Genetic Susceptibility to Rheumatic Heart Disease in the Pacific Region

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

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.

Study Overview

• Status: Completed
• Conditions: 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 Type: Observational
• Enrollment (Actual): 2372

Contacts and Locations

Study Locations

• Fiji
  • Suva, Fiji
    • Colonial War Memorial Hospital
• New Caledonia
  • Noumea, New Caledonia
    • Centre Hospitalier Territorial de Nouvelle Caledonie
• United Kingdom
  • Oxford, United Kingdom, OX3 7BN
    • Wellcome Trust Centre for Human Genetics, University of Oxford

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Cases:

• Prevalent and incident cases of rheumatic heart disease ascertained from disease registers, primary care clinics and hospital services.

New Controls:

• Individuals volunteering from communities where cases were identified.

Existing Controls:

• Individuals from this region who have previously been recruited to population genetics research studies.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rheumatic heart disease diagnosis	Diagnosis of rheumatic heart disease as layout in enrolment criteria for cases.	At enrolment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitral stenosis diagnosis	History or echocardiographic diagnosis of mitral stenosis	At enrolment

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: July 10, 2014
• First Submitted That Met QC Criteria: July 11, 2014
• First Posted (Estimate): July 14, 2014

Study Record Updates

• Last Update Posted (Estimate): July 15, 2014
• Last Update Submitted That Met QC Criteria: July 14, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: Genetics; Streptococcus pyogenes; Rheumatic heart disease; Acute rheumatic fever; Group A streptococcal disease; Oceania
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Infections; Musculoskeletal Diseases; Connective Tissue Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Streptococcal Infections; Gram-Positive Bacterial Infections; Heart Valve Diseases; Rheumatic Fever; Heart Diseases; Rheumatic Diseases; Mitral Valve Stenosis; Rheumatic Heart Disease
• Other Study ID Numbers: PACIFICRHDGEN