BACKGROUND: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. METHODS: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. RESULTS: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc score of 3. CONCLUSIONS: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores.
BACKGROUND: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. METHODS: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. RESULTS: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc score of 3. CONCLUSIONS: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores.
Authors: Benjamin M Scirica; Deepak L Bhatt; Eugene Braunwald; P Gabriel Steg; Jaime Davidson; Boaz Hirshberg; Peter Ohman; Robert Frederich; Stephen D Wiviott; Elaine B Hoffman; Matthew A Cavender; Jacob A Udell; Nihar R Desai; Ofri Mosenzon; Darren K McGuire; Kausik K Ray; Lawrence A Leiter; Itamar Raz Journal: N Engl J Med Date: 2013-09-02 Impact factor: 91.245
Authors: Nicholas A Marston; Frederick K Kamanu; Francesco Nordio; Yared Gurmu; Carolina Roselli; Peter S Sever; Terje R Pedersen; Anthony C Keech; Huei Wang; Armando Lira Pineda; Robert P Giugliano; Steven A Lubitz; Patrick T Ellinor; Marc S Sabatine; Christian T Ruff Journal: Circulation Date: 2019-11-11 Impact factor: 29.690
Authors: Sayantan Das; Lukas Forer; Sebastian Schönherr; Carlo Sidore; Adam E Locke; Alan Kwong; Scott I Vrieze; Emily Y Chew; Shawn Levy; Matt McGue; David Schlessinger; Dwight Stambolian; Po-Ru Loh; William G Iacono; Anand Swaroop; Laura J Scott; Francesco Cucca; Florian Kronenberg; Michael Boehnke; Gonçalo R Abecasis; Christian Fuchsberger Journal: Nat Genet Date: 2016-08-29 Impact factor: 38.330
Authors: Rainer Malik; Ganesh Chauhan; Matthew Traylor; Muralidharan Sargurupremraj; Yukinori Okada; Kari Stefansson; Bradford B Worrall; Steven J Kittner; Sudha Seshadri; Myriam Fornage; Hugh S Markus; Joanna M M Howson; Yoichiro Kamatani; Stephanie Debette; Martin Dichgans; Aniket Mishra; Loes Rutten-Jacobs; Anne-Katrin Giese; Sander W van der Laan; Solveig Gretarsdottir; Christopher D Anderson; Michael Chong; Hieab H H Adams; Tetsuro Ago; Peter Almgren; Philippe Amouyel; Hakan Ay; Traci M Bartz; Oscar R Benavente; Steve Bevan; Giorgio B Boncoraglio; Robert D Brown; Adam S Butterworth; Caty Carrera; Cara L Carty; Daniel I Chasman; Wei-Min Chen; John W Cole; Adolfo Correa; Ioana Cotlarciuc; Carlos Cruchaga; John Danesh; Paul I W de Bakker; Anita L DeStefano; Marcel den Hoed; Qing Duan; Stefan T Engelter; Guido J Falcone; Rebecca F Gottesman; Raji P Grewal; Vilmundur Gudnason; Stefan Gustafsson; Jeffrey Haessler; Tamara B Harris; Ahamad Hassan; Aki S Havulinna; Susan R Heckbert; Elizabeth G Holliday; George Howard; Fang-Chi Hsu; Hyacinth I Hyacinth; M Arfan Ikram; Erik Ingelsson; Marguerite R Irvin; Xueqiu Jian; Jordi Jiménez-Conde; Julie A Johnson; J Wouter Jukema; Masahiro Kanai; Keith L Keene; Brett M Kissela; Dawn O Kleindorfer; Charles Kooperberg; Michiaki Kubo; Leslie A Lange; Carl D Langefeld; Claudia Langenberg; Lenore J Launer; Jin-Moo