Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry.

Lesley-Ann Gray,Genevieve Syn,Steven Y C Tong,Michael Inouye,Ngiare Brown,Heather A D’Antoine,Bo Reményi,Jenefer M Blackwell,Jonathan R Carapetis,Dawn Bessarab,Melita Mckinnon,Andrew Steer

doi:10.1093/infdis/jix497

Abstract

Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P = 1.86 × 10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.09-1.90; P = 9.56 × 10-3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07-1.52; P = 7.15 × 10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P = 2.36 × 10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the 2-risk haplotypes than the protective haplotype. Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.

Highlights

Acute rheumatic fever (ARF) results from an autoimmune response to infections due to group A Streptococcus (GAS), Streptococcus pyogenes
Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of rheumatic heart disease (RHD) pathogenesis
Genetic population structure was clearly evident from principal components analysis, largely capturing the geographic distribution of the remote Aboriginal Australian communities

Summary

Introduction

Acute rheumatic fever (ARF) results from an autoimmune response to infections due to group A Streptococcus (GAS), Streptococcus pyogenes. Recurrences of ARF and its associated cardiac valvular inflammation lead to chronic valvular damage and rheumatic heart disease (RHD). In. Australia, RHD is most prevalent in the Indigenous population, affecting 2-6 per individuals (and as high as 15/1000 school aged children in the northern tropical regions[2])[3, 4]. One hypothesis to explain inflammation of valvular tissue is molecular mimicry (reviewed [1, 5-8]). Peptides from GAS proteins are processed by antigen presenting cells in the throat and heart tissue and presented on Human. Rheumatic heart disease (RHD) following Group A Streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers pro-inflammatory cardiac valve-reactive T-cells

Methods

Results

Conclusion