Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting
Pradeep Natarajan,Robin Young,Nathan O. Stitziel,Sandosh Padmanabhan,Usman Baber,Roxana Mehran,Samantha Sartori,Valentin Fuster,Dermot F. Reilly,Adam S. Butterworth,Daniel J. Rader,Ian Ford,Naveed Sattar,Sekar Kathiresan +13 more
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TLDR
Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event.Abstract:
Background —Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of two randomized controlled primary prevention trials (ASCOT and JUPITER), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we sought to confirm this observation in a third primary prevention randomized controlled trial. Additionally, we assessed if those at high genetic risk had a greater burden of subclinical coronary atherosclerosis.
Methods —We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS, n=4,910) and two observational cohort studies (CARDIA and BioImage, n=1,154 and 4,392). For each participant, we calculated a polygenic risk score (PRS) derived from up to 57 common DNA sequence variants previously associated with coronary heart disease (CHD). We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of PRS) versus all others (WOSCOP)S as well as the association between the PRS and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage).
Results —Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% CI, 22%-60%; P < 0.001) whereas in all others, relative risk reduction was 24% (95% CI 8%-37%; P = 0.004) despite similar LDL cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others ( P for heterogeneity = 0.05). Across all three studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0%-5.1%) among those in the high genetic risk group and was 1.3% (95% CI, 0.6%-1.9%) in all others. Each standard deviation increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8%) burden of carotid plaque.
Conclusions —Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first CHD event.
Clinical Trial Registration —BioImage: [NCT00738725][1] www.clinicaltrials.gov, CARDIA: [NCT00005130][2] clinicaltrials.gov
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00738725&atom=%2Fcirculationaha%2Fearly%2F2017%2F02%2F20%2FCIRCULATIONAHA.116.024436.atom
[2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00005130&atom=%2Fcirculationaha%2Fearly%2F2017%2F02%2F20%2FCIRCULATIONAHA.116.024436.atomread more
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Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations
Amit Khera,Mark Chaffin,Krishna G. Aragam,Mary E. Haas,Carolina Roselli,Seung Hoan Choi,Pradeep Natarajan,Eric S. Lander,Steven A. Lubitz,Steven A. Lubitz,Patrick T. Ellinor,Patrick T. Ellinor,Sekar Kathiresan +12 more
TL;DR: Genome-wide polygenic risk scores derived from GWAS data for five common diseases can identify subgroups of the population with risk approaching or exceeding that of a monogenic mutation.
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Clinical use of current polygenic risk scores may exacerbate health disparities.
Alicia R. Martin,Masahiro Kanai,Yoichiro Kamatani,Yukinori Okada,Benjamin M. Neale,Benjamin M. Neale,Mark J. Daly +6 more
TL;DR: To realize the full and equitable potential of polygenic risk scores, greater diversity must be prioritized in genetic studies, and summary statistics must be publically disseminated to ensure that health disparities are not increased for those individuals already most underserved.
Journal ArticleDOI
The personal and clinical utility of polygenic risk scores.
TL;DR: The authors review recent studies that have demonstrated the utility of polygenic risk scores for disease risk stratification and their potential impact on early disease detection, prevention, therapeutic intervention and life planning.
Journal ArticleDOI
Benefits and limitations of genome-wide association studies.
Vivian W.Y. Tam,Nikunj Patel,Michelle Turcotte,Yohan Bossé,Guillaume Paré,David Meyre,David Meyre +6 more
TL;DR: This Review comprehensively assess the benefits and limitations of GWAS in human populations and discusses the relevance of performing more GWAS, with a focus on the cardiometabolic field.
Journal ArticleDOI
PRSice-2: Polygenic Risk Score software for biobank-scale data.
TL;DR: PRSice-2 is introduced, an efficient and scalable software program for automating and simplifying PRS analyses on large-scale data, and its combination of efficiency and power will be increasingly important as data sizes grow and as the applications of PRS become more sophisticated, e.g., when incorporated into high-dimensional or gene set–based analyses.