Lee; Robin Lemmens; Didier Leys; Cathryn M Lewis; Wei-Yu Lin; Arne G Lindgren; Erik Lorentzen; Patrik K Magnusson; Jane Maguire; Ani Manichaikul; Patrick F McArdle; James F Meschia; Braxton D Mitchell; Thomas H Mosley; Michael A Nalls; Toshiharu Ninomiya; Martin J O'Donnell; Bruce M Psaty; Sara L Pulit; Kristiina Rannikmäe; Alexander P Reiner; Kathryn M Rexrode; Kenneth Rice; Stephen S Rich; Paul M Ridker; Natalia S Rost; Peter M Rothwell; Jerome I Rotter; Tatjana Rundek; Ralph L Sacco; Saori Sakaue; Michele M Sale; Veikko Salomaa; Bishwa R Sapkota; Reinhold Schmidt; Carsten O Schmidt; Ulf Schminke; Pankaj Sharma; Agnieszka Slowik; Cathie L M Sudlow; Christian Tanislav; Turgut Tatlisumak; Kent D Taylor; Vincent N S Thijs; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Steffen Tiedt; Stella Trompet; Christophe Tzourio; Cornelia M van Duijn; Matthew Walters; Nicholas J Wareham; Sylvia Wassertheil-Smoller; James G Wilson; Kerri L Wiggins; Qiong Yang; Salim Yusuf; Joshua C Bis; Tomi Pastinen; Arno Ruusalepp; Eric E Schadt; Simon Koplev; Johan L M Björkegren; Veronica Codoni; Mete Civelek; Nicholas L Smith; David A Trégouët; Ingrid E Christophersen; Carolina Roselli; Steven A Lubitz; Patrick T Ellinor; E Shyong Tai; Jaspal S Kooner; Norihiro Kato; Jiang He; Pim van der Harst; Paul Elliott; John C Chambers; Fumihiko Takeuchi; Andrew D Johnson; Dharambir K Sanghera; Olle Melander; Christina Jern; Daniel Strbian; Israel Fernandez-Cadenas; W T Longstreth; Arndt Rolfs; Jun Hata; Daniel Woo; Jonathan Rosand; Guillaume Pare; Jemma C Hopewell; Danish Saleheen Journal: Nat Genet Date: 2018-03-12 Impact factor: 38.330
Authors: Christopher C Chang; Carson C Chow; Laurent Cam Tellier; Shashaank Vattikuti; Shaun M Purcell; James J Lee Journal: Gigascience Date: 2015-02-25 Impact factor: 6.524
Authors: Adam Auton; Lisa D Brooks; Richard M Durbin; Erik P Garrison; Hyun Min Kang; Jan O Korbel; Jonathan L Marchini; Shane McCarthy; Gil A McVean; Gonçalo R Abecasis Journal: Nature Date: 2015-10-01 Impact factor: 49.962
Authors: Hayato Tada; Dov Shiffman; Sekar Kathiresan; Olle Melander; J Gustav Smith; Marketa Sjögren; Steven A Lubitz; Patrick T Ellinor; Judy Z Louie; Joseph J Catanese; Gunnar Engström; James J Devlin Journal: Stroke Date: 2014-08-14 Impact factor: 7.914
Authors: Loes Ca Rutten-Jacobs; Susanna C Larsson; Rainer Malik; Kristiina Rannikmäe; Cathie L Sudlow; Martin Dichgans; Hugh S Markus; Matthew Traylor Journal: BMJ Date: 2018-10-24
Authors: Aniket Mishra; Rainer Malik; Tsuyoshi Hachiya; Tuuli Jürgenson; Shinichi Namba; Daniel C Posner; Frederick K Kamanu; Masaru Koido; Quentin Le Grand; Mingyang Shi; Yunye He; Marios K Georgakis; Ilana Caro; Kristi Krebs; Yi-Ching Liaw; Felix C Vaura; Kuang Lin; Bendik Slagsvold Winsvold; Vinodh Srinivasasainagendra; Livia Parodi; Hee-Joon Bae; Ganesh Chauhan; Michael R Chong; Liisa Tomppo; Rufus Akinyemi; Gennady V Roshchupkin; Naomi Habib; Yon Ho Jee; Jesper Qvist Thomassen; Vida Abedi; Jara Cárcel-Márquez; Marianne Nygaard; Hampton