The MRC British Genetics of Hypertension Study

Lead Research Organisation: Queen Mary, University of London
Department Name: Unlisted

Abstract

At the beginning of the Twenty First Century heart disease remains a major cause of death and illness within our nation. High blood pressure affects at least 10 million people in the United Kingdom and is a major risk factor for stroke and heart attack. In spite of considerable improvements in treatment we still have a limited understanding of the inherited, or genetic factors, which may run through families and predispose to raised blood pressure. The MRC British Genetics of Hypertension (BRIGHT) study is a national collaboration with the aim of identifying the genes for high blood pressure, by using large scale family studies, undertaken with the help of the MRC General Practice Framework. The scientific tests we are using to map these genes for raised blood pressure are similar to looking for a needle buried in a haystack. Nevertheless, through the generosity of British families with high blood pressure and technological advances we believe we have a real chance of finding the genes that cause this disorder. The BRIGHT Study results suggest there are several areas of our genetic code that may be involved in elevating blood pressure. We are now seeking funding to investigate these further within the BRIGHT study families. We believe this resource will permit scientists to map the specific variations in genetic make-up that contribute to high blood pressure. By understanding these factors we may be able to develop new and better treatments for those with raised blood pressure and reduce strokes and heart attacks.

Technical Summary

The MRC British Genetics of Hypertension (BRIGHT) Study represents a vibrant and highly successful research collaboration between the universities Aberdeen and Barts and the London (Queen Mary), Cambridge, Leicester, Glasgow, Oxford. The aims of the MRC BRIGHT study are to facilitate identification of those at maximum risk of development of complications from raised blood pressure by elucidating the genetic factors. In pursuit of these goals the MRC BRIGHT Programme (funded late 1996) aimed to establish 1500 severely hypertensive families, based upon, affected sibling pairs with the goal of identification of up to 5 major genes for hypertension by genome-wide screen. During 2000 we received supplementary funding to phenotype up to parent-offspring trios for future fine mapping, replication and extensive candidate survey using the Transmission Disequilibrium Test. The BRIGHT consortium intended from the outset to generate immortalised cell lines and create a national hypertensive family DNA repository for hypothesis testing by other collaborating cardiovascular scientists. This has recently been initiated through an MRC Strategic Grant under the Human Samples Collections Initiative. This will significantly enhance the value and longevity of the MRC investment in this repository and the associated dataset for UK science. In this application for programme renewal we report our substantial progress during the first five years of MRC support and delineate our plans for the next 5 years. A salient strength of the MRC BRIGHT consortium has been the formulation of new and exciting national and international collaborative research relationships. These will build upon existing research relationships to bring considerable potential added value to this MRC investment. This may in turn lead to new diagnostics, improved therapeutic targets and better prediction of those at greatest risk. These goals are entirely coherent with national healthcare strategy to reduce blood pressure in the UK population and prevent cardiovascular end-points.

Publications

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Asselbergs FW (2012) Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. in American journal of human genetics

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Cabrera CP (2015) Exploring hypertension genome-wide association studies findings and impact on pathophysiology, pathways, and pharmacogenetics. in Wiley interdisciplinary reviews. Systems biology and medicine

 
Description Chief Scientist Genomics England
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.genomicsengland.co.uk
 
Description Chief Scientist Genomics England
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.genomicsengland.co.uk
 
Description Chief Scientist Genomics England
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.genomicsengland.co.uk
 
Description Chief Scientist Genomics England
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
URL http://www.genomicsengland.co.uk
 
Description British Heart Foundation Programme Grant
Amount £450,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2010 
End 03/2015
 
Description British Heart Foundation Special Project
Amount £890,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 02/2011
 
Description British Heart Foundation Special Project Grant
Amount £314,875 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2007 
End 03/2008
 
Description HEFCE Science Research Infrastructure fund
Amount £12,000,000 (GBP)
Organisation Higher Education Funding Council for England 
Sector Public
Country United Kingdom
Start 04/2006 
End 03/2010
 
Description Health Informatics Research Centres
Amount £4,444,103 (GBP)
Funding ID MR/K006584/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2013 
End 05/2018
 
Description NIHR Cardiovascular Biomedical Research Units
Amount £5,450,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Barts Cardiovascular Biomedical Research Unit
Sector Public
Country United Kingdom
Start 04/2008 
End 03/2012
 
