Genetic Susceptibility to Rheumatic Heart Disease in the Pacific Region
Rheumatic Heart Disease
|Study Design:||Observational Model: Case Control
Time Perspective: Retrospective
|Official Title:||Genome-wide Association Study of Susceptibility to Rheumatic Heart Disease in Fiji and New Caledonia|
- Rheumatic heart disease diagnosis [ Time Frame: At enrolment ]Diagnosis of rheumatic heart disease as layout in enrolment criteria for cases.
- Mitral stenosis diagnosis [ Time Frame: At enrolment ]History or echocardiographic diagnosis of mitral stenosis
Biospecimen Retention: Samples With DNA
|Study Start Date:||September 2012|
|Study Completion Date:||December 2013|
|Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Rheumatic heart disease cases
Patients with rheumatic heart disease as defined in the case criteria
Individuals from the general population divided into new controls (recruited specifically for this study) and existing controls (recruited to previous population genetics studies in the region)
The investigators will micro-array genotype approximately 300,000 single nucleotide polymorphisms (SNP) using DNA samples from patients with rheumatic heart disease (cases) from New Caledonia and Fiji, and members of the general population (controls) from New Caledonia, Vanuatu and Fiji. The investigators will perform standard quality control checks on the SNP data using measures such as call rate, heterozygosity, duplication and relatedness, and exclude variants on the basis of deviation from Hardy-Weinberg equilibrium and minor allele frequency. We will also impute variants not present on the micro-array with reference to the latest release of 1000 Genomes data and whole-genome sequence data from sixty Melanesian individuals from New Caledonia from the phenotypic extremes in this study.
The investigators will conduct a discovery analysis in using a genome-wide association study approach focusing on Oceanic cases and controls from the Francophone nations of New Caledonia and Vanuatu. This analysis will be corrected for bias due to population stratification using the Linear Mixed Model (LMM) and consider additive, dominant and recessive genetic models. The investigators will then perform LMM association testing for variants with P-value in the discovery analysis less than 1x10^-5 in Oceanic cases and controls from Fiji and combine the association statistics by fixed-effects meta-analysis. The investigators will consider variants with significant effects in the same direction in discovery and replication analyses with combined P-value less than 1x10^-8 to have replicated. Unless there is clear evidence that associated variants are specific to Oceanic populations, further replication analyses for associated variants in cases and controls of Indian Descent from Fiji, as well as individuals of other and admixed ethnicities from both Fiji and New Caledonia.
Recruitment completed in December 2013. After receipt of funding from the British Heart Foundation, genotyping and analysis will begin in July 2014.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02188862
|Colonial War Memorial Hospital|
|Centre Hospitalier Territorial de Nouvelle Caledonie|
|Noumea, New Caledonia|
|Wellcome Trust Centre for Human Genetics, University of Oxford|
|Oxford, United Kingdom, OX3 7BN|
|Principal Investigator:||Tom Parks, MRCP DTM&H||University of Oxford|
|Principal Investigator:||Mariana Mirabel, MD||Institut National de la Santé Et de la Recherche Médicale, France|
|Principal Investigator:||Andrew C Steer, FRACP PhD||University of Melbourne|
|Study Chair:||Adrian VS Hill, DPhil DM||University of Oxford|