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Genetics of rheumatic fever and rheumatic heart disease

Nature Reviews Cardiology volume 17, pages 145–154 (2020)Cite this article

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Abstract

Rheumatic heart disease (RHD) is a complication of group A streptococcal infection that results from a complex interaction between the genetic make-up of the host, the infection itself and several other environmental factors, largely reflecting poverty. RHD is estimated to affect 33.4 million people and results in 10.5 million disability-adjusted life-years lost globally. The disease has long been considered heritable but still little is known about the host genetic factors that increase or reduce the risk of developing RHD. In the 1980s and 1990s, several reports linked the disease to the human leukocyte antigen (HLA) locus on chromosome 6, followed in the 2000s by reports implicating additional candidate regions elsewhere in the genome. Subsequently, the search for susceptibility loci has been reinvigorated by the use of genome-wide association studies (GWAS) through which millions of variants can be tested for association in thousands of individuals. Early findings implicate not only HLA, particularly the HLA-DQA1 to HLA-DQB1 region, but also the immunoglobulin heavy chain locus, including the IGHV4-61 gene segment, on chromosome 14. In this Review, we assess the emerging role of GWAS in assessing RHD, outlining both the advantages and disadvantages of this approach. We also highlight the potential use of large-scale, publicly available data and the value of international collaboration to facilitate comprehensive studies that produce findings that have implications for clinical practice.

Key points

  • Rheumatic heart disease (RHD) remains a public health priority in low-income and middle-income countries, despite being nearly eliminated in high-income countries.

  • A combination of risk factors can contribute to increased susceptibility to group A streptococcal infection, rheumatic fever and, ultimately, RHD.

  • The risk of rheumatic fever in an individual with a family history of RHD is nearly fivefold higher than that in an individual with no family history of RHD.

  • Plausible susceptibility loci have been evaluated on chromosome 6 in the human leukocyte antigen (HLA) region and elsewhere in the human genome.

  • Initial findings from genome-wide association studies (GWAS), through which millions of variants can be tested for association in thousands of individuals, implicate not only the HLA region, but also the immunoglobulin heavy chain (IGH) locus on chromosome 14.

  • Large-scale collaborative efforts to combine GWAS data have the potential to advance our understanding of the genetics of RHD.

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Fig. 1: Pathogenesis of rheumatic fever and rheumatic heart disease.
Fig. 2: Reported susceptibility genes for rheumatic fever and rheumatic heart disease.
Fig. 3: Detection of underlying causal variation.
Fig. 4: Effect sizes for the IGHV4-61*02 risk allele by diagnostic certainty.
Fig. 5: Power calculations for genome-wide association studies.
Fig. 6: Statistical estimation of variants using imputation.

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Acknowledgements

T.P. is supported by the UK National Institute for Health Research (ACF-2016–20–001). The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health.

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Authors and Affiliations

  1. Hatter Institute for Cardiovascular Diseases Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa

    Babu Muhamed & Karen Sliwa

  2. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

    Tom Parks

  3. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

    Tom Parks

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B.M. and K.S. discussed the content of the article, T.P. compiled an outline version, and B.M. and T.P. wrote the first draft. All the authors reviewed and edited the manuscript before submission.

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Correspondence to Karen Sliwa.

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Nature Reviews Cardiology thanks L. Guilherme, E. Okello and C. Sable for their contribution to the peer review of this work.

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Related links

23andMe: https://www.23andme.com/

ExAC database: http://exac.broadinstitute.org/

RHDGen Network: https://h3africa.org/index.php/consortium/projects/the-rhdgen-network-genetics-of-rheumatic-heart-disease-and-molecular-epidemiology-of-streptococcus-pyogenes-pharyngitis/

UK Biobank: https://www.ukbiobank.ac.uk/

Glossary

Monozygotic twins

Often termed ‘identical’, monozygotic twins result from the fertilization of a single egg that splits into two and share close to 100% of their genetic material.

Dizygotic twins

Often termed ‘non-identical’, dizygotic twins result from the fertilization of two separate eggs during the same pregnancy; like most other siblings, they share approximately 50% of their genetic material.

Traits

A character or phenotype in genetic research.

Alleles

A version of a gene or other genetic sequence.

Population structure

The presence of a systematic difference in allele frequencies between subgroups of a population, possibly owing to different ancestry.

Linkage disequilibrium

Statistical association between particular alleles at separate but linked loci, normally the result of the ancestral haplotype being common in population studies.

Cryptic relatedness

When individuals in a genetic association study are more closely related to one another than assumed by the investigators, which can be a confounding factor in both case–control and genome-wide association studies.

Mendelian randomization

A method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies.

Imputation

A statistical process used in genetics research to estimate genotypes that are not directly assayed in a sample of individuals.

Linear mixed models

Regression models that take into account both variation that is explained by the independent variables of interest (fixed effects) and variation that is not explained by the independent variables of interest (random effects).

Haplotypes

A collection of genetic variants that occur in close proximity on a single chromosome and are inherited together.

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Muhamed, B., Parks, T. & Sliwa, K. Genetics of rheumatic fever and rheumatic heart disease. Nat Rev Cardiol 17, 145–154 (2020). https://doi.org/10.1038/s41569-019-0258-2

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