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A genome-wide association study has revealed how a person’s unique genetic makeup can influence the fungi in their intestinal tract and the impact this interaction can have their risk of chronic diseases.
The research, in PLOS Biology, is the first of its kind to examine how human genetics underpins the gut mycobiome.
It highlights a previously unknown triangulation between human genetics, gut fungi, and chronic disease.
“Gut fungi are greatly understudied compared to other gut microbes like bacteria and archaea,” said researcher Emily Davenport, PhD, from Penn State University.
“We know much less about what determines the fungi that reside in the gut, and whether they are important for human health.
“These results demonstrate for the first time that host genetics can influence the fungi that live in the gut, and provide clues about the physiological mechanisms that determine their abundances.”
Despite growing evidence that human genetic variation is linked with the composition of gut bacteria and risk of disease, there is a striking gap in knowledge when it comes to gut fungi.
Indeed, it has been widely perceived that gut fungi are diet-sourced passengers that transiently pass through the gastrointestinal tract.
This has hindered investigations into how fungi assemble into a complex, multidimensional community and counters mounting evidence that gut fungi underpin human diseases and gut inflammation.
To investigate further, Davenport and team paired gut mycobiome profiles with human genotypes from 125 participants in the Human Microbiome Project.
This revealed 148 fungi associated variants (FAVs) across seven chromosomes that were statistically associated with nine fungal taxa.
Post hoc analyses identified FAVs that overlapped with the protein-coding genes PTPRC, ANAPC10, NAV2, and CDH13. FAVs were also associated with tissue-specific gene expression, suggesting triadic interactions with human genetic background, gut fungi, and antifungal immunity.
Of note, all gut fungi that statistically linked to FAV tissue-specific gene expression were lineages with known human pathogens.
The researchers point out that the relative abundance of the gut yeast Kazachstania was associated with genetic risk variants associated with cardiovascular disease. Specifically, it was linked with genetic variation in CDH13 encoding T-cadherin, a protein linked to cardiovascular disease.
Two-sample Mendelian randomization analysis further demonstrated a causal link between Kazachstania and cardiovascular disease risk, using an outcome GWAS on coronary artery disease.
“Determining whether human genetics simultaneously associates with differential microbial abundance and disease risk is a central challenge to resolve with substantive potential for personalized diagnostics and/or biotherapeutics,” the authors wrote. “Taken together, this work advances the canonical, two-dimensional focus on human genetics and gut bacteria to the gut fungal biosphere.”
Davenport added: “These results offer an exciting first glimpse into host genetic regulation of the mycobiome. Even more exciting, they open up many more questions about how that occurs.
“Will we see different associations in different populations? Are there interactions between gut fungi and gut bacteria that are modulated by genetics? We are excited to see the new avenues this research opens up.”