Integrative genomic, epigenetic and functional studies in diabetic kidney disease

Lead Research Organisation: Queen's University of Belfast

Abstract

Kidney disease is a common and devastating complication of diabetes, and represents a major public health problem worldwide. The inherited, genetic factors that play a role in determining who will get this complication are beginning to be discovered, creating opportunities to understand the underlying biological basis of diabetic kidney disease, which will guide the development of improved treatments and preventive measures. We will combine and integrate data from several complementary approaches (genetics, epigenetics, gene expression analysis and studies in model systems) to identify genes and biological processes that influence the development of diabetic kidney disease.

Technical Summary

Diabetic kidney disease (DKD) is a leading cause of kidney failure and end stage renal disease, and brings a substantial burden of early mortality and accompanying health care costs. Genetic factors contribute to the risk of DKD. If we could identify these genetic factors, we could better understand the mechanisms by which DKD occurs, and thereby accelerate the development of better therapies. We established the GENIE consortium, a collaboration between Queen's University Belfast, University of Dublin, University of Helsinki, and the Broad Institute. Together, we completed the largest genetic study to date of DKD, and successfully identified the first two robust genetic risk factors for DKD. In a separately funded genetic study, we are collaborating with additional groups to extend our efforts and encompass larger samples. To better understand the underlying biology and pathophysiology of DKD, we propose to complement and build on our past and ongoing genetic studies in several critical ways. We will leverage a co-funding mechanism between Ireland, Northern Ireland and the US to carry out a multidisciplinary investigation of DKD. We will assemble and jointly analyze all available genetic data pertinent to DKD, to begin the process of discovering rarer variants with stronger effects on DKD. We will also generate DNA methylation data in kidney and blood, and in patients with and without DKD, and also expression data in samples relevant to DKD. We use a novel and powerful method to integrate the genetic, epigenetic and genomic data to generate hypotheses about the biological causes of DKD, and test these hypotheses with further genetic studies (sequencing in a large follow-up sample) and with functional studies in models of DKD. This international, multidisciplinary collaboration will build on genetic discoveries to help decipher the underlying biology and pathophysiology of DKD and thereby guide the prevention and treatment of this important disease.

Publications

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Cañadas-Garre M (2018) Genomic approaches in the search for molecular biomarkers in chronic kidney disease. in Journal of translational medicine

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Devine PA (2019) Cardiovascular risk in renal transplant recipients. in Journal of nephrology

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Hernandez-Fuentes MP (2018) Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

 
Description European Union Horizon 2020
Amount € 5,900,000 (EUR)
Organisation European Union 
Sector Public
Country European Union (EU)
Start 08/2015 
End 07/2020
 
Description Northern Ireland Kidney Research Fund - Clinical Research Fellowship
Amount £149,000 (GBP)
Organisation Northern Ireland Kidney Research Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 07/2019
 
Title Northern Ireland Kidney Transplant Research Database 
Description Prospectively collected data on renal transplantation since 1968 with clinical information on >2200 kidney transplants. IRAS Project ID: 239344 This database received favourable REC opinion in 2013 and was renewed as a research database in 2018 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Integration of anonymised clinical and genomic data from this research database has been used in meta-analyses of kidney transplant outcomes. Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study. Hernandez-Fuentes MP, Franklin C, Rebollo-Mesa I, Mollon J, Delaney F, Perucha E, Stapleton C, Borrows R, Byrne C, Cavalleri G, Clarke B, Clatworthy M, Feehally J, Fuggle S, Gagliano SA, Griffin S, Hammad A, Higgins R, Jardine A, Keogan M, Leach T, MacPhee I, Mark PB, Marsh J, Maxwell P, McKane W, McLean A, Newstead C, Augustine T, Phelan P, Powis S, Rowe P, Sheerin N, Solomon E, Stephens H, Thuraisingham R, Trembath R, Topham P, Vaughan R, Sacks SH, Conlon P, Opelz G, Soranzo N, Weale ME, Lord GM; United Kingdom and Ireland Renal Transplant Consortium (UKIRTC) and the Wellcome Trust Case Control Consortium (WTCCC)-3. Am J Transplant. 2018 Jun;18(6):1370-1379. doi: 10.1111/ajt.14594. Epub 2018 Feb 1. PMID: 29392897 Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort. Stapleton CP, Birdwell KA, McKnight AJ, Maxwell AP, Mark PB, Sanders ML, Chapman FA, van Setten J, Phelan PJ, Kennedy C, Jardine A, Traynor JP, Keating B, Conlon PJ, Cavalleri GL. Am J Transplant. 2018 Aug 7. doi: 10.1111/ajt.15057. [Epub ahead of print] PMID: 30085400 
 
