Ioanna Ntalla1, Stavroula Kanoni1, Lingyao Zeng2, Olga Giannakopoulou1, John Danesh3, Hugh Watkins4, Nilesh J Samani5, Panos Deloukas6, Heribert Schunkert7. 1. Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary University of London, London, United Kingdom; Centre for Genomic Health, Queen Mary University of London, London, United Kingdom. 2. Deutsches Herzzentrum München, Klinik für Herz und Kreislauferkrankungen, Technische Universität München, Munich, Germany. 3. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom. 4. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. 5. Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Cardiovascular Biomedical Research Centre, Leicester, United Kingdom. 6. Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, Queen Mary University of London, London, United Kingdom; Centre for Genomic Health, Queen Mary University of London, London, United Kingdom; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: p.deloukas@qmul.ac.uk. 7. Deutsches Herzzentrum München, Klinik für Herz und Kreislauferkrankungen, Technische Universität München, Munich, Germany; Deutsches Zentrum für Herz und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Abstract
BACKGROUND: The taxonomy of cardiovascular (CV) diseases is divided into a broad spectrum of clinical entities. Many such diseases coincide in specific patient groups and suggest shared predisposition. OBJECTIVES: This study focused on coronary artery disease (CAD) and investigated the genetic relationship to CV and non-CV diseases with reported CAD comorbidity. METHODS: This study examined 425,196 UK Biobank participants to determine a genetic risk score (GRS) based on 300 CAD associated variants (CAD-GRS). This score was associated with 22 traits, including risk factors, diseases secondary to CAD, as well as comorbid and non-CV conditions. Sensitivity analyses were performed in individuals free from CAD or stable angina diagnosis. RESULTS: Hypercholesterolemia (odds ratio [OR]: 1.27; 95% CI: 1.26 to 1.29) and hypertension (OR: 1.11; 95% CI: 1.10 to 1.12) were strongly associated with the CAD-GRS, which indicated that the score contained variants predisposing to these conditions. However, the CAD-GRS was also significant in patients with CAD who were free of CAD risk factors (OR: 1.37; 95% CI: 1.30 to 1.44). The study observed significant associations between the CAD-GRS and peripheral arterial disease (OR: 1.28; 95% CI: 1.23 to 1.32), abdominal aortic aneurysms (OR: 1.28; 95% CI: 1.20 to 1.37), and stroke (OR: 1.08; 95% CI: 1.05 to 1.10), which remained significant in sensitivity analyses that suggested shared genetic predisposition. The score was also associated with heart failure (OR: 1.25; 95% CI: 1.22 to 1.29), atrial fibrillation (OR: 1.08; 95% CI: 1.05 to 1.10), and premature death (OR: 1.04; 95% CI: 1.02 to 1.06). These associations were abolished in sensitivity analyses that indicated that they were secondary to prevalent CAD. Finally, an inverse association was observed between the score and migraine headaches (OR: 0.94; 95% CI: 0.93 to 0.96). CONCLUSIONS: A wide spectrum of CV conditions, including premature death, might develop consecutively or in parallel with CAD for the same genetic roots. In conditions like heart failure, the study found evidence that the CAD-GRS could be used to stratify patients with no or limited genetic overlap with CAD risk. Increased genetic predisposition to CAD was inversely associated with migraine headaches.
BACKGROUND: The taxonomy of cardiovascular (CV) diseases is divided into a broad spectrum of clinical entities. Many such diseases coincide in specific patient groups and suggest shared predisposition. OBJECTIVES: This study focused on coronary artery disease (CAD) and investigated the genetic relationship to CV and non-CV diseases with reported CAD comorbidity. METHODS: This study examined 425,196 UK Biobank participants to determine a genetic risk score (GRS) based on 300 CAD associated variants (CAD-GRS). This score was associated with 22 traits, including risk factors, diseases secondary to CAD, as well as comorbid and non-CV conditions. Sensitivity analyses were performed in individuals free from CAD or stable angina diagnosis. RESULTS:Hypercholesterolemia (odds ratio [OR]: 1.27; 95% CI: 1.26 to 1.29) and hypertension (OR: 1.11; 95% CI: 1.10 to 1.12) were strongly associated with the CAD-GRS, which indicated that the score contained variants predisposing to these conditions. However, the CAD-GRS was also significant in patients with CAD who were free of CAD risk factors (OR: 1.37; 95% CI: 1.30 to 1.44). The study observed significant associations between the CAD-GRS and peripheral arterial disease (OR: 1.28; 95% CI: 1.23 to 1.32), abdominal aortic aneurysms (OR: 1.28; 95% CI: 1.20 to 1.37), and stroke (OR: 1.08; 95% CI: 1.05 to 1.10), which remained significant in sensitivity analyses that suggested shared genetic predisposition. The score was also associated with heart failure (OR: 1.25; 95% CI: 1.22 to 1.29), atrial fibrillation (OR: 1.08; 95% CI: 1.05 to 1.10), and premature death (OR: 1.04; 95% CI: 1.02 to 1.06). These associations were abolished in sensitivity analyses that indicated that they were secondary to prevalent CAD. Finally, an inverse association was observed between the score and migraine headaches (OR: 0.94; 95% CI: 0.93 to 0.96). CONCLUSIONS: A wide spectrum of CV conditions, including premature death, might develop consecutively or in parallel with CAD for the same genetic roots. In conditions like heart failure, the study found evidence that the CAD-GRS could be used to stratify patients with no or limited genetic overlap with CAD risk. Increased genetic predisposition to CAD was inversely associated with migraine headaches.