Description NIHR Cardiovascular Biomedical Research Units
Amount £6,557,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Barts Cardiovascular Biomedical Research Unit
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description Wellcome Trust Strategic Grant
Amount £7,200,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2007 
End 06/2011
 
Title Genotyping technology 
Description Taqman genotyping is a main workhorse for SNP genotyping. We adapted a methodology for reaction miniturisation from KBioscience for nanolitre reaction volumes reducing the cost of genotyping by 50% 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact added value for funders 
 
Title High throughput genotyping and sequencing hub 
Description Barts and The London Genome Centre. Offers high throughput genomics infrastructure to internal and external users including hotel facilities for scientists. 
Type Of Material Improvements to research infrastructure 
Year Produced 2008 
Provided To Others? Yes  
Impact Multiple major publications in common disease. 
 
Title Improved techniques 
Description The sampling handling approaches and standard operating procedures for phenotyping been used to develop the automated Biobank sample handling system 
Type Of Material Improvements to research infrastructure 
Year Produced 2006 
Provided To Others? Yes  
Impact Handling 500000 samples now for UK Biobank 
 
Title New capital building 
Description At Barts and The London a new Heart Centre for translating gene discovery into novel therapies (3172 metres squared). Plus faculty a 24.7M sterling project 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact The project is ongoing 
 
Title Phanotypic and genotypic database 
Description Initially a microsoft access relational database which we migrated to MySQL database holding all phenotypic and genotypic data for analysis and ease of collaboration. Several other studies have copied or been helped to adapt our approach 
Type Of Material Biological samples 
Year Produced 2007 
Provided To Others? Yes  
Impact Others have adopted the database structure for similar phenotypic collections 
 
Title UK Clinical Genomics Research Infrastructure 
Description Data Centre 
Type Of Material Improvements to research infrastructure 
Year Produced 2014 
Provided To Others? Yes  
Impact The research data centre for analysis and interpretation of the 100,000 Genomes Project 
 
Description ASCOT study 
Organisation Leiden University
Country Netherlands 
Sector Academic/University 
PI Contribution Pfizer funded creation of a genetic repository for which we have now completed a genome scan of hypertension and pharmacogenetics of blood pressure response or lipid response to therapies
Collaborator Contribution By funding the repository cost £1M they created the platform for this studypulling together a pharmacogenomics collaboration for statin response
Impact Metaanalysis underway
 
Description ASCOT study 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Pfizer funded creation of a genetic repository for which we have now completed a genome scan of hypertension and pharmacogenetics of blood pressure response or lipid response to therapies
Collaborator Contribution By funding the repository cost £1M they created the platform for this studypulling together a pharmacogenomics collaboration for statin response
Impact Metaanalysis underway
 
Description CKD Gen 
Organisation Imperial College London
Department Department of Epidemiology and Biostatistics
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed genomewide association data from the MRC BRIGHT study
Collaborator Contribution This allowed us to use the MRC BRIGHT data to identify genes affecting measures of renal function leading to a Nature Genetics paper. 20383145
Impact Multidisciplinary involving geneticists, statisticians, epidemiologists and bioinformaticians leading to Nature Genetics paper 20383145
Start Year 2009
 
Description GIANT consortium 
Organisation Medical Research Council (MRC)
Department MRC Centre for Obesity and Related Metabolic Diseases
Country United Kingdom 
Sector Public 
PI Contribution We have supplied data for genetic studies into genetics of anthropmetric traits
Collaborator Contribution They have in return shared data from EPIC Norfolk for the Global BP gen collaboration
Impact 6 Nature Genetics/Nature papers 19079261 19557161 18454148 18391952 20935630 20881960
Start Year 2008
 
Description GIANT consortium 
Organisation University of Oxford
Department Wellcome Trust Centre for Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution We have supplied data for genetic studies into genetics of anthropmetric traits
Collaborator Contribution They have in return shared data from EPIC Norfolk for the Global BP gen collaboration
Impact 6 Nature Genetics/Nature papers 19079261 19557161 18454148 18391952 20935630 20881960
Start Year 2008
 
Description Global BP Gen consortium 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution This cohort made available genome scan data for analysis alongside the BRIGHT study in the new international collaboration GLOBAL BP Gen. This discovered 8 genes for blood pressure.
Collaborator Contribution GSK funded establishment of the Cohort Lausannoise (CoLaus study). This collaboration with 160 scientists led directly to discovery of 16 novel BP loci
Impact GSK funded establishment of the Cohort Lausannoise (CoLaus study). We have worked with them and 22000 others to undertake meta-analysis for Blood pressure genes
Start Year 2007
 