Description Discovery of an integrated risk profile for chronic kidney disease and development of a clinical biomarker panel for personalising medicine (Stratified medicine for chronic kidney disease) 
Organisation Department for Employment and Learning (DEL)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution This application was founded on the original data obtained from research grants supported by the US Ireland R&D Partnership. There has been a long term strategic collaboration between Prof Catherine Godson (UCD) and my research group at QUB. This collaboration supported by the US Ireland R&D Partnership has been fundamental in generating new genomic data for diabetic kidney disease and more generally for chronic kidney disease. This data was integral to the successful application to the SFI-DfE partnership scheme.
Collaborator Contribution We have used a combination of genome-wide association studies and epigenome-wide association studies to generate data for up to 20,000 individuals with kidney disease. These data were coupled with original in vitro observations in diabetic kidney disease models developed by our colleagues in UCD. This integrated data was used to secure the 5 year programme grant (SFI-DfE RoI-NI funding)
Impact Grant started in August 2016 with recruitment of post-doctoral research fellow in January 2017 and postgraduate research student (commencing September 2017)
Start Year 2016
 
Description Discovery of an integrated risk profile for chronic kidney disease and development of a clinical biomarker panel for personalising medicine (Stratified medicine for chronic kidney disease) 
Organisation Science Foundation Ireland (SFI)
Country Ireland 
Sector Charity/Non Profit 
PI Contribution This application was founded on the original data obtained from research grants supported by the US Ireland R&D Partnership. There has been a long term strategic collaboration between Prof Catherine Godson (UCD) and my research group at QUB. This collaboration supported by the US Ireland R&D Partnership has been fundamental in generating new genomic data for diabetic kidney disease and more generally for chronic kidney disease. This data was integral to the successful application to the SFI-DfE partnership scheme.
Collaborator Contribution We have used a combination of genome-wide association studies and epigenome-wide association studies to generate data for up to 20,000 individuals with kidney disease. These data were coupled with original in vitro observations in diabetic kidney disease models developed by our colleagues in UCD. This integrated data was used to secure the 5 year programme grant (SFI-DfE RoI-NI funding)
Impact Grant started in August 2016 with recruitment of post-doctoral research fellow in January 2017 and postgraduate research student (commencing September 2017)
Start Year 2016
 
Description NOVEL STROMAL CELL THERAPY FOR DIABETIC KIDNEY DISEASE (NEPHSTROM Study) 
Organisation National University of Ireland, Galway
Country Ireland 
Sector Academic/University 
PI Contribution Clinical trial of mesenchymal stem cells for diabetic kidney disease Primary Objective The primary objective of this trial is to establish the safety and tolerability of a single intravenous infusion of NEPHSTROM ORBCEL-M in study participants with T2D and progressive DKD. Secondary Objective The secondary objectives of this study are to evaluate the potential efficacy of an intravenous infusion of NEPHSTROM ORBCEL-M to halt or slow the progression of DKD and to acquire mechanistic data regarding the anti-inflammatory and immune-modulatory activity of NEPHSTROM ORBCEL-M in these study participants. Belfast City Hospital is a clinical trial recruitment site and the laboratory site for anti-HLA testing
Collaborator Contribution This is a Horizon2020 EU grant lead by National University of Ireland, Galway and in partnership with Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII Nephrology and Dialysis Unit Piazza OMS, 1 - Bergamo, Italy Clinical Research Centre for Rare Diseases Aldo e Cele Daccò IRCCS-Istituto di Ricerche Farmacologiche Mario Negri Via G.B. Camozzi, 3 - 24020 Ranica, Bergamo, Italy Principal Investigator: Prof. Giuseppe Remuzzi Clinical Trial Coordinating Centre Belfast Health and Social Care Trust Belfast City Hospital Belfast, UK Principal Investigator: Prof. Peter Maxwell University Hospital Birmingham NHS Foundation Trust Queen Elizabeth Medical Centre Birmingham, UK Principal Investigator: Prof. Paul Cockwell National University of Ireland & Galway University Hospital Galway, Ireland Principal Investigator: Prof. Matthew Griffin
Impact Chronic kidney disease, health-related quality of life and their associated economic burden among a nationally representative sample of community dwelling adults in England. Nguyen NTQ, Cockwell P, Maxwell AP, Griffin M, O'Brien T, O'Neill C. PLoS One. 2018 Nov 26;13(11):e0207960. doi: 10.1371/journal.pone.0207960. eCollection 2018. PMID: 30475893
Start Year 2014
 