Authors: Jacqueline Saw; Min-Lee Yang; Mark Trinder; Catherine Tcheandjieu; Chang Xu; Andrew Starovoytov; Isabelle Birt; Michael R Mathis; Kristina L Hunker; Ellen M Schmidt; Linda Jackson; Natalia Fendrikova-Mahlay; Matthew Zawistowski; Chad M Brummett; Sebastian Zoellner; Alexander Katz; Dawn M Coleman; Kirby Swan; Christopher J O'Donnell; Xiang Zhou; Jun Z Li; Heather L Gornik; Themistocles L Assimes; James C Stanley; Liam R Brunham; Santhi K Ganesh Journal: Nat Commun Date: 2020-09-04 Impact factor: 14.919
Authors: Jan Borén; M John Chapman; Ronald M Krauss; Chris J Packard; Jacob F Bentzon; Christoph J Binder; Mat J Daemen; Linda L Demer; Robert A Hegele; Stephen J Nicholls; Børge G Nordestgaard; Gerald F Watts; Eric Bruckert; Sergio Fazio; Brian A Ference; Ian Graham; Jay D Horton; Ulf Landmesser; Ulrich Laufs; Luis Masana; Gerard Pasterkamp; Frederick J Raal; Kausik K Ray; Heribert Schunkert; Marja-Riitta Taskinen; Bart van de Sluis; Olov Wiklund; Lale Tokgozoglu; Alberico L Catapano; Henry N Ginsberg Journal: Eur Heart J Date: 2020-06-21 Impact factor: 29.983
Authors: Sonia Shah; Albert Henry; Carolina Roselli; Honghuang Lin; Garðar Sveinbjörnsson; Ghazaleh Fatemifar; Åsa K Hedman; Jemma B Wilk; Michael P Morley; Mark D Chaffin; Anna Helgadottir; Niek Verweij; Abbas Dehghan; Peter Almgren; Charlotte Andersson; Krishna G Aragam; Johan Ärnlöv; Joshua D Backman; Mary L Biggs; Heather L Bloom; Jeffrey Brandimarto; Michael R Brown; Leonard Buckbinder; David J Carey; Daniel I Chasman; Xing Chen; Xu Chen; Jonathan Chung; William Chutkow; James P Cook; Graciela E Delgado; Spiros Denaxas; Alexander S Doney; Marcus Dörr; Samuel C Dudley; Michael E Dunn; Gunnar Engström; Tõnu Esko; Stephan B Felix; Chris Finan; Ian Ford; Mohsen Ghanbari; Sahar Ghasemi; Vilmantas Giedraitis; Franco Giulianini; John S Gottdiener; Stefan Gross; Daníel F Guðbjartsson; Rebecca Gutmann; Christopher M Haggerty; Pim van der Harst; Craig L Hyde; Erik Ingelsson; J Wouter Jukema; Maryam Kavousi; Kay-Tee Khaw; Marcus E Kleber; Lars Køber; Andrea Koekemoer; Claudia Langenberg; Lars Lind; Cecilia M Lindgren; Barry London; Luca A Lotta; Ruth C Lovering; Jian'an Luan; Patrik Magnusson; Anubha Mahajan; Kenneth B Margulies; Winfried März; Olle Melander; Ify R Mordi; Thomas Morgan; Andrew D Morris; Andrew P Morris; Alanna C Morrison; Michael W Nagle; Christopher P Nelson; Alexander Niessner; Teemu Niiranen; Michelle L O'Donoghue; Anjali T Owens; Colin N A Palmer; Helen M Parry; Markus Perola; Eliana Portilla-Fernandez; Bruce M Psaty; Kenneth M Rice; Paul M Ridker; Simon P R Romaine; Jerome I Rotter; Perttu Salo; Veikko Salomaa; Jessica van Setten; Alaa A Shalaby; Diane T Smelser; Nicholas L Smith; Steen Stender; David J Stott; Per Svensson; Mari-Liis Tammesoo; Kent D Taylor; Maris Teder-Laving; Alexander Teumer; Guðmundur Thorgeirsson; Unnur Thorsteinsdottir; Christian Torp-Pedersen; Stella Trompet; Benoit Tyl; Andre G Uitterlinden; Abirami Veluchamy; Uwe Völker; Adriaan A Voors; Xiaosong Wang; Nicholas J Wareham; Dawn Waterworth; Peter E Weeke; Raul Weiss; Kerri L Wiggins; Heming Xing; Laura M Yerges-Armstrong; Bing Yu; Faiez Zannad; Jing Hua Zhao; Harry Hemingway; Nilesh J Samani; John J V McMurray; Jian Yang; Peter M Visscher; Christopher Newton-Cheh; Anders Malarstig; Hilma Holm; Steven A Lubitz; Naveed Sattar; Michael V Holmes; Thomas P Cappola; Folkert W Asselbergs; Aroon D Hingorani; Karoline Kuchenbaecker; Patrick T Ellinor; Chim C Lang; Kari Stefansson; J Gustav Smith; Ramachandran S Vasan; Daniel I Swerdlow; R Thomas Lumbers Journal: Nat Commun Date: 2020-01-09 Impact factor: 14.919