah, Park, Jeong E., Pedersen, Nancy L., Peters, Annette, Quertermous, Thomas, Rader, Daniel J., Schadt, Eric, Shah, Svati H., Sinisalo, Juha, Stark, Klaus, Stefansson, Kari, Trégouët, David-Alexandre, Virtamo, Jarmo, Wareham, Nicholas, Zimmermann, Martina E., Nieminen, Markku S., Hengsten, Christian, Sandhu, Manjinder S., Pastinen, Tomi, Syvänen, Ann-Christine, Hovingh, G. Kees, Dedoussis, George, Lehtimäki, Terho, Metspalu, Andres, Zalloua, Pierre A., Siegbahn, Agneta, Schreiber, Stefan, Ripatti, Samuli, Blankenberg, Stefan S., Perola, Markus, Clarke, Robert, Oboehm, Bernhard, O’Donnell, Christopher, Reilly, Muredach P., März, Winfried, Collins, Rory, Kathiresan, Sekar, Hamsten, Anders, Kooner, Jaspal S., Thorsteinsdottir, Unnur, Danesh, John, Palmer, Colin N. A., Roberts, Robert, Watkins, Hugh, Hall, Alistair, Hengstenberg, Christian, McPherson, Ruth, and Ziegler, Andreas
- Abstract
Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10−12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10−10 and 2.21 × 10−6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.
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- 2017
40. Large-scale association analysis identifies new risk loci for coronary artery disease
- Author
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Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Assimes, TL, Thompson, JR, Goldstein, BA, König, IR, Cazier, JB, Hall, AS, Lee, JY, Willer, CJ, Chambers, JC, Havulinna, AS, Ho, WK, Hopewell, JC, Kleber, ME, Lyytikäinen, LP, Strawbridge, RJ, Voight, BF, Waite, LL, Balmforth, AJ, Braund, PS, Doney, ASF, El Mokhtari, NE, Han, BG, Hunt, SE, Kang, HM, Knowles, JW, Lokki, ML, McCarthy, MI, Morris, AD, Peden, JF, Rayner, NW, Rumpf, MP, Stewart, AFR, Tan, S. T, van der Schoot, CE, Wagner, PJ, Wells, GA, Wild, PS, Yang, T. P, Cupples, AL, Epstein, SE, Ferrario, MM, Go, AS, Goodall, AH, Hazen, SL, Kim, H. S, Lee, J. Y, Ouwehand, WH, Park, JE, Pedersen, NL, Rader, DJ, Shah, SH, Trégouët, D. A, Zimmermann, ME, Nieminen, MS, Sandhu, MS, Syvänen, A. C, Hovingh, GK, Franks, PW, Zalloua, PA, Blankenberg, SS, Boehm, BO, Reilly, MP, Kooner, JS, Palmer, CNA, Samani, NJ, BRAMBILLA, PAOLO, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Assimes, TL, Thompson, JR, Goldstein, BA, König, IR, Cazier, JB, Hall, AS, Lee, JY, Willer, CJ, Chambers, JC, Havulinna, AS, Ho, WK, Hopewell, JC, Kleber, ME, Lyytikäinen, LP, Strawbridge, RJ, Voight, BF, Waite, LL, Balmforth, AJ, Braund, PS, Doney, ASF, El Mokhtari, NE, Han, BG, Hunt, SE, Kang, HM, Knowles, JW, Lokki, ML, McCarthy, MI, Morris, AD, Peden, JF, Rayner, NW, Rumpf, MP, Stewart, AFR, Tan, S. T, van der Schoot, CE, Wagner, PJ, Wells, GA, Wild, PS, Yang, T. P, Cupples, AL, Epstein, SE, Ferrario, MM, Go, AS, Goodall, AH, Hazen, SL, Kim, H. S, Lee, J. Y, Ouwehand, WH, Park, JE, Pedersen, NL, Rader, DJ, Shah, SH, Trégouët, D. A, Zimmermann, ME, Nieminen, MS, Sandhu, MS, Syvänen, A. C, Hovingh, GK, Franks, PW, Zalloua, PA, Blankenberg, SS, Boehm, BO, Reilly, MP, Kooner, JS, Palmer, CNA, Samani, NJ, and BRAMBILLA, PAOLO
- Abstract
Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways
- Published
- 2013
41. Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk
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Suchon, P., primary, Germain, M., additional, Delluc, A., additional, Smadja, D., additional, Jouven, X., additional, Gyorgy, B., additional, Saut, N., additional, Ibrahim, M., additional, Deleuze, J. F., additional, Alessi, M. C., additional, Morange, P. E., additional, and Trégouët, D. A., additional
- Published
- 2017
- Full Text
- View/download PDF
42. PDGFB, a new candidate plasma biomarker for venous thromboembolism : Results from the VEREMA affinity proteomics study