Description Wellcome Trust-HRB Irish Clinical Academic Training (ICAT) Programme 
Organisation Health Research Board (HRB)
Country Ireland 
Sector Public 
PI Contribution Wellcome Trust in combination with Health Research Board (RoI) and Public Health Agency R&D Division have invested in an Irish Clinical Academic Training (ICAT) Programme involving six partner universities in Ireland (QUB, UCD, RSCI, TCD, UCC and NUI Galway). I am the director of the Clinical Academic Training Programme in Northern Ireland (QUB and NIMDTA). Wellcome Trust, HRB and PHA R&D Division investment is more than £10 million over the next 5 years. Eight ICAT fellows will be recruited each year up to at least 2021. Each fellowship is for 4 years (Year 1 - clinical academic training; Years 2-4 postgraduate research for PhD). US Ireland R&D Partnership grants have enabled high quality genomics research projects to be completed through collaborations between QUB, UCD, Broad Institute (MIT & Harvard) and University of Helsinki. This high quality research underpins several projects offered within the ICAT programme in Ireland.
Collaborator Contribution Queen's University is a full partner in the Wellcome ICAT programme which involves six universities in Ireland (Trinity College Dublin, University College Dublin, Royal College of Surgeons Ireland, NUI Galway, Queens University Belfast and University College Cork)
Impact Eight ICAT programme clinical research fellowships have been awarded in the first round of applications (2016-17) with starting date for these clinical academic trainees in July 2017
Start Year 2016
 
Description Wellcome Trust-HRB Irish Clinical Academic Training (ICAT) Programme 
Organisation Public Health Agency (PHA)
Country United Kingdom 
Sector Public 
PI Contribution Wellcome Trust in combination with Health Research Board (RoI) and Public Health Agency R&D Division have invested in an Irish Clinical Academic Training (ICAT) Programme involving six partner universities in Ireland (QUB, UCD, RSCI, TCD, UCC and NUI Galway). I am the director of the Clinical Academic Training Programme in Northern Ireland (QUB and NIMDTA). Wellcome Trust, HRB and PHA R&D Division investment is more than £10 million over the next 5 years. Eight ICAT fellows will be recruited each year up to at least 2021. Each fellowship is for 4 years (Year 1 - clinical academic training; Years 2-4 postgraduate research for PhD). US Ireland R&D Partnership grants have enabled high quality genomics research projects to be completed through collaborations between QUB, UCD, Broad Institute (MIT & Harvard) and University of Helsinki. This high quality research underpins several projects offered within the ICAT programme in Ireland.
Collaborator Contribution Queen's University is a full partner in the Wellcome ICAT programme which involves six universities in Ireland (Trinity College Dublin, University College Dublin, Royal College of Surgeons Ireland, NUI Galway, Queens University Belfast and University College Cork)
Impact Eight ICAT programme clinical research fellowships have been awarded in the first round of applications (2016-17) with starting date for these clinical academic trainees in July 2017
Start Year 2016
 
Description Wellcome Trust-HRB Irish Clinical Academic Training (ICAT) Programme 
Organisation Wellcome Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Wellcome Trust in combination with Health Research Board (RoI) and Public Health Agency R&D Division have invested in an Irish Clinical Academic Training (ICAT) Programme involving six partner universities in Ireland (QUB, UCD, RSCI, TCD, UCC and NUI Galway). I am the director of the Clinical Academic Training Programme in Northern Ireland (QUB and NIMDTA). Wellcome Trust, HRB and PHA R&D Division investment is more than £10 million over the next 5 years. Eight ICAT fellows will be recruited each year up to at least 2021. Each fellowship is for 4 years (Year 1 - clinical academic training; Years 2-4 postgraduate research for PhD). US Ireland R&D Partnership grants have enabled high quality genomics research projects to be completed through collaborations between QUB, UCD, Broad Institute (MIT & Harvard) and University of Helsinki. This high quality research underpins several projects offered within the ICAT programme in Ireland.
Collaborator Contribution Queen's University is a full partner in the Wellcome ICAT programme which involves six universities in Ireland (Trinity College Dublin, University College Dublin, Royal College of Surgeons Ireland, NUI Galway, Queens University Belfast and University College Cork)
Impact Eight ICAT programme clinical research fellowships have been awarded in the first round of applications (2016-17) with starting date for these clinical academic trainees in July 2017
Start Year 2016
 