Description Global BP Gen consortium 
Organisation University of Glasgow
Department BHF Glasgow Cardiovascular Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution the Global BP Gen involves collaboration with 93 Institutons across Europe and the US and including 160 co-authors. We used the MRC funded platform of the British Genetics of Hypertension study to establish this consortium for blood pressure genome scans in 34,433 subjects. This was in essence made possible by MRC and Wellcome Trust funding.
Collaborator Contribution Genotypes have been provided for replication study 21076409Key collaborator in the BRIGHT programme aka the British Genetics of Hypertension study 21082022
Impact Identifcation of 8 genes for blood pressure Newton cheh et al Nature Genetics Caulfield and Munroe are joint last authors 19430483
Start Year 2007
 
Description Global BP Gen consortium 
Organisation University of Leicester
Department Department of Cardiovascular Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution the Global BP Gen involves collaboration with 93 Institutons across Europe and the US and including 160 co-authors. We used the MRC funded platform of the British Genetics of Hypertension study to establish this consortium for blood pressure genome scans in 34,433 subjects. This was in essence made possible by MRC and Wellcome Trust funding.
Collaborator Contribution Genotypes have been provided for replication study 21076409Key collaborator in the BRIGHT programme aka the British Genetics of Hypertension study 21082022
Impact Identifcation of 8 genes for blood pressure Newton cheh et al Nature Genetics Caulfield and Munroe are joint last authors 19430483
Start Year 2007
 
Description Global Investigation of Statin Therapy 
Organisation University Medical Center Utrecht (UMC)
Department Experimental Cardiology
Country Netherlands 
Sector Hospitals 
PI Contribution Co-lead this consortium- Wouter Jukema
Collaborator Contribution intellectual leadership, analysis plan, data submission and interpretation
Impact meta-analysis of statin therapy published as output. Published in Nature Communications 2014 Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN, Fuller JH, Livingstone S, Charlton-Menys V, Neil A, Poulter N, Sever P, Shields DC, Stanton AV, Chatterjee A, Hyde C, Calle RA, Demicco DA, Trompet S, Postmus I, Ford I, Jukema JW, Caulfield M, Hitman GA; CARDS, ASCOT, and PROSPER Investigators. J Lipid Res. 2012 May;53(5):1000-11. Epub 2012 Feb 24. PMID: 22368281
Start Year 2010
 
Description Global Investigation of Statin Therapy 
Organisation University of Dundee
Department Dundee Diabetes Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-lead this consortium- Wouter Jukema
Collaborator Contribution intellectual leadership, analysis plan, data submission and interpretation
Impact meta-analysis of statin therapy published as output. Published in Nature Communications 2014 Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN, Fuller JH, Livingstone S, Charlton-Menys V, Neil A, Poulter N, Sever P, Shields DC, Stanton AV, Chatterjee A, Hyde C, Calle RA, Demicco DA, Trompet S, Postmus I, Ford I, Jukema JW, Caulfield M, Hitman GA; CARDS, ASCOT, and PROSPER Investigators. J Lipid Res. 2012 May;53(5):1000-11. Epub 2012 Feb 24. PMID: 22368281
Start Year 2010
 
Description Global Lipids Consortium 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Genomewide scan data contributed from MRC BRIGHT Study to this consortium
Collaborator Contribution in 2008 we published the first paper identifying lipid genes in the American Journal of Human Genetics. This collaboration has taken this to a new height
Impact Multidisciplinary collaboration of geneticists, bioinformaticians and statisticians leading to 95 loci influencing lipids published in Nature August 2010 20686565
Start Year 2009
 
Description Global Urate Genome Consortium 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Department of Epidemiology
Country Germany 
Sector Academic/University 
PI Contribution Leadership, data from this MRC funded programme
Collaborator Contribution we have 2000 subjects but the total study is 70000 people - this is the added value of the collaboration
Impact Paper in Nature Genetics in February 2013 (see publications - 'Genome-wide association analyses identify 18 new loci associated with serum urate concentrations')
Start Year 2011
 