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Bruzelius, M., Iglesias, Maria Jesus, Hong, Mun-Gwan, Sanchez-Rivera, Laura, Gyorgy, B., Souto, J. C., Franberg, M., Fredolini, Claudia, Strawbridge, R. J., Holmström, M., Hamsten, A., Uhlén, Mathias, Silveira, A., Soria, J. M., Smadja, D. M., Butler, L. M., Schwenk, Jochen M., Morange, P. -E, Trégouët, D. -A, Odeberg, Jacob, Bruzelius, M., Iglesias, Maria Jesus, Hong, Mun-Gwan, Sanchez-Rivera, Laura, Gyorgy, B., Souto, J. C., Franberg, M., Fredolini, Claudia, Strawbridge, R. J., Holmström, M., Hamsten, A., Uhlén, Mathias, Silveira, A., Soria, J. M., Smadja, D. M., Butler, L. M., Schwenk, Jochen M., Morange, P. -E, Trégouët, D. -A, 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 (p ~ 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P 5 .002). PDGF 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., QC 20170523
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- 2016
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- View/download PDF
43. Multilocus genetic risk scores for venous thromboembolism risk assessment
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Soria J.M., Morange P.-E., Vila J., Souto J.C., Moyano M., Trégouët D.-A., Mateo J., Saut N., Salas E., and Elosua R.
- Subjects
Male ,genetic association ,clinical evaluation ,genotype ,multilocus sequence typing ,regression analysis ,single nucleotide polymorphism ,genetic variability ,middle aged ,odds ratio ,genetics ,gene mutation ,SERPINA10 gene ,comparative study ,predictive value ,adult ,Incidence ,risk assessment ,genetic screening ,blood clotting factor 5 ,aged ,female ,priority journal ,marker gene ,Thrombo inCode score ,venous thromboembolism ,prothrombin gene ,Article ,Humans ,controlled study ,Genetic Predisposition to Disease ,human ,procedures ,Genetic Testing ,Multilocu ,intermethod comparison ,prothrombin ,scoring system ,SERPINC1 gene ,Factor V ,Genetic Variation ,antithrombin III ,prediction ,case control study ,major clinical study ,blood clotting factor 5 Leiden ,Spain ,Case-Control Studies ,mutation ,FVL gene ,genetic predisposition - Abstract
Background-Genetics plays an important role in venous thromboembolism (VTE). Factor V Leiden (FVL or rs6025) and prothrombin gene G20210A (PT or rs1799963) are the genetic variants currently tested for VTE risk assessment. We hypothesized that primary VTE risk assessment can be improved by using genetic risk scores with more genetic markers than just FVL-rs6025 and prothrombin gene PT-rs1799963. To this end, we have designed a new genetic risk score called Thrombo inCode (TiC). Methods and Results-TiC was evaluated in terms of discrimination ( of the area under the receiver operating characteristic curve) and reclassification (integrated discrimination improvement and net reclassification improvement). This evaluation was performed using 2 age- and sex-matched case-control populations: SANTPAU (248 cases, 249 controls) and the Marseille Thrombosis Association study (MARTHA; 477 cases, 477 controls). TiC was compared with other literature-based genetic risk scores. TiC including F5 rs6025/rs118203906/rs118203905, F2 rs1799963, F12 rs1801020, F13 rs5985, SERPINC1 rs121909548, and SERPINA10 rs2232698 plus the A1 blood group (rs8176719, rs7853989, rs8176743, rs8176750) improved the area under the curve compared with a model based only on F5-rs6025 and F2-rs1799963 in SANTPAU (0.677 versus 0.575, P
- Published
- 2014
44. Identification de gènes candidats par séquençage d’exome dans l’obésité syndromique
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Huvenne, H., primary, Trégouët, D.-A., additional, Pelloux, V., additional, Alili, R., additional, Clément, K., additional, Poitou, C., additional, and Dubern, B., additional