Description A talk for Association of Clinical Biochemists on Diabetic Kidney Disease 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Approx 50 Clinical Biochemists attended a regional meeting and I made a presentation on diabetic kidney disease (DKD) including genetic and epigenetic risk factors associated with DKD. This triggered broader interest in the application of "-omics" approaches to clinical chemistry populations
Year(s) Of Engagement Activity 2017
 
Description Annual general meeting - Northern Ireland Kidney Patients Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Talk about the translation of research into improved services for patients and families
Year(s) Of Engagement Activity 2017
 
Description Clinical academic training presentation at national meeting (UK Kidney Week) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A workshop on encouraging clinical trainees to consider academic pathways and longer term scholarly projects including all aspects of clinical research
Year(s) Of Engagement Activity 2018
 
Description European Renal Association - European Dialysis & Transplant Association (ERA-EDTA), annual scientific meeting, Madrid 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited lecture on Genetics of Diabetic Kidney Disease at ERA-EDTA annual conference in Madrid, Spain
Year(s) Of Engagement Activity 2017
 
Description Hyperkalaemia revisited 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation on the evidence base for management of hyperkalaemia in end-stage renal disease
Year(s) Of Engagement Activity 2018
 
Description International Society of Nephrology Forefronts Meeting, Shenzhen, China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact I presented a talk on epigenetic mechanisms and their role in diabetic kidney disease which triggered an extensive discussion at the meeting and has generated new research ideas

Multiple requests from international collaborators to consider new research studies
Year(s) Of Engagement Activity 2015
 
Description NIMDTA-Queens University Belfast-Ulster Medical Society: Trainee Research Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact A conference for clinical trainees to showcase all aspects of integrated clinical and academic training and opportunities for research in clinical education as well as basic science to clinical trials
Year(s) Of Engagement Activity 2018
 
Description Patient and carers fundraising group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Report to Northern Ireland Kidney Research Fund illustrated by the research highlights 2017-18
Year(s) Of Engagement Activity 2018
 
Description Patient group workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Presentation and discussion of funded research programme, postgraduate research student activity, post-doctoral research training and the implications for service development. Talk and discussion included the impact of genomics on diagnosis and management of renal disease with special focus on diabetic kidney disease
Year(s) Of Engagement Activity 2017
 
Description Patient workshop exploring choices in renal replacement therapy 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Workshop supported by Kidney Care UK and Northern Ireland Kidney Research Fund with an international faculty. The workshop had multiple elements exploring choices of renal replacement therapy for persons with end-stage renal disease
Year(s) Of Engagement Activity 2018
 
Description Research Workshop 
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 NEPHSTROM Plenary Meeting in Belfast with delegates from UK, RoI, Italy, Germany and Netherlands discussing next steps in genetic and cell therapies for diabetic kidney disease.
Year(s) Of Engagement Activity 2017
 
Description Royal College of Physicians of Edinburgh - Regional Update in Medicine 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact ~80 clinicians attended Regional Update in Medicine meeting organised by Royal College of Physicians. I presented a talk on the rising epidemic of Diabetic Kidney Disease (illustrated in part with examples of the research supported by this award)
Year(s) Of Engagement Activity 2018
 
Description Using Evidence in Research and Clinical Practice 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Research ethics and governance talk to clinical trainees as part of a 1-day workshop on Using Evidence sponsored by the Northern Ireland Postgraduate Deanery and open to medical and dental graduates
Year(s) Of Engagement Activity 2018
 
Description Wellcome-HRB Irish Clinical Academic Training programme induction meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Tutorials on undertaking a PhD, designing a project, research governance and ethics, skills gap analysis
Year(s) Of Engagement Activity 2018