Complement susceptibility factors in atypical haemolytic uraemic syndrome, age related macular degeneration and ageing.

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

Haemolytic uraemic syndrome (HUS) is usually a serious complication of infection with the bacteria E.Coli O157. This organism causes a severe gastrointestinal infection from which recovery is usual. However, 5-10% of patients develop kidney failure. This is secondary to a bacterial toxin which attaches itself to the lining of blood vessels in the kidney causing them to become blocked. Most patients recover but in a few the illness is severe enough to cause death.

There is a rarer form of HUS , called atypical, which is not associated with E.Coli O157 infection. Atypical HUS (aHUS) has two variants, sporadic and familial. The sporadic form occurs often without any preceding illness but can be associated with use of certain drugs (most notably the oral contraceptive), pregnancy and HIV infection. Recovery of kidney function is less common and many patients require long term dialysis. In the familial form several members of a family will, over a period of time, be affected in a way similar to the sporadic form.

We have found abnormalities in the genes for four proteins, called factor H, membrane cofactor protein, factor I and C3 in approximately 50% of aHUS. These all belong to a common group of proteins, named complement. They have an important role in allowing the body to differentiate between its own and foreign cells. If any of these genes is faulty then the body?s own cells can be damaged by mechanisms designed to destroy foreign cells.

There is evidence that in a small number of patients with aHUS that there are faults in more than one of these genes. We have DNA samples from nearly 250 patients with aHUS and wish to screen all the known genes even in those patients in whom we have already found one fault.

We have recently found that the structure of the chromosome on which these genes lies is in some individuals with aHUS rearranged to form new genes, the presence of which predispose to the disease. We have also found that such rearrangements can lead to loss of genes and that this can predispose to another more common disease called age related macular degeneration. This is the commonest form of blindness in the elderly and has been shown to be associated with the factor H gene. We now wish to determine what the biological effect of loss of these genes is and whether it is more common with increasing age.

Technical Summary

It is now well established that the complement pathway is associated with both atypical haemolytic uraemic syndrome (aHUS) and age related macular degeneration (AMD). It has been shown that both mutations and susceptibility factors (SNPs and copy number variability) in complement genes including factor H, membrane cofactor protein, factor I, factor B and C3 predispose to aHUS. There is evidence to suggest that multiple such factors in individual patients can act in a summative manner to increase the risk of disease development. In the Newcastle cohort of 246 aHUS patients we will use a systems biology approach to model these multiple factors. Mutation screening, genotyping and dosage analysis will be undertaken to provide a complete profile of all these factors in the entire cohort. We will in the cohort also undertake mutation screening of other potential candidate genes including CD59, CR1 and properdin. We recently showed that a hybrid factor H/factor H related protein 1 gene formed by non-allelic homologous recombination (NAHR) was associated with aHUS. In this application we will confirm the presence of the reverse factor H related protein 1/factor H hybrid gene in association with aHUS using cDNA analysis and southern blotting. We have also shown that NAHR results in deletion of the genes encoding factor H related proteins 1 and 3 (CFHR1 and CFHR3), and that this deletion protects against the development of AMD but predisposes to aHUS. We will examine in normal subjects whether copy number of CFHR1 and CFHR3 is associated with serum levels of the proteins encoded by these genes and serum levels of factor H. To do this we will develop an ELISA for CFHR1 and CFHR3. In our studies examining copy number of CFHR1 and CFHR3 in aHUS and AMD we have observed that in control groups that the allele frequency of the deletion increases with ageing. We will examine the hypothesis that cumulative survival in the general population is associated with this deletion by examining the allele frequency in 4 independent cohorts of normal controls.

Publications

10 25 50

publication icon
Bresin E (2013) Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. in Journal of the American Society of Nephrology : JASN

publication icon
Brown JH (2012) Postpartum aHUS secondary to a genetic abnormality in factor H acquired through liver transplantation. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

publication icon
Dhillon B (2010) Complement factor h autoantibodies and age-related macular degeneration. in Investigative ophthalmology & visual science

publication icon
Haller W (2010) Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

 
Description NHS England Clinical Commissioning Policy Statment: Eculizumab for atypical HUS
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Based on the results of the trials on eculizumab for which I was the UK chief investigator NHS England have funded eculizumab for the treatment of new aHUS patients and for those aHUS patients on dialysis who are suitable for transplantation.
 
Description National service for aHUS
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact We applied for a national commissioned service for the treatment and investigation of aHUS. This was considered by the Advisory Group for National Specialised Services (AGNSS). Subsequently the Department of Health asked NICE to undertake a review. This recommended funding of eculizumab by NHS England. We in 2016 (Newcastle upon Tyne Hospitals NHS Foundation Trust) then successfully applied to NHS England to provide the national specialist service for aHUS.
 
