Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada.
JC Wilt Infectious Diseases Research Centre, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Mycoses. 2024 Sep;67(9):e13800. doi: 10.1111/myc.13800.
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.
芽生菌病是一种肺部疾病，由芽生菌属引起，这是一组在多个地理区域流行的致病性二态真菌，特别是在加拿大马尼托巴省和安大略省西北部。免疫抑制是影响疾病易感性的一个主要危险因素，但宿主免疫尚未得到很好的理解。遗传免疫缺陷也会影响疾病，IL6、GATA2 和 VDBP 的变异已被证明会影响易感性。疾病易感性和严重程度的其他遗传因素仍未被发现。我们的研究旨在确定来自加拿大马尼托巴省和安大略省西北部芽生菌病病例对照队列中的潜在遗传危险因素。
对 18 例芽生菌病病例和 9 例对照的外显子组进行测序，对变体进行识别和准确性和质量过滤。我们进行了候选基因优先级排序和变体聚集，以确定遗传关联，并探索了全外显子组数据集。
在外显子组数据集中发现了 42 个候选基因中的 99 个遗传变异。虽然 TYK2 中的两个非同义变体在病例中富集，但在单变体分析中没有发现与易感性相关的变体，这表明它们可能在易感性中起作用。基于基因的关联分析发现 TLR1 中的变体在对照组中富集（p=0.024），这表明可能存在保护作用。基因簇分析发现染色质重塑、蛋白酶体和鞭毛内运输相关基因中的遗传变异在病例中显著富集（错误发现率<14%）。
本研究的发现显示了与芽生菌病易感性的新关联。更好地了解宿主免疫和对芽生菌感染的遗传易感性有助于为改善结果提供临床实践信息。