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- 2016
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45. Genetic risk factors for venous thrombosis in women using combined oral contraceptives: update of the PILGRIM study
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Suchon, P., primary, Al Frouh, F., additional, Ibrahim, M., additional, Sarlon, G., additional, Venton, G., additional, Alessi, M.‐C., additional, Trégouët, D.‐A., additional, and Morange, P.‐E., additional
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- 2016
- Full Text
- View/download PDF
46. New genetic loci link adipose and insulin biology to body fat distribution
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Shungin, D, Winkler, T, Croteau Chonka, D, Ferreira, T, Locke, A, Mägi, R, Strawbridge, R, Pers, T, Fischer, K, Justice, A, Workalemahu, T, Wu, J, Buchkovich, M, Heard Costa, N, Roman, T, Drong, A, Song, C, Gustafsson, S, Day, F, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, J, Scherag, A, Vedantam, S, Wood, A, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg Gresham, J, Buyske, S, Demirkan, A, Ehret, G, Feitosa, M, Goel, A, Jackson, A, Johnson, T, Kleber, M, Kristiansson, K, Mangino, M, Leach, I, Medina Gomez, C, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Stanca'Kova', A, Sung, Y, Tanaka, T, Teumer, A, Van Vliet Ostaptchouk, J, Yengo, L, Zhang, W, Albrecht, E, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Böhringer, S, Bonnet, F, Böttcher, Y, Bruinenberg, M, Carba, D, Caspersen, I, Clarke, R, Daw, E, Deelen, J, Deelman, E, Delgado, G, Doney, A, Eklund, N, Erdos, M, Estrada, K, Eury, E, Friedrich, N, Garcia, M, Giedraitis, V, Gigante, B, Go, A, Golay, A, Grallert, H, Grammer, T, Gräsler, J, Grewal, J, Groves, C, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heikkilä, K, Herzig, K, Helmer, Q, Hillege, H, Holmen, O, Hunt, S, Isaacs, A, Ittermann, T, James, A, Johansson, I, Juliusdottir, T, Kalafati, I, Kinnunen, L, Koenig, W, Kooner, I, Kratzer, W, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Menni, C, Merger, S, Mihailov, E, Milani, L, Mills, R, Moayyeri, A, Monda, K, Mooijaart, S, Mühleisen, T, Mulas, A, Müller, G, Müller Nurasyid, M, Nagaraja, R, Nalls, M, Narisu, N, Glorioso, N, Nolte, I, Olden, M, Rayner, N, Renstrom, F, Ried, J, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Sennblad, B, Seufferlein, T, Sitlani, C, Smith, A, Stirrups, K, Stringham, H, Sundström, J, Swertz, M, Swift, A, Syvänen, A, Tayo, B, Thorand, B, Thorleifsson, G, Tomaschitz, A, Troffa, C, Van Oort, F, Verweij, N, Vonk, J, Waite, L, Wennauer, R, Wilsgaard, T, Wojczynski, M, Wong, A, Zhang, Q, Zhao, J, Brennan, E, Choi, M, Eriksson, P, Folkersen, L, Franco Cereceda, A, Gharavi, A, Hedman, A, Hivert, M, Huang, J, Kanoni, S, Karpe, F, Keildson, S, Kiryluk, K, Liang, L, Lifton, R, Ma, B, Mcknight, A, Mcpherson, R, Metspalu, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Olsson, C, Perry, J, Reinmaa, E, Salem, R, Sandholm, N, Schadt, E, Scott, R, Stolk, L, Vallejo, E, Westra, H, Zondervan, K, Amouyel, P, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Brown, M, Burnier, M, Campbell, H, Chakravarti, A, Chines, P, Claudi Boehm, S, Collins, F, Crawford, D, Danesh, J, De Faire, U, De Geus, E, Dörr, M, Erbel, R, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gieger, C, Gudnason, V, Haiman, C, Harris, T, Hattersley, A, Heliövaara, M, Hicks, A, Hingorani, A, Hoffmann, W, Hofman, A, Homuth, G, Humphries, S, Hyppönen, E, Illig, T, Jarvelin, M, Johansen, B, Jousilahti, P, Jula, A, Kaprio, J, Kee, F, Keinanen