Objectives: Candida albicans (C.albicans) is the most common opportunistic fungal pathogen, causing a bloodstream infection (candidemia). However, not all at-risk patients develop candidemia, indicating that genetics influence their susceptibility. Cytokines play a critical role in anti-fungal host defense, but a comprehensive approach to understanding the genetic architecture of cytokine responses against fungi and their role in fungal disease susceptibility is still lacking.
Materials/methods: To identify susceptibility genes, we performed the first genome-wide association analysis (GWAS) by using the largest candidemia cohort to date of European ancestry. We assessed the cytokine production capacity in different cellular systems following stimulation with three different opportunistic fungal pathogens: Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans. To strengthen the GWAS, we followed a systems approach to integrate genetic variants that showed association with cytokine production. We profiled transcriptome response to C. albicans in peripheral blood mononuclear cells (PBMCs) of 75 healthy individuals and identified the Candida-response expression QTLs (eQTs).  Candida-induced cytokine profiling in PBMCs from healthy volunteers was also assessed and we mapped cytokine QTLs (cQTLs). 
Results: The inter-individual variation pattern in cytokine production was specific for each fungal stimulus, but was similar between C. albicans yeast and hyphae. Using cytokine QTL mapping we identified a novel significant locus that regulates IL-17A production upon stimulation with C. albicans hyphae and 10 shared significant loci in response to both C. albicans morphotypes, including the TLR2 gene that regulates cytokine production. We observed enrichment of common genetic loci that regulate T-cell-derived cytokine levels in response to both C. albicans and C. neoformans, and identified seven significant genetic loci including the well-known chronic mucocutaneous candidiasis susceptibility gene, TRAF3IP2. To explain susceptibility to disseminated fungal infections, we performed the first candidemia genome-wide association study and identified genes at independent cytokine QTLs important for susceptibility to infection. These loci were enriched for the lipid metabolism functional pathway. 
Conclusion: Our data suggest that genetic loci that affect cytokine responses to C. albicans can partly explain an individual’s disease susceptibility

4 / A genetic and genomics approach identifies novel pathways of human antifungal immune responses