Genome-wide analysis of blood pressure variability and ischemic stroke.
OBJECTIVE
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.
Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom.
Sunaina
S
Yadav
Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom.
Ioana
I
Cotlarciuc
Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, London, UK.
Patricia B
PB
Munroe
Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom.
Muhammad S
MS
Khan
Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Michael A
MA
Nalls
Stroke and Dementia Research Centre, St. George's University of London, London, UK.
Steve
S
Bevan
Baltimore Veterans Affairs Medical Centre, Baltimore, Maryland, USA.|Department of Medicine, University of Maryland, Baltimore, Maryland, USA.
Yu-Ching
YC
Cheng
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.|Department of Public Health Science, University of Virginia, Charlottesville, VA, USA.
Wei-Min
WM
Chen
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.
Rainer
R
Malik
Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, WA 6009, Australia.|Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Nina S
NS
McCarthy
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Elizabeth G
EG
Holliday
UCL Genetics Institute, University College London, London, UK.
Douglas
D
Speed
Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom.
Nazeeha
N
Hasan
Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom.
Mateusz
M
Pucek
Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom.
Paul E
PE
Rinne
International Centre for Circulatory Health, Imperial College London, London W2 1PG, UK.
Peter
P
Sever
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Alice
A
Stanton
Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland.
Denis C
DC
Shields
Hunter Medical Research Institute, Newcastle, New South Wales, Australia.|School of Nursing and Midwifery, University of Newcastle, Newcastle, New South Wales, Australia.|Department of Neurosciences, Gosford Hospital, Central Coast Area Health, Gosford, New South Wales, Australia.
Jane M
JM
Maguire
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Mark
M
McEvoy
Hunter Medical Research Institute, Newcastle, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.|Division of Genetics, Hunter Area Pathology Service, Newcastle, New South Wales, Australia.
Rodney J
RJ
Scott
Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21225, USA.
Luigi
L
Ferrucci
Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.
Mary J
MJ
Macleod
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.|Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
John
J
Attia
Stroke and Dementia Research Centre, St. George's University of London, London, UK.
Hugh S
HS
Markus
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA.|Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Michele M
MM
Sale
Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
Bradford B
BB
Worrall
Department of Medicine, University of Maryland, Baltimore, Maryland, USA.
Braxton D
BD
Mitchell
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.
Martin
M
Dichgans
Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK.|Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Cathy
C
Sudlow
Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
James F
JF
Meschia
Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK.
Peter M
PM
Rothwell
Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London Medical School, London, UK.
Mark
M
Caulfield
Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London W6 8RF, United Kingdom.
Pankaj
P
Sharma
D000328:Adult; D000368:Aged; D001794:Blood Pressure; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020521:Stroke / Q000235:genetics / Q000503:physiopathology
D015816:Cell Adhesion Molecules, Neuronal; C093438:neuroligin 1
GWAS; blood pressure variability; genes; polymorphism; stroke