About the Project
Bacterial infection is a major cause of disability and death in children worldwide. The EUCLIDS project aims to understand the genetic basis underlying susceptibility and outcome to the major childhood infections including meningitis, septicaemia, bone and joint infections due to meningococcus, pneumococcus, staphylococcus aureous, Group A streptococcus and salmonella. The project aims to use existing cohorts of patients with meningococcal disease, those undergoing vaccines against meningococcus, and newly recruited patients with a range of bacterial infections assembled from across Europe. These unique and well characterised patient groups will be used to undertake a metaanalysis of genome wide association studies (GWAS) of meningococcal disease. The meta‐analysis will also allow genes controlling severity and outcome to be identified. To understand the genetic basis of success or failure of childhood vaccines, a genome wide association study will be undertaken in UK infants undergoing vaccination against meningococcal infection.
Candidate genes identified in the genome wide association studies will be validated using fine mapping and sequencing of the candidates.
A newly established cohort of patients from UK, Spain, Austria, Germany, Italy, Holland and an African cohort from The Gambia, West Africa, with a range of childhood infections will be studied using whole exome sequencing, epigenetic sequencing and RNA expression analysis using an extreme phenotype approach in which a sub‐set of the most severely affected patients undergo detailed analysis and the genes and pathways identified are then tested in the remaining, less severely affected cohorts.
To identify the functional basis on which genetic differences operate, we will undertake gene function analysis and explore identified genes in animal models. The study thus aims to produce a new understanding of the genetic and genomic basis underlying severity and outcome of childhood infection, and to identify novel biomarkers to predict susceptibility and outcome of childhood infection.
A specific focus of the program will be to extend our original observation of the association of genetic variation in the Factor H region with meningococcal disease susceptibility by exploring mechanisms by which factor H genetic variants contribute to disease susceptibility. We will identify the specific genetic variants responsible for the association by sequencing the factor H region of affected patients and controls. We aim to define the function of the Factor H genetic variants by studying the binding of FH and FH related proteins to the Factor H binding protein of meningococcus (FHBp). We will examine the hypothesis that genetic variation on the meningococcal FHBp interacts with variation in the human gene region by investigating whether there is a “fit” between the host FH and bacterial FHBP genetic variation. The role of FH in meningococcal and other infections will also be defined in animal models.
We aim to produce a comprehensive understanding of how genetic variation in the FH region controls susceptibility to childhood bacterial infection.