Sunaina Yadav1, Ioana Cotlarciuc1, Patricia B Munroe2, Mark Caulfield2, Pankaj Sharma1, Muhammad S Khan1, Michael A Nalls3, Steve Bevan4, Yu-Ching Cheng5,6, Wei-Min Chen7,8, Rainer Malik9, Nina S McCarthy10,11, Elizabeth G Holliday12,13, Douglas Speed14, Nazeeha Hasan1, Mateusz Pucek1, Paul E Rinne1, Peter Sever15, Alice Stanton11, Denis C Shields16, Jane M Maguire13,17,18, Mark McEvoy12,13, Rodney J Scott13,19,20, Luigi Ferrucci21, Mary J Macleod22, John Attia12,13, Hugh S Markus4, Michele M Sale23,7, Bradford B Worrall24, Braxton D Mitchell6, Martin Dichgans9, Cathy Sudlow25,26, James F Meschia27, Peter M Rothwell28. 1. Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom. 2. Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, London, UK. 3. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. 4. Stroke and Dementia Research Centre, St. George's University of London, London, UK. 5. Baltimore Veterans Affairs Medical Centre, Baltimore, Maryland, USA. 6. Department of Medicine, University of Maryland, Baltimore, Maryland, USA. 7. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. 8. Department of Public Health Science, University of Virginia, Charlottesville, VA, USA. 9. Institute for Stroke and Dementia Research (ISD), Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 10. Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, WA 6009, Australia. 11. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. 12. Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia. 13. Hunter Medical Research Institute, Newcastle, New South Wales, Australia. 14. UCL Genetics Institute, University College London, London, UK. 15. International Centre for Circulatory Health, Imperial College London, London W2 1PG, UK. 16. Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland. 17. School of Nursing and Midwifery, University of Newcastle, Newcastle, New South Wales, Australia. 18. Department of Neurosciences, Gosford Hospital, Central Coast Area Health, Gosford, New South Wales, Australia. 19. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia. 20. Division of Genetics, Hunter Area Pathology Service, Newcastle, New South Wales, Australia. 21. Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21225, USA. 22. Division of Applied Medicine, University of Aberdeen, Aberdeen, UK. 23. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA. 24. Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA. 25. Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK. 26. Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. 27. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA. 28. Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.
Abstract
BACKGROUND AND PURPOSE: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. METHODS: A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. RESULTS: The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4×10(-8)). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97-1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97-1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89-1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97-1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18). CONCLUSIONS: We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.
BACKGROUND AND PURPOSE: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. METHODS: A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. RESULTS: The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4×10(-8)). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97-1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97-1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89-1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97-1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18). CONCLUSIONS: We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.
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