Description International Consortium of Blood Pressure Genomewide Studies 
Organisation National Heart, Lung, and Blood Institute (NHLBI)
Country United States 
Sector Public 
PI Contribution We formed, lead and financed genotyping (MRC funds from G9520101)
Collaborator Contribution this allowed us to partner the US CHARGE consortium and identify 16 novel loci for blood pressure
Impact Paper published in Nature 2011
Start Year 2008
 
Description QRS duration consortium 
Organisation University of Leicester
Department Department of Cardiovascular Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We had extensive automated ECG data from MRC BRIGHT study. This allowed us to contribute genome scan and phenotypic data
Collaborator Contribution Publications using MRC BRIGHT data
Impact Nat Genet. 2010 PMID: 21076409
Start Year 2009
 
Description Smoking addiction 
Organisation University of Oxford
Department Wellcome Trust Centre for Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed phenotypic and genotypic data
Collaborator Contribution we had collected extensive phenotyping on MRC BRIGHT participants which allowed us to contribute comprehensive data on smoking habit and led to a Nat Genet. 2010 PMID: 20418889
Impact Multidisciplinary - genetics, statistics, bioinfomatics and pharmacologists leading to Nat Genet. 2010 May;42(5):436-40. Epub 2010 Apr 25. PubMed PMID: 20418889
Start Year 2008
 
Description 'Let's talk hearts' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Our CV BRU and Farr team coordinates lay talks on aspects of heart disease around East London. In 2013/14 to date we have held 8 Let's talk hearts events in the community in 2013-14.

Community engagement
Year(s) Of Engagement Activity 2013,2014
 
Description Barts and Queen Mary's Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact 200 school students ages 10-14

http://www.qmul.ac.uk/events/items/2012/76523.html
Year(s) Of Engagement Activity 2012,2013
URL http://www.qmul.ac.uk/events/items/2012/76523.html
 
Description Barts and The London and Queen Mary Annual Science Festival (2012-2018) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact As NIHR Barts Biomedical Research Centre Director (and formerly that of the BRU), I have initiated the NIHR Barts Biomedical Research Centre (formerly CV BRU) which has consistently had 350+ visitors of which 250+ were school children. This work is now led by Dr David Collier and enables the public to see what research is going on at Barts Health and to interact with scientists.

School children participating in this have followed with university applications
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
URL https://www.qmul.ac.uk/whri/patient-public-engagement/barts-and-queen-mary-science-festival/
 
Description Design your own clinical trial 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact New clinical trials participation workshop developed by school children and BRU staff to improve recruitment into trials and public involvement. The workshop was successfully piloted with 13-14 year old school. Design your own clinical trial has been incorporated as an activity within the framework of "Trials Connect". This is a collaboration between Barts Health, WHRI, The University of the Third Age (U3A), and our PPAG group. Group members are developing a cross-generational educational project which uses clinical trials as a way of connecting patients, U3A special project groups and sixth form students. With the support of the CVBRU the initial pilot phase of Trials Connect involved workshops with patients and students and the U3A facilitated by Florida State University psychology students and support from The Health Psychology Department of City University (Dr Paula Corcoran) (July 2013).

Increased knowledge in community of clinical trials and their purpose
Year(s) Of Engagement Activity 2013
 
Description Genomics England - 100k Genome Project (Multiple National & International Talks 2015-2018) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Multiple talks about the 100k Genomes project as GEL Chief Scientist
Year(s) Of Engagement Activity 2015,2016,2017,2018
URL http://www.genomicsengland.co.uk
 
Description International Clinical Trials Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Coordinated activities took place at each of Barts Health NHS Trust 6 hospitals. A range of information stalls, with staff on hand at each to engage with patients and respond to queries, and interactive activities.

Increased public and patient engagement, possible increase in clinical trials participants due to increase in awareness.
Year(s) Of Engagement Activity 2013
 
Description Plenary at European Atherosclerosis Society 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Final talk at Euroepan atherosclerosis society

difficult to say but highly rated
Year(s) Of Engagement Activity 2008
 
Description Video and press describing gene discoveries for blood pressure 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We made a video describing our gene discoveries for blood pressure
see link below
http://www.youtube.com/watch?v=WVqxqb0_Ljk&feature=related

207 views on You Tube

Press coverage on the bbc
http://www.bbc.co.uk/news/health-14851651
Year(s) Of Engagement Activity 2011
URL http://www.youtube.com/watch?v=WVqxqb0_Ljk