Kiukaanniemi, S, Kooner, J, Kooperberg, C, Kovacs, P, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lyssenko, V, Männistö, S, Marette, A, Matise, T, Mckenzie, C, Mcknight, B, Musk, A, Möhlenkamp, S, Morris, A, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Palmer, L, Penninx, B, Peters, A, Pramstaller, P, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ridker, P, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Shuldiner, A, Staessen, J, Steinthorsdottir, V, Stolk, R, Strauch, K, Tönjes, A, Tremblay, A, Tremoli, E, Vohl, M, Völker, U, Vollenweider, P, Wilson, J, Witteman, J, Adair, L, Bochud, M, Boehm, B, Bornstein, S, Bouchard, C, Cauchi, S, Caulfield, M, Chambers, J, Chasman, D, Cooper, R, Dedoussis, G, Ferrucci, L, Froguel, P, Grabe, H, Hamsten, A, Hui, J, Hveem, K, Jöckel, K, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, März, W, Munroe, P, Njolstad, I, Oostra, B, Pedersen, N, Perola, M, Pe'Russe, L, Peters, U, Power, C, Quertermous, T, Rauramaa, R, Rivadeneira, F, Saaristo, T, Saleheen, D, Sinisalo, J, Slagboom, P, Snieder, H, Spector, T, Thorsteinsdottir, U, Stumvoll, M, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Van Der Harst, P, Veronesi, G, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Abecasis, G, Assimes, T, Berndt, S, Boehnke, M, Borecki, I, Deloukas, P, Franke, L, Frayling, T, Groop, L, Hunter, D, Kaplan, R, O'Connell, J, Qi, L, Schlessinger, D, Strachan, D, Stefansson, K, Van Duijn, C, Willer, C, Visscher, P, Yang, J, Hirschhorn, J, Zillikens, M, Mccarthy, M, Speliotes, E, North, K, Fox, C, Barroso, I, Franks, P, Ingelsson, E, Heid, I, Loos, R, Cupples, L, Lindgren, C, Mohlke, K, Dastani, Z, Timpson, N, Yuan, X, Henneman, P, Kizer, J, Lyytikainen, L, Fuchsberger, C, Small, K, Coassin, S, Lohman, K, Pankow, J, Uh, H, Wu, Y, Bidulescu, A, Rasmussen Torvik, L, Greenwood, C, Ladouceur, M, Grimsby, J, Manning, A, Mooser, V, Kapur, K, Frants, R, Willemsvan vanDijk, K, Willems, S, Psaty, B, Tracy, R, Brody, J, Chen, I, Viikari, J, Kähönen, M, Evans, D, St Pourcain, B, Sattar, N, Carlson, O, Egan, J, van Heemst, D, Kedenko, L, Nuotio, M, Loo, B, Kanaya, A, Haun, M, Klopp, N, Katsareli, E, Couper, D, Duncan, B, Kloppenburg, M, Borja, J, Musani, S, Guo, X, Semple, R, Teslovich, T, Allison, M, Redline, S, Buxbaum, S, Meulenbelt, I, Ballantyne, C, Hu, F, Paulweber, B, Florez, J, Smith, G, Siscovick, D, Kronenberg, F, van Duijn, C, Waterworth, D, Meigs, J, Dupuis, J, Richards, J, Willenborg, C, Thompson, J, Erdmann, J, Goldstein, B, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Lundmark, P, Lyytikäinen, L, Rafelt, S, Tikkanen, E, Van Zuydam, N, Voight, B, Ziegler, A, Altshuler, D, Balmforth, A, Braund, P, 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- Abstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10-8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
- Published
- 2015
47. Genetically determined height and coronary artery disease
- Author
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Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, Van, D, Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, De, F, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Quertermous, T, Rader, D, Schadt, E, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Zimmermann, M, Sandhu, M, Pastinen, T, Syvänen, A, Nelson,CP, Hamby,SE, Saleheen,D, Hopewell,JC, Zeng,L, Assimes,TL, Kanoni,S, Willenborg,C, Burgess,S, Amouyel,P, Anand,S, Blankenberg,S, Boehm,BO, Clarke,RJ, Collins,R, Dedoussis,G, Farrall,M, Franks,PW, Groop,L, Hall,AS, Hamsten,A, Hengstenberg,C, Hovingh,GK, Ingelsson,E, Kathiresan,S, Kee,F, König,IR, Kooner,J, Lehtimäki,T, März,W, McPherson,R, Metspalu,A, Nieminen,MS, O'Donnell,CJ, Palmer,CN, Peters,A, Perola,M, Reilly,MP, Ripatti,S, Roberts,R, Salomaa,V, Shah,SH, Schreiber,S, Siegbahn,A, Thorsteinsdottir,U, Veronesi,G, Wareham,N, Willer,CJ, Zalloua,PA, Erdmann,J, Deloukas,P, Watkins,H, Schunkert,H, Danesh,J, Thompson,JR, Samani,NJ, Assimes,T, Goldstein,BA, Stirrups,K, Cazier,JB, Johansson,Å, Lee,JY, Chambers,JC, Esko,T, Folkersen,L, Goel,A, Grundberg,E, Havulinna,AS, Ho,WK, Eriksson,N, Kleber,ME, Kristiansson,K, Lundmark,P, Lyytikäinen,LP, Rafelt,S, Shungin,D, Strawbridge,RJ, Thorleifsson,G, Tikkanen,E, Van, Zuydam, Voight,BF, Waite,LL, Zhang,W, Ziegler,A, Absher,D, Altshuler,D, Balmforth,AJ, Barroso,I, Braund,PS, Burgdorf,C, Claudi