Guideline Title Clinical Practice Guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom (Pubmed 19821824)
Description aHUS UK Guidelines
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
URL http://europepmc.org/abstract/MED/19821824
 
Description FP7-HEALTH-2012-INNOVATION-1
Amount £106,851 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 10/2012 
End 09/2017
 
Description Project grant
Amount £56,711 (GBP)
Organisation Kids Kidney Research 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2010 
End 06/2011
 
Description Project grant
Amount £137,741 (GBP)
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2010 
End 06/2012
 
Description Project grant/Northern Counties Kidney Research Fund
Amount £12,000 (GBP)
Organisation Northern Counties Kidney Research Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2009 
End 03/2010
 
Description Rare Disease Working Groups
Amount £15,000 (GBP)
Funding ID SP9/RDWG/2011 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 06/2016
 
Title Use of MLPA for idenfity genomic disorders in the RCA cluster at 1q32 
Description We have refined the use of multiplex ligation-dependent probe amplification (MLPA) for the diagnosis of genomic disorders affecting the RCA cluster at 1q32 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact We have recently published a paper in Blood (Pubmed 19861685) which describes a novel deletion identified using MLPA 
URL http://europepmc.org/abstract/MED/19861685
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation Cardiff University
Department School of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation European Hopital Georges Pompidou
Country France 
Sector Hospitals 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation Leibniz Association
Department Leibniz Institute for Natural Product Research and Infection Biology
Country Germany 
Sector Academic/University 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation Mario Negri Institute for Pharmacological Research
Country Italy 
Sector Academic/University 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation Spanish National Research Council (CSIC)
Country Spain 
Sector Public 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation University Hospital La Paz
Country Spain 
Sector Hospitals 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Description The European Working Party on Complement Genetics in Renal Disease 
Organisation University of Edinburgh
Department School of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaking analyses on serum and DNA samples. Sharing reagents and methods. Sharing data.
Collaborator Contribution Undertaking analyses on serum and DNA samplesUndertaking analyses on serum and DNA samples. Sharing data.Undertaking analyses on serum and DNA samples. Sharing dataUndertaking analyses on serum and DNA samples. Sharing data and methods.Undertaking analyses on serum and DNA samples. Sharing data and methodsUndertaking analyses on serum samplesUndertaking analyses on DNA samples. Sharing methodsSharing reagents and methodsUndertaking structural analyses
Impact With MRC Funding we have so far published one paper (18796626) in the period up to the end of 2008
Start Year 2006
 
Title Use of eculizumab in aHUS 
Description We have participated in a multicentre study examining the use of eculizumab, a monoclonal anti-C5 antibody, in aHUS. The results of the study have resulted in licences being granted for the use of eculizumab in aHUS by the FDA and EMA. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2011
Development Status Actively seeking support
Clinical Trial? Yes
Impact The results of the study have been extremely encouraging and are likely to have a dramatic effect on the poor prognosis associated with aHUS. 
 
Description Article in the Newcastle Evening Chronicle 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact An article in the Evening Chronicle described the experiences of one member of a family from the North East where multiple individuals have been affected by aHUS. I wrote a short accompanying article describing what aHUS was.

Since this article there have been two further articles in the Evening Chronicle describing the experiences of other local individuals affected by aHUS.
Year(s) Of Engagement Activity 2009
 
Description Parliamentary seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact About 30 people attended including MPs, patients, family members, carers and clinicians. There were also representative from Kidney Research UK, Alexion Pharmaceuticals, Rare Diseases UK, the Department of Health and aHUSUK.

The impact of the disease on patients and their families was well documented by a patient who spoke
Year(s) Of Engagement Activity 2012
 
Description Radio Interview for BBC Radio York 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact I was interviewed for a lunch time programme broadcast on BBC Radio York about atypical haemolytic uraemic syndrome. This was in response to a local patient with the disease who had called the station about how the disease had affected her.

This raised the profile of a rare disease through local media.
Year(s) Of Engagement Activity 2012
 
Description School Visit - Newcastle upon Tyne 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact I gave a lecture on the genetics of haemolytic uraemic syndrome to the Medical Society of the Royal Grammar School, Newcastle upon Tyne.

I received the following e-mail after my lecture. "Dear Professor Goodship, I would like to thank you on behalf of the society for giving the RGS an excellent talk on Genetics and its role in Hemolytic-uremic syndrome. All those I have spoken to found the talk extremely insightful, and I'm sure it will provide a useful talking point for any potential interviews our members have. We hope you enjoyed your time at the RGS and wish you all the best for the future. Yours sincerely, Sami Anjum RGS Medical Society Chairman
Year(s) Of Engagement Activity 2009
 
Description aHUS action 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Policymakers/politicians
Results and Impact We have established a coalition group called aHUS Action which is campaigning for better NHS care for patients with atypical haemolytic uremic syndrome (aHUS) in England.We are calling for a national specialised service for the diagnosis and treatment of aHUS, and to ensure that new therapies are available to all patients who need them. Details of the group are available at www.ahus-action.org.


An online e-petition "Treatment of atypical haemolytic uraemic syndrome" has been signed by over 1200 individuals. The petition is available at http://epetitions.direct.gov.uk/petitions/16053
An early day motion (http://www.parliament.uk/edm/2010-12/2046) has been signed by 21 MPs.
Year(s) Of Engagement Activity 2011
URL http://www.ahus-action.org
 
Description aHUS patient/family conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 100 individuals attended a series of talks covering all aspects of aHUS. The talks were all recorded and are online at www.ahus.org.uk.

As a consequence of the meeting a patient/family support group (aHUSUK) has been established.
Year(s) Of Engagement Activity 2011
URL http://www.ahus.org.uk