L Leonard; Chaojie Yang; Ekaterina Yonova-Doing; Maria J Knol; Adam J Lewis; Renae L Judy; Tetsuro Ago; Philippe Amouyel; Nicole D Armstrong; Mark K Bakker; Traci M Bartz; David A Bennett; Joshua C Bis; Constance Bordes; Sigrid Børte; Anael Cain; Paul M Ridker; Kelly Cho; Zhengming Chen; Carlos Cruchaga; John W Cole; Phil L de Jager; Rafael de Cid; Matthias Endres; Leslie E Ferreira; Mirjam I Geerlings; Natalie C Gasca; Vilmundur Gudnason; Jun Hata; Jing He; Alicia K Heath; Yuk-Lam Ho; Aki S Havulinna; Jemma C Hopewell; Hyacinth I Hyacinth; Michael Inouye; Mina A Jacob; Christina E Jeon; Christina Jern; Masahiro Kamouchi; Keith L Keene; Takanari Kitazono; Steven J Kittner; Takahiro Konuma; Amit Kumar; Paul Lacaze; Lenore J Launer; Keon-Joo Lee; Kaido Lepik; Jiang Li; Liming Li; Ani Manichaikul; Hugh S Markus; Nicholas A Marston; Thomas Meitinger; Braxton D Mitchell; Felipe A Montellano; Takayuki Morisaki; Thomas H Mosley; Mike A Nalls; Børge G Nordestgaard; Martin J O'Donnell; Yukinori Okada; N Charlotte Onland-Moret; Bruce Ovbiagele; Annette Peters; Bruce M Psaty; Stephen S Rich; Jonathan Rosand; Marc S Sabatine; Ralph L Sacco; Danish Saleheen; Else Charlotte Sandset; Veikko Salomaa; Muralidharan Sargurupremraj; Makoto Sasaki; Claudia L Satizabal; Carsten O Schmidt; Atsushi Shimizu; Nicholas L Smith; Kelly L Sloane; Yoichi Sutoh; Yan V Sun; Kozo Tanno; Steffen Tiedt; Turgut Tatlisumak; Nuria P Torres-Aguila; Hemant K Tiwari; David-Alexandre Trégouët; Stella Trompet; Anil Man Tuladhar; Anne Tybjærg-Hansen; Marion van Vugt; Riina Vibo; Shefali S Verma; Kerri L Wiggins; Patrik Wennberg; Daniel Woo; Peter W F Wilson; Huichun Xu; Qiong Yang; Kyungheon Yoon; Iona Y Millwood; Christian Gieger; Toshiharu Ninomiya; Hans J Grabe; J Wouter Jukema; Ina L Rissanen; Daniel Strbian; Young Jin Kim; Pei-Hsin Chen; Ernst Mayerhofer; Joanna M M Howson; Marguerite R Irvin; Hieab Adams; Sylvia Wassertheil-Smoller; Kaare Christensen; Mohammad A Ikram; Tatjana Rundek; Bradford B Worrall; G Mark Lathrop; Moeen Riaz; Eleanor M Simonsick; Janika Kõrv; Paulo H C França; Ramin Zand; Kameshwar Prasad; Ruth Frikke-Schmidt; Frank-Erik de Leeuw; Thomas Liman; Karl Georg Haeusler; Ynte M Ruigrok; Peter Ulrich Heuschmann; W T Longstreth; Keum Ji Jung; Lisa Bastarache; Guillaume Paré; Scott M Damrauer; Daniel I Chasman; Jerome I Rotter; Christopher D Anderson; John-Anker Zwart; Teemu J Niiranen; Myriam Fornage; Yung-Po Liaw; Sudha Seshadri; Israel Fernández-Cadenas; Robin G Walters; Christian T Ruff; Mayowa O Owolabi; Jennifer E Huffman; Lili Milani; Yoichiro Kamatani; Martin Dichgans; Stephanie Debette Journal: Nature Date: 2022-09-30 Impact factor: 69.504
Authors: Shinwan Kany; Bruno Reissmann; Andreas Metzner; Paulus Kirchhof; Dawood Darbar; Renate B Schnabel Journal: Cardiovasc Res Date: 2021-06-16 Impact factor: 10.787
Authors: Aleksandra Ekkert; Aleksandra Šliachtenko; Julija Grigaitė; Birutė Burnytė; Algirdas Utkus; Dalius Jatužis Journal: Genes (Basel) Date: 2021-12-24 Impact factor: 4.096