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.
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 reveal 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.
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 reveal 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.
