Large-effect genetic variants in susceptibility to invasive pneumococcal disease
Lead Research Organisation:
University of Oxford
Department Name: Wellcome Trust Centre for Human Genetics
Abstract
Respiratory infection is the single largest contributor to the global burden of disease and the leading cause of death in children world-wide, killing more children annually than AIDS, malaria, and measles combined. The bacteria Streptococcus pneumoniae (the pneumococcus) remains the most common cause of community-acquired pneumonia in Europe and the United States and accounts for the deaths of more than one million children under the age of five world-wide each year. Invasive pneumococcal disease (IPD) is a severe manifestation of S. pneumoniae infection which occurs most commonly when infection enters the bloodstream (causing septicaemia) or meninges (causing meningitis). Even in developed countries, a significant proportion of individuals who develop IPD die.
Increasing evidence suggests that an individual?s genetic make-up plays an important role in determining their likelihood of developing severe infectious disease, although the specific genes responsible remain largely unknown. Recent advances in DNA sequencing technology have lead to the possibility of performing detailed and large-scale studies of the human genome to identify DNA sequence variants which differ between individuals. The proposed research aims to identify novel genetic variants that exert a large effect on the risk of developing IPD. The project will utilise new sequencing technologies together with the largest available collection of samples from individuals with IPD and related severe bacterial diseases. Gene variants that exert a major effect on the risk of developing IPD will be identified by analysing DNA sequence in samples from patients with IPD and comparing them with samples from healthy subjects; these samples have been anonymised and were collected with consent. Samples will be studied from both UK and Kenyan individuals, and as a result any possible benefits may be applicable to both populations.
The identification of novel gene associations from this approach may explain why some individuals are particularly vulnerable to developing severe bacterial disease. This knowledge may aid medical practice, for example through the use of vaccines or antibiotics to prevent disease in high-risk individuals. The results may also lead to an increased understanding of the human body?s immune defence mechanisms and perhaps the development of more effective treatments. Definition of the molecules and pathways that are important in individual patients may eventually lead to a personalised approach to care, with prophylaxis and therapy tailored on the basis of an individual?s genetic background.
Increasing evidence suggests that an individual?s genetic make-up plays an important role in determining their likelihood of developing severe infectious disease, although the specific genes responsible remain largely unknown. Recent advances in DNA sequencing technology have lead to the possibility of performing detailed and large-scale studies of the human genome to identify DNA sequence variants which differ between individuals. The proposed research aims to identify novel genetic variants that exert a large effect on the risk of developing IPD. The project will utilise new sequencing technologies together with the largest available collection of samples from individuals with IPD and related severe bacterial diseases. Gene variants that exert a major effect on the risk of developing IPD will be identified by analysing DNA sequence in samples from patients with IPD and comparing them with samples from healthy subjects; these samples have been anonymised and were collected with consent. Samples will be studied from both UK and Kenyan individuals, and as a result any possible benefits may be applicable to both populations.
The identification of novel gene associations from this approach may explain why some individuals are particularly vulnerable to developing severe bacterial disease. This knowledge may aid medical practice, for example through the use of vaccines or antibiotics to prevent disease in high-risk individuals. The results may also lead to an increased understanding of the human body?s immune defence mechanisms and perhaps the development of more effective treatments. Definition of the molecules and pathways that are important in individual patients may eventually lead to a personalised approach to care, with prophylaxis and therapy tailored on the basis of an individual?s genetic background.
Technical Summary
The aim of the project is to utilise next-generation sequencing technology to identify novel, large-effect genetic susceptibility variants for invasive pneumococcal disease (IPD) in European and African populations.
Streptococcus pneumoniae is a leading cause of death in children world-wide and the most common cause of pneumonia in the UK. Nasopharyngeal colonisation by the pneumococcus is widespread, yet only a minority of individuals develop invasive disease. Host genetic factors play an important role in explaining this inter-individual variation in susceptibility, but the genes involved are largely unknown. We are currently performing genome-wide association (GWA) studies for IPD in UK and Kenyan populations. Whilst this approach may detect common polymorphisms that associate with IPD, it will not identify large-effect, rare variants.
Increasing evidence suggests that individually rare mutations of large effect are collectively responsible for a significant portion of susceptibility to common disease. This interest in rare variants is particularly relevant to infectious disease, as it parallels a paradigm shift in the concept of primary immunodeficiency (PID), with recent descriptions of ?selective? PIDs which underlie single episodes of severe infectious disease in otherwise healthy adults. The enormous selective pressure exerted by pneumococcal disease further supports the concept that most major IPD susceptibility variants will be rare.
Advances in sequencing technology now permit the systematic study of rare variants in susceptibility to IPD and related bacterial disease phenotypes. This project represents a collaboration between European and African centres to assemble the largest sample collection available world-wide for the study of IPD (n=1970) and related phenotypes of bacterial respiratory disease (n=6100). Two approaches will be taken to evaluate the burden of rare variants in IPD cases compared with controls: sequencing of candidate genes (those underlying GWA signals and monogenic PIDs), and whole-exome sequencing in individuals with extreme pneumococcal disease phenotypes. These sequencing approaches will be followed by replication and functional studies.
Parallel study of European and African individuals is particularly valuable as it may reveal population-specific susceptibility variants and pathways. Combined use of sequencing and GWA data will enable dissection of the genetic architecture of IPD susceptibility, and for the first time define the relative contributions of rare and common variants both in individuals and at the population level. This approach will establish the frequency of known PIDs, and potentially characterise novel PID states. Identification of large-effect variants may also have direct clinical implications, for example the use of prophylactic interventions in high-risk individuals.
Streptococcus pneumoniae is a leading cause of death in children world-wide and the most common cause of pneumonia in the UK. Nasopharyngeal colonisation by the pneumococcus is widespread, yet only a minority of individuals develop invasive disease. Host genetic factors play an important role in explaining this inter-individual variation in susceptibility, but the genes involved are largely unknown. We are currently performing genome-wide association (GWA) studies for IPD in UK and Kenyan populations. Whilst this approach may detect common polymorphisms that associate with IPD, it will not identify large-effect, rare variants.
Increasing evidence suggests that individually rare mutations of large effect are collectively responsible for a significant portion of susceptibility to common disease. This interest in rare variants is particularly relevant to infectious disease, as it parallels a paradigm shift in the concept of primary immunodeficiency (PID), with recent descriptions of ?selective? PIDs which underlie single episodes of severe infectious disease in otherwise healthy adults. The enormous selective pressure exerted by pneumococcal disease further supports the concept that most major IPD susceptibility variants will be rare.
Advances in sequencing technology now permit the systematic study of rare variants in susceptibility to IPD and related bacterial disease phenotypes. This project represents a collaboration between European and African centres to assemble the largest sample collection available world-wide for the study of IPD (n=1970) and related phenotypes of bacterial respiratory disease (n=6100). Two approaches will be taken to evaluate the burden of rare variants in IPD cases compared with controls: sequencing of candidate genes (those underlying GWA signals and monogenic PIDs), and whole-exome sequencing in individuals with extreme pneumococcal disease phenotypes. These sequencing approaches will be followed by replication and functional studies.
Parallel study of European and African individuals is particularly valuable as it may reveal population-specific susceptibility variants and pathways. Combined use of sequencing and GWA data will enable dissection of the genetic architecture of IPD susceptibility, and for the first time define the relative contributions of rare and common variants both in individuals and at the population level. This approach will establish the frequency of known PIDs, and potentially characterise novel PID states. Identification of large-effect variants may also have direct clinical implications, for example the use of prophylactic interventions in high-risk individuals.