Common genetic variants of autoimmunity confer susceptibility to candididemia. V. Magadi Gopalaiah1, S. Cheng2, M. D. Johnson3,4, S. S. Smeekens2, L. A. B. Joosten2, J. R. Perfect3,4, B. Kullberg2, C. Wijmenga1, M. G. Netea2 1) Genetics, University Medical Center Groningen, Groningen, The Netherlands; 2) Department of Internal Medicine and Nijmegen Institute for infection, Inflammation, and Immunity, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 3) Duke University Medical Center, Durham, North Carolina, USA; 4) Department of Clinical Research, Campbell University School of Pharmacy, Buies Creek North Carolina USA.

   Candidemia is the fourth most common cause of sepsis, with a high mortality rate of up to 40% despite the availability of potent antifungal drugs. Identification of host genetic factors that confer susceptibility to candidemia may aid in designing adjunctive preventive and therapeutic strategies. Ten monogenetic diseases are associated with increased susceptibility to chronic mucocutaneous candidiasis. Intriguingly, single nucleotide polymorphisms (SNPs) in eight out of the ten of these monogenetic disease genes are also associated with susceptibility to different immune-mediated diseases. Thus, we hypothesized that genes involved in the immune system could be strong susceptibility candidates to candidemia. To test our hypothesis, we analyzed around 200,000 SNPs in 186 loci that are associated with 12 different immune-mediated diseases using Immunochip SNP array in the largest candidemia cohort to-date of 316 cases, and in 11,995 controls. The significant associations were replicated in two independent candidemia cohorts. We found SNPs in the CD58 (P = 1.97 x 10-11; OR = 4.68), LCE4A-C1orf68 (P = 1.98 x 10-10; OR = 4.25) and TAGAP (P = 1.84 x 10-8; OR = 2.96) regions to be significantly associated with candidemia. The cumulative effect of these three SNPs indicated that individuals with 2 or more risk alleles have 17.6-fold higher risk of candidemia compared with those with one or no risk allele, implying that these SNPs could be of clinical use for risk prediction. All three SNPs are located within non-coding region and thus may be regulatory in function. Transcriptomics and pathway analysis on macrophages in which CD58 was blocked by siRNA suggested defects in phagocytosis and IL-6 pathway. Blocking CD58 by siRNA induced the incapacity of human macrophages to inhibit yeast-fungal transformation and fungal growth. The physical co-localization of CD58 and Candida during the phagocytosis suggested that CD58 might play a role in recognition and phagocytosis of Candida in macrophages. In contrast, TAGAP was involved in Candida-induced cytokine production. The role of TAGAP was tested in an in vivo disseminated candidiasis model. The fungal loads in liver and kidney were significantly increased in TAGAP -/- mice, demonstrating that TAGAP is important for host defense against Candida infection. In summary, our study not only identified novel genetic risk factors to candidemia but also validated these pathways to be important for antifungal host defense.

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