# Systems-level genetic patterns underlying disseminated coccidioidomycosis in humans

> **NIH NIH R21** · UNIVERSITY OF ARIZONA · 2020 · $244,304

## Abstract

PROJECT SUMMARY
Disseminated coccidioidomycosis (DCM) is a rare and potentially life-threatening consequence of infection
with a desert soil dwelling fungal pathogen native to the Southwestern USA (Coccidioides spp.). The reason
why a subset (<5%) of otherwise healthy people develop this adverse outcome after infection while most others
do not is largely unknown. However, evidence points to genetics, primarily involving variation in the immune
system. To discover the systems genetic patterns and pathways associated with DCM, we will examine the
differential distribution of variants in biologically meaningful gene sets at genome-wide scale to find patterns
that underlie disease susceptibility. Focusing on aggregated systems-level sets allows us to find patterns in the
presence of cross-patient differences, and substantially increases our statistical discovery power by reducing
the number of features being directly tested. This study will be the first of its scope and kind, using the largest
cohort ever assembled for this disease (DNA collected from 147 susceptible DCM cases and 388 resistant
controls presenting as self-limited pulmonary coccidioidomycosis). The data and results gathered under this
proposal thus present a unique resource to lay important foundations for the study of DCM pathogenesis. The
DNA has been both (i) genome-wide genotyped for common variation, and (ii) exome sequenced to look for
rare, protein-altering variation. In our first Aim, we will study the genotype data in three different ways. First,
we will look for association between DCM and variation in the human leukocyte antigen region (HLA) which
plays an important role in many infectious diseases. Second, we will look at the distribution of patient
genotypes at infection-relevant reQTL variant sets to model if DCM versus PUL have differences correlated
with their phenotype. These reQTL variant sets are groups of DNA positions where different alleles can cause
stronger or weaker gene expression responses after infection or stimulation, and differences between DCM and
PUL at those positions could imply that their Coccidioides-response capacity may differ. Third, we will conduct
a pathway-association study using both hypothesis-driven and unbiasedly selected pathways (sets of genes) to
see if these genesets are enriched for variants associated with DCM. For our second Aim, we will analyze the
rare variants found in patient exomes to compare whether DCM participants have an excess of rare and
protein-damaging mutations in immune or other candidate pathways. We will use a two-step version of the
small sample size optimized Sequence Kernel Association test, comparing the distribution of these mutations
between DCM and PUL participants. Using a pathway, or gene set approach allows us to look at differentially
impacted systems, rather than requiring each participant to carry the same single-gene mutation. Results of the
studies under these two aims will lead to a better understan...

## Key facts

- **NIH application ID:** 9995276
- **Project number:** 1R21AI152394-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** YVES A LUSSIER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $244,304
- **Award type:** 1
- **Project period:** 2020-03-06 → 2021-02-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995276

## Citation

> US National Institutes of Health, RePORTER application 9995276, Systems-level genetic patterns underlying disseminated coccidioidomycosis in humans (1R21AI152394-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9995276. Licensed CC0.

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