Genetic Susceptibility to Rheumatic Heart Disease

Lead Research Organisation: University of Oxford
Department Name: Wellcome Trust Centre for Human Genetics

Abstract

Rheumatic heart disease (RHD) results from an excessive response to common bacteria called either Streptococcus pyogenes or Group A Streptococcus. An excessive response to the bacteria, mediated by the immune system, our toolkit for fighting infection, leads to damage to heart valves, termed RHD. The consequences include heart failure, stroke and infective endocarditis (heart valve infection) and together kill at least 500 000 people worldwide each year, as many as breast cancer.

In areas of poverty and over-crowded living conditions, particularly in the developing world, both RHD and bacterial skin and throat infections are common. Only a fraction of individuals infected by the causative bacteria go on to develop RHD. Although environmental factors such as poverty play a part, I believe that differences in our genome, the inherited blueprint for our bodies, might play a role as has been shown to be the case in other diseases. To read the genome we will ask patients and volunteers for a blood sample and use technology that simultaneously reads variation at approximately 200 000 points. Knowledge of these differences might further understanding of the interaction between infection and immunity, and potentially generate approaches to vaccine development.

Technical Summary

Background: Rheumatic heart disease (RHD) and its precursor acute rheumatic fever (ARF) result from an autoimmune response to infection with Streptococcus pyogenes (Group A Streptococcus, GAS). A significant cause of morbidity and mortality in the developing world, accounting for 500 000 deaths annually, half as many as malaria. Control of the disease is limited to antibiotic prophylaxis. Investment in research and development for ARF is only 0.4% of that for malaria and there is currently little prospect of developing a GAS vaccine effective in the developing world.

Objectives: To identify genetic variants associated with susceptibility to RHD allowing for potential confounders.

Study sample: Two thousand patients of Melanesian ethnicity from New Caledonia, Oceania, diagnosed with RHD by echocardiography (recruited to a cardiac imaging study planned by our collaborators) and an equivalent number of peer-nominated controls to be recruited from the same population will be consented for enrolment in genetic studies. Complete demographic and epidemiological data will be collected from each individual case and control as well as detailed clinical data including at a minimum a detailed echocardiographic study of all the cases.

Association study: Using a case-control association study approach, microarray technology will be used to genotype at least 200 000 single nucleotide polymorphisms in 1000 cases and 1000 controls. Putative associated alleles will be replicated in a further 1000 cases and 1000 controls using genotyping technology such as the Sequenom‘s MassArray primer extension assay. This approach will give 80% power to detect significant association at allelic odds ratio of 1.5 or greater for alleles with a minor allele frequency of 10% or more at genome-wide significance (p-value = 5 x 10-7).

Implications: Rheumatic heart disease is unique example of an autoimmune process associated with a known specific pathogen. Therefore, with the potential to real genetic variation associated with susceptibility RHD, this study might further our understanding of the complex interaction between human genetics, susceptibility to infection and autoimmunity. In addition the results might generate new approaches to GAS vaccine development.

Publications

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Mills TC (2014) IFITM3 and susceptibility to respiratory viral infections in the community. in The Journal of infectious diseases

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Parks T (2015) Invasive streptococcal disease: a review for clinicians. in British medical bulletin

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Parks T (2015) ASO titer or not? When to use streptococcal serology: a guide for clinicians. in European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology

 
Description Use of research by Fiji Ministry of Health Department of Non-Communicable Diseases
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description BMA Research Grants Programme
Amount £45,000 (GBP)
Funding ID Josephine Lansdell 2012 
Organisation British Medical Association (BMA) 
Sector Learned Society
Country United Kingdom
Start 09/2012 
End 08/2015
 
Description ESCMID Research Grants
Amount € 20,000 (EUR)
Organisation European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 
Sector Learned Society
Country European Union (EU)
Start 06/2013 
End 05/2015
 
Description IMPC Testing dst1 in susceptibility to infection
Amount £36,618 (GBP)
Funding ID MR/R01454X/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 09/2019
 
Description Project Grant
Amount £300,000 (GBP)
Funding ID PG/14/26/30509 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2014 
End 05/2016
 
Description Sir Halley Stewart Trust Research Project Grant
Amount £34,000 (GBP)
Organisation Sir Halley Stewart Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 10/2016
 
Title Fiji Rheumatic Heart Disease Data-Linkage study 
Description Little data is available pertaining to the epidemiology of rheumatic heart disease in developing countries. This database bringing together routine data for the period 2008-2012 from a patient information system, a database of death certificates, the national disease control programme's (NDCP) register, and information collected from echocardiography clinic registers permits estimates of prevalence, incidence, relative survival and rates of complications. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Preliminary findings from this research have been reported to the Fiji Ministry of Health to guide public health policy for control of rheumatic heart disease. A summary of the findings have also been shared with the Global Burden of Disease Project who will use the information to update estimates of global burden of rheumatic heart disease. 
 
Title Pacific Islands Rheumatic Heart Disease Network DNA Collection 
Description Prior to this project little research into genetic susceptibility to rheumatic heart disease had been conducted. We have established the world's largest collection of DNA samples from patients with rheumatic heart disease and healthy volunteers. 
Type Of Material Biological samples 
Provided To Others? No  
Impact This has enabled initial steps towards studies of genetic susceptibility to rheumatic heart disease. 
 
Description Genetics and Severe Streptococcal Infections in the UK 
Organisation Columbia University Medical Center
Department Division of Infectious Diseases
Country United States 
Sector Academic/University 
PI Contribution This collaboration aims to establish a collection of DNA samples from survivors of invasive streptococcal disease and necrotising fasciitis and their family members with a view to genetic analysis by whole-exome sequencing analysis. I contribute to this network through having designed the research study, co-ordinating recruitment and conducting the genetic analysis.
Collaborator Contribution Public Health England have assisted with design of the research and will assist with recruitment of survivors. They provide expertise on the epidemiology of invasive streptococcal disease in the UK. Imperial College London provide expertise on invasive streptococcal disease and will pursue functional analysis of putative susceptibility variants.
Impact Preparation including ethical approval for sample collection in UK.
Start Year 2013
 
Description Genetics and Severe Streptococcal Infections in the UK 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution This collaboration aims to establish a collection of DNA samples from survivors of invasive streptococcal disease and necrotising fasciitis and their family members with a view to genetic analysis by whole-exome sequencing analysis. I contribute to this network through having designed the research study, co-ordinating recruitment and conducting the genetic analysis.
Collaborator Contribution Public Health England have assisted with design of the research and will assist with recruitment of survivors. They provide expertise on the epidemiology of invasive streptococcal disease in the UK. Imperial College London provide expertise on invasive streptococcal disease and will pursue functional analysis of putative susceptibility variants.
Impact Preparation including ethical approval for sample collection in UK.
Start Year 2013
 
Description International Rheumatic Heart Disease Meta-Analysis Consortium 
Organisation Telethon Kids Institute
Country Australia 
Sector Academic/University 
PI Contribution Coordinating consortium Leading analysis
Collaborator Contribution Contributing to analysis and collection of samples/data
Impact Preparing for genetics meta-analysis
Start Year 2014
 
Description International Rheumatic Heart Disease Meta-Analysis Consortium 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution Coordinating consortium Leading analysis
Collaborator Contribution Contributing to analysis and collection of samples/data
Impact Preparing for genetics meta-analysis
Start Year 2014