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Szatkiewicz,Erik Sderman,Srinivas Thirumalai,Draga Toncheva,Paul A. Tooney,Sarah Tosato,Juha Veijola,John L. Waddington,Dermot Walsh,Dai Wang,Qiang Wang,Bradley T. Webb,Mark Weiser,Dieter B. Wildenauer,Nigel Williams,Stephanie Williams,Stephanie H. Witt,Aaron R. Wolen,Emily H. M. Wong,Brandon Wormley,Jing Qin Wu,Hualin Simon Xi,Clement C. Zai,Xuebin Zheng,Fritz Zimprich,Naomi R. Wray,Kari Stefansson,Peter M. Visscher,Rolf Adolfsson,Ole A. Andreassen,Douglas Blackwood,Elvira Bramon,Joseph D. Buxbaum,Anders D. Børglum,Sven Cichon,Ariel Darvasi,Enrico Domenici,Hannelore Ehrenreich,Tõnu Esko,Pablo V. Gejman,Michael Gill,Hugh Gurling,Christina M. Hultman,Nakao Iwata,Assen Jablensky,Erik G. Jönsson,Kenneth S. Kendler,George Kirov,Jo Knight,Todd Lencz,Douglas F. Levinson,Qingqin S. Li,Jianjun Liu,Anil K. Malhotra,Steven A. McCarroll,Andrew McQuillin,Jennifer L. Moran,Bryan J. Mowry,Markus M. Nthen,Roel A. Ophoff,Michael John Owen,A. Palotie,Carlos N. Pato,Tracey L. Petryshen,Danielle Posthuma,Marcella Rietschel,Brien P. Riley,Dan Rujescu,Pak C. Sham,Pamela Sklar,David St Clair,Daniel R. Weinberger,Jens R. Wendland,Thomas Werge,Mark J. Daly,Patrick F. Sullivan,Michael Conlon O'Donovan,Peter Kraft,David J. Hunter,Muriel A. Adank,Habibul Ahsan,Kristiina Aittomäki,Laura Baglietto,Sonja I. Berndt,Carl Blomquist,Federico Canzian,Jenny Chang-Claude,Stephen J. Chanock,Laura Crisponi,Kamila Czene,Norbert Dahmen,Isabel dos Santos Silva,Douglas F. Easton,A. Heather Eliassen,Jonine D. Figueroa,Olivia Fletcher,Montserrat Garcia-Closas,Mia M. Gaudet,Lorna Gibson,Christopher A. Haiman,Per Hall,Aditi Hazra,Rebecca Hein,Brian E. Henderson,Albert Hofman,John L. Hopper,Astrid Irwanto,Mattias Johansson,Rudolf Kaaks,Muhammad G. Kibriya,Peter Lichtner,Eiliv Lund,Enes Makalic,Alfons Meindl,Hanne Meijers-Heijboer,Bertram Müller-Myhsok,Taru A. Muranen,Heli Nevanlinna,Petra H.M. Peeters,Julian Peto,Ross L. Prentice,Nazneen Rahman,María José Sánchez,Daniel F. Schmidt,Rita K. Schmutzler,Melissa C. Southey,Rulla M. Tamimi,Ruth C. Travis,Clare Turnbull,André G. Uitterlinden,Rob B. van der Luijt,Quinten Waisfisz,Zhaoming Wang,Alice S. Whittemore,Rose Yang,Wei Zheng,Wei Zheng,Sekar Kathiresan,Michele T. Pato,Carlos N. Pato,E Stahl,Noah Zaitlen,Bogdan Pasaniuc,Gillian M. Belbin,Eimear E. Kenny,Mikkel H. Schierup,Phillip L. De Jager,Nikolaos A. Patsopoulos,Steve McCarroll,Mark J. Daly,Shaun M. Purcell,Daniel I. Chasman,Benjamin M. Neale,Michael E. Goddard,Nick Patterson,Alkes L. Price +394 more
A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease
Majid Nikpay,Anuj Goel,Won H-H.,Leanne M. Hall,Christina Willenborg,Stavroula Kanoni,Danish Saleheen,Theodosios Kyriakou,Christopher P. Nelson,Christopher P. Nelson,Jemma C. Hopewell,Tom R. Webb,Tom R. Webb,Lingyao Zeng,Abbas Dehghan,Maris Alver,Sebastian M. Armasu,Kirsi Auro,Kirsi Auro,Andrew Bjonnes,Daniel I. Chasman,Shufeng Chen,Ian Ford,Nora Franceschini,Christian Gieger,Christopher Grace,Stefan Gustafsson,Jie Huang,Hwang S-J.,Yun Kyoung Kim,Marcus E. Kleber,King Wai Lau,Xiangfeng