Rheumatic Heart Disease Clinical Trial
Official title:
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.
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.
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Observational Model: Case Control, Time Perspective: Retrospective
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