Candidemia is the fourth most common cause of bloodstream infection, with a high mortality rate of up to 40%. Identification of host genetic factors that confer susceptibility to candidemia may aid in designing adjunctive immunotherapeutic strategies. We hypothesized that variation in immune genes may predispose to candidemia. We analyzed 118,989 SNPs across 186 loci known to be associated with immune-mediated diseases in the largest candidemia cohort to date of 217 patients of European ancestry and a group of 11,920 controls. The significant associations were validated by comparison with a disease-matched control group. We observed significant association between candidemia and SNPs in the CD58 (P = 1.97×10−11; OR = 4.68), LCE4A-C1orf68 (P = 1.98×10−10; OR = 4.25) and TAGAP (P = 1.84×10−8; OR = 2.96) loci. Individuals carrying two or more risk alleles had an increased risk for candidemia of 19.4-fold compared to individuals carrying no risk allele. While latent cornified envelope (LCE) genes contribute to mucosal integrity, the role of CD58 and TAGAP in host defense is unknown. Studies using transcriptomics, pathway analysis, and immunological validation showed that CD58 plays a role in the recognition and phagocytosis of Candida by macrophages, while TAGAP was involved in Candida-induced cytokine production. TAGAP-deficient mice were more susceptible to systemic Candida infection. We identified three novel genetic risk factors for candidemia, which we subsequently validated for their role in antifungal host defense.

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Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients' risk stratification.

Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in solid-organ transplant recipients, particularly in patients not receiving antiviral prophylaxis.