Lu,Yingchang Lu,Lyytikäinen L-P.,Evelin Mihailov,Alanna C. Morrison,Natalia Pervjakova,Natalia Pervjakova,Natalia Pervjakova,Liming Qu,Lynda M. Rose,Elias Salfati,Richa Saxena,Markus Scholz,Albert V. Smith,Emmi Tikkanen,André G. Uitterlinden,Xueli Yang,Weihua Zhang,Wei Zhao,M. De Andrade,P. De Vries,N. R. van Zuydam,N. R. van Zuydam,Sonia S. Anand,Lars Bertram,Frank Beutner,George Dedoussis,Philippe M. Frossard,Dominique Gauguier,Alison H. Goodall,Omri Gottesman,Marc Haber,Han B-G.,Shapour Jalilzadeh,Thorsten Kessler,Inke R. König,Lars Lannfelt,Wolfgang Lieb,Lars Lind,Cecilia M. Lindgren,Lokki M-L.,Lokki M-L.,Patrik K. E. Magnusson,Nadeem Hayyat Mallick,Narinder K. Mehra,Thomas Meitinger,Memon F-U-R.,Andrew P. Morris,Andrew P. Morris,Markku S. Nieminen,Nancy L. Pedersen,Annette Peters,Loukianos S. Rallidis,Adil Rasheed,M Samuel,Svati H. Shah,Juha Sinisalo,Kathleen Stirrups,Stella Trompet,Ligui Wang,Ligui Wang,Khan Shah Zaman,Diego Ardissino,Eric Boerwinkle,Ingrid B. Borecki,Erwin P. Bottinger,Julie E. Buring,John C. Chambers,Rory Collins,L. A. Cupples,L. A. Cupples,John Danesh,Ilja Demuth,Roberto Elosua,Stephen E. Epstein,Tõnu Esko,Mary F. Feitosa,Oscar H. Franco,MariaGrazia Franzosi,Christopher B. Granger,Dongfeng Gu,Vilmundur Gudnason,Alistair S. Hall,Anders Hamsten,Tamara B. Harris,Stanley L. Hazen,Christian Hengstenberg,Albert Hofman,Erik Ingelsson,Carlos Iribarren,J W Jukema,Pekka J. Karhunen,Kim B-J.,Jaspal S. Kooner,Iftikhar J. Kullo,Terho Lehtimäki,Loos Rjf.,Olle Melander,Andres Metspalu,Winfried März,Winfried März,Winfried März,Colin N. A. Palmer,Markus Perola,Markus Perola,Markus Perola,Thomas Quertermous,Daniel J. Rader,Paul M. Ridker,Samuli Ripatti,Samuli Ripatti,Robert Roberts,Veikko Salomaa,Dharambir K. Sanghera,Stephen M. Schwartz,Udo Seedorf,Alexandre F.R. Stewart,David J. Stott,Joachim Thiery,Pierre Zalloua,Christopher J. O'Donnell,Christopher J. O'Donnell,Muredach P. Reilly,Themistocles L. Assimes,John R. Thompson,Jeanette Erdmann,Robert Clarke,Hugh Watkins,Sekar Kathiresan,Ruth McPherson,Panos Deloukas,Panos Deloukas,Heribert Schunkert,Nilesh J. Samani,Nilesh J. Samani,Martin Farrall +167 more
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Adam Auton,Gonçalo R. Abecasis,David Altshuler,Richard Durbin,David R. Bentley,Aravinda Chakravarti,Andrew G. Clark,Peter Donnelly,Evan E. Eichler,Paul Flicek,Stacey Gabriel,Richard A. Gibbs,Eric D. Green,Matthew E. Hurles,Bartha Maria Knoppers,Jan O. Korbel,Eric S. Lander,Charles Lee,Hans Lehrach,Elaine R. Mardis,Gabor T. Marth,Gil McVean,Deborah A. Nickerson,Jeanette Schmidt,Stephen T. Sherry,Jun Wang,Richard K. Wilson,Eric Boerwinkle,Harsha Doddapaneni,Yi Han,Viktoriya Korchina,Christie Kovar,Sandra L. Lee,Donna M. Muzny,Jeffrey G. Reid,Yiming Zhu,Yuqi Chang,Qiang Feng,Qiang Feng,Xiaodong Fang,Xiaodong Fang,Xiaosen Guo,Xiaosen Guo,Min Jian,Min Jian,Hui Jiang,Hui Jiang,Xin Jin,Tianming Lan,Guoqing Li,Jingxiang Li,Yingrui Li,Shengmao Liu,Xiao Liu,Xiao Liu,Yao Lu,Xuedi Ma,Meifang Tang,Bo Wang,Guangbiao Wang,Honglong Wu,Renhua Wu,Xun Xu,Ye Yin,Dandan Zhang,Wenwei Zhang,Jiao Zhao,Meiru Zhao,Xiaole Zheng,Namrata Gupta,Neda Gharani,Lorraine Toji,Norman P. Gerry,Alissa M. 