Genetic Susceptibility to Rheumatic Heart Disease in the Pacific Region


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.

Full Title of Study: “Genome-wide Association Study of Susceptibility to Rheumatic Heart Disease in Fiji and New Caledonia”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Retrospective
  • Study Primary Completion Date: December 2013

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 1×10^-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 1×10^-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.

Arms, Groups and Cohorts

  • 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)

Clinical Trial Outcome Measures

Primary Measures

  • Rheumatic heart disease diagnosis
    • Time Frame: At enrolment
    • Diagnosis of rheumatic heart disease as layout in enrolment criteria for cases.

Secondary Measures

  • Mitral stenosis diagnosis
    • Time Frame: At enrolment
    • History or echocardiographic diagnosis of mitral stenosis

Participating in This Clinical Trial

1. Cases

1. 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

2. Exclusion Criteria:

  • Age less than five years
  • Inability to give consent

2. New Controls

1. Inclusion criteria:

  • Healthy individual living in a community where cases were identified

2. 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

Gender Eligibility: All

Minimum Age: 5 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Oxford
  • Collaborator
    • Ministry of Health, Fiji
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Tom Parks, MRCP DTM&H, Principal Investigator, University of Oxford
    • Mariana Mirabel, MD, Principal Investigator, Institut National de la Santé Et de la Recherche Médicale, France
    • Andrew C Steer, FRACP PhD, Principal Investigator, University of Melbourne
    • Adrian VS Hill, DPhil DM, Study Chair, University of Oxford

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