Exome Sequencing of a Blastomycosis Case-Control Cohort From Manitoba and Northwestern Ontario, Canada.
Blastomyces
Manitoba
Ontario
blastomycosis
case–control
exome sequencing
genetic predisposition
risk factor
Journal
Mycoses
ISSN: 1439-0507
Titre abrégé: Mycoses
Pays: Germany
ID NLM: 8805008
Informations de publication
Date de publication:
Sep 2024
Sep 2024
Historique:
revised:
05
09
2024
received:
23
06
2024
accepted:
08
09
2024
medline:
23
9
2024
pubmed:
23
9
2024
entrez:
22
9
2024
Statut:
ppublish
Résumé
Blastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case-control cohort from Manitoba and northwestern Ontario, Canada. Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset. Ninety-nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single-variant analysis although two non-synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene-based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%). The findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes.
Sections du résumé
BACKGROUND
BACKGROUND
Blastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case-control cohort from Manitoba and northwestern Ontario, Canada.
METHODS
METHODS
Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset.
RESULTS
RESULTS
Ninety-nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single-variant analysis although two non-synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene-based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%).
CONCLUSIONS
CONCLUSIONS
The findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13800Subventions
Organisme : Public Health Agency of Canada
Organisme : Health Sciences Centre Foundation
Informations de copyright
© 2024 The Author(s). Mycoses published by Wiley‐VCH GmbH.
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