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Sabeti,Pardis C. Sabeti,Ilya Shlyakhter,Ilya Shlyakhter,Stephen F. Schaffner,Stephen F. Schaffner,Joseph J. Vitti,Joseph J. Vitti,David Neil Cooper,Edward V. Ball,Peter D. Stenson,Bret Barnes,Markus J. Bauer,R. Keira Cheetham,Anthony J. Cox,Michael A. Eberle,Scott Kahn,Lisa Murray,John F. Peden,Richard Shaw,Eimear E. Kenny,Mark A. Batzer,Miriam K. Konkel,Jerilyn A. Walker,Daniel G. MacArthur,Monkol Lek,Ralf Herwig,Li Ding,Daniel C. Koboldt,David E. Larson,Kai Ye,Simon Gravel,Anand Swaroop,Emily Y. Chew,Tuuli Lappalainen,Yaniv Erlich,Melissa Gymrek,Melissa Gymrek,Thomas Willems,Jared T. Simpson,Mark D. Shriver,Jeffrey A. Rosenfeld,Carlos Bustamante,Stephen B. Montgomery,Francisco M. De La Vega,Jake K. Byrnes,Andrew Carroll,Marianne K. DeGorter,Phil Lacroute,Brian K. Maples,Alicia R. Martin,Andrés Moreno-Estrada,Andrés Moreno-Estrada,Suyash Shringarpure,Fouad Zakharia,Eran Halperin,Eran Halperin,Yael Baran,Eliza Cerveira,Jaeho Hwang,Ankit Malhotra,Dariusz Plewczynski,Kamen Radew,Mallory Romanovitch,Chengsheng Zhang,Fiona Hyland,David Craig,Alexis Christoforides,Nils Homer,Tyler Izatt,Ahmet Kurdoglu,Shripad Sinari,Kevin Squire,Chunlin Xiao,Jonathan Sebat,Danny Antaki,Madhusudan Gujral,Amina Noor,Kenny Ye,Esteban G. Burchard,Ryan D. Hernandez,Christopher R. Gignoux,David Haussler,David Haussler,Sol Katzman,W. James Kent,Bryan Howie,Andres Ruiz-Linares,Emmanouil T. Dermitzakis,Emmanouil T. Dermitzakis,Scott E. Devine,Hyun Min Kang,Jeffrey M. Kidd,Thomas W. Blackwell,Sean Caron,Wei Chen,S. Emery,Lars G. Fritsche,Christian Fuchsberger,Goo Jun,Goo Jun,Bingshan Li,Robert H. Lyons,Chris Scheller,Carlo Sidore,Carlo Sidore,Carlo Sidore,Shiya Song,Elzbieta Sliwerska,Daniel Taliun,Adrian Tan,Ryan P. 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Henn,Danielle Jones,Jane Kaye,Alastair Kent,Angeliki Kerasidou,Rasika A. Mathias,Pilar N. Ossorio,Michael Parker,Charles N. Rotimi,Charmaine D.M. Royal,Karla Sandoval,Yeyang Su,Zhongming Tian,Sarah A. Tishkoff,Marc Via,Yuhong Wang,Huanming Yang,Ling Yang,Jiayong Zhu,Walter F. Bodmer,Gabriel Bedoya,Zhiming Cai,Yang Gao,Jiayou Chu,Leena Peltonen,Andrés C. García-Montero,Alberto Orfao,Julie Dutil,Juan Carlos Martínez-Cruzado,R. Mathias,Anselm Hennis,Harold Watson,Colin A. McKenzie,Firdausi Qadri,Regina C. LaRocque,Xiaoyan Deng,Danny Asogun,Onikepe A. Folarin,Christian T. Happi,Omonwunmi Omoniwa,Matt Stremlau,Matt Stremlau,Ridhi Tariyal,Ridhi Tariyal,M Jallow,M Jallow,Fatoumatta Sisay Joof,Fatoumatta Sisay Joof,Tumani Corrah,Tumani Corrah,Kirk A. Rockett,Kirk A. Rockett,Dominic P. Kwiatkowski,Dominic P. Kwiatkowski,Jaspal S. Kooner,Tran Tinh Hien,Sarah J. Dunstan,Sarah J. Dunstan,Nguyen ThuyHang,Richard Fonnie,Robert F. Garry,Lansana Kanneh,Lina M. Moses,John S. Schieffelin,Donald S. Grant,Carla Gallo,Giovanni Poletti,Danish Saleheen,Asif Rasheed,Lisa D. Brooks,Adam Felsenfeld,Jean E. McEwen,Yekaterina Vaydylevich,Audrey Duncanson,Michael Dunn,Jeffery A. Schloss +517 more