Genetic Susceptibility to Rheumatic Heart Disease in the Pacific Region

Sponsor

University of Oxford (Other)

Overall Status

Completed

CT.gov ID

NCT02188862

Collaborator

Ministry of Health, Fiji (Other), Fiji National University (Other), Institut National de la Santé Et de la Recherche Médicale, France (Other), Institut Necker Enfants Malades (Other), Centre Hospitalier Territorial de Nouvelle-Calédonie (Other), University of Melbourne (Other)

2,372

Enrollment

Locations

Duration (Months)

790.7

Patients Per Site

52.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate whether there are genetic differences between patients with rheumatic heart disease and members of the general population.

Condition or Disease	Intervention/Treatment	Phase
Rheumatic Heart Disease Mitral Stenosis

Detailed Description

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.

Study Design

Study Type:

Observational

Actual Enrollment :

2372 participants

Observational Model:

Case-Control

Time Perspective:

Retrospective

Official Title:

Genome-wide Association Study of Susceptibility to Rheumatic Heart Disease in Fiji and New Caledonia

Study Start Date :

Sep 1, 2012

Actual Primary Completion Date :

Dec 1, 2013

Actual Study Completion Date :

Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Rheumatic heart disease cases Patients with rheumatic heart disease as defined in the case criteria
Population controls 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)

Outcome Measures

Primary Outcome Measures

Rheumatic heart disease diagnosis [At enrolment]
Diagnosis of rheumatic heart disease as layout in enrolment criteria for cases.

Secondary Outcome Measures

Mitral stenosis diagnosis [At enrolment]
History or echocardiographic diagnosis of mitral stenosis

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Cases
Inclusion Criteria:

Diagnosis of rheumatic heart disease based on one of:
World Heart Federation definite echocardiographic criteria
World Heart Federation borderline echocardiographic criteria and history of acute rheumatic fever
Mitral stenosis with valve area less than 2.0 cm2
Previous surgery for rheumatic heart disease

Exclusion Criteria:

Age less than five years
Inability to give consent

New Controls
Inclusion criteria:

Healthy individual living in a community where cases were identified

Exclusion Criteria:

Past medical history or systems suggestive of rheumatic heart disease, acute rheumatic fever or other valvular heart disease
Age less than five years
Inability to give consent

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Colonial War Memorial Hospital	Suva	Fiji
2	Centre Hospitalier Territorial de Nouvelle Caledonie	Noumea	New Caledonia
3	Wellcome Trust Centre for Human Genetics, University of Oxford	Oxford	United Kingdom	OX3 7BN

Sponsors and Collaborators

University of Oxford
Ministry of Health, Fiji
Fiji National University
Institut National de la Santé Et de la Recherche Médicale, France
Institut Necker Enfants Malades
Centre Hospitalier Territorial de Nouvelle-Calédonie
University of Melbourne

Investigators

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