Boehm,S, Cox,D, Dimitriou,M, Do,R, Doney,AS, El, Mokhtari, Eriksson,P, Fischer,K, Fontanillas,P, Franco Cereceda,A, Gigante,B, Gustafsson,S, Hager,J, Hallmans,G, Han,BG, Hunt,SE, Kang,HM, Illig,T, Kessler,T, Knowles,JW, Kolovou,G, Kuusisto,J, Langenberg,C, Langford,C, Leander,K, Lokki,ML, Lundmark,A, McCarthy,MI, Meisinger,C, Melander,O, Mihailov,E, Maouche,S, Morris,AD, Müller Nurasyid,M, Nikus,K, Peden,JF, Rayner,NW, Rasheed,A, Rosinger,S, Rubin,D, Rumpf,MP, Schäfer,A, Sivananthan,M, Song,C, Stewart,AF, Tan,ST, Thorgeirsson,G, van, der, Schoot, CE, Wagner,PJ, Wells,GA, Wild,PS, Yang,TP, Arveiler,D, Basart,H, Boehnke,M, Boerwinkle,E, BRAMBILLA, PAOLO, Cambien,F, Cupples,AL, de, Faire, Dehghan,A, Diemert,P, Epstein,SE, Evans,A, Ferrario,MM, Ferrières,J, Gauguier,D, Go,AS, Goodall,AH, Gudnason,V, Hazen,SL, Holm,H, Iribarren,C, Jang,Y, Kähönen,M, Kim,HS, Klopp,N, Koenig,W, Kratzer,W, Kuulasmaa,K, Laakso,M, Laaksonen,R, Lind,L, Ouwehand,WH, Parish,S, Park,JE, Pedersen,NL, Quertermous,T, Rader,DJ, Schadt,E, Sinisalo,J, Stark,K, Stefansson,K, Trégouët,DA, Virtamo,J, Wallentin,L, Zimmermann,ME, Sandhu,MS, Pastinen,T, Syvänen,AC, Blankenberg,SS, Clarke,R, O'Donnell,C, and Kooner,JS
- Abstract
BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.)
- Published
- 2015
48. High-throughput sequencing and better understanding of aetiological spectrum of Hypertrophic cardiomyopathy
- Author
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Mallet, S., Roux, M., Ader, F., Donal, E., Degroote, P., Faivre, L., Réant, P., Babuty, D., Mansencal, N., N’guyen, K., David, A., Grotto, S., Isnard, R., Tregouet, D., Richard, P., and Charron, P.
- Published
- 2018
- Full Text
- View/download PDF
49. Lack of association of non‐synonymous FUT2 and ALPL polymorphisms with venous thrombosis
- Author
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TREGOUET, D.‐A., SABATER‐LLEAL, M., BRUZELIUS, M., EMMERICH, J., AMOUYEL, P., DARTIGUES, J.‐F., KIELER, H., and MORANGE, P.‐E.
- Published
- 2012
- Full Text
- View/download PDF
50. Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome
- Author
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Duchatelet, S, Crotti, L, Peat, R, Denjoy, I, Itoh, H, Berthet, M, Ohno, S, Fressart, V, Monti, M, Crocamo, C, Pedrazzini, M, Dagradi, F, Vicentini, A, Klug, D, Brink, P, Goosen, A, Swan, H, Toivonen, L, Lahtinen, A, Kontula, K, Shimizu, W, Horie, M, George, A, Trégouët, D, Guicheney, P, Schwartz, P, Monti, MC, George, AL, Trégouët, DA, Schwartz, PJ., Duchatelet, S, Crotti, L, Peat, R, Denjoy, I, Itoh, H, Berthet, M, Ohno, S, Fressart, V, Monti, M, Crocamo, C, Pedrazzini, M, Dagradi, F, Vicentini, A, Klug, D, Brink, P, Goosen, A, Swan, H, Toivonen, L, Lahtinen, A, Kontula, K, Shimizu, W, Horie, M, George, A, Trégouët, D, Guicheney, P, Schwartz, P, Monti, MC, George, AL, Trégouët, DA, and Schwartz, PJ.
- Abstract
Background-Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS. Methods and Results-In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a metaanalysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts. Conclusions-We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS. © 2013 American Heart Association, Inc
- Published
- 2013
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