Inflammatory Protein Profiles in Plasma of Candidaemia Patients and the Contribution of Host Genetics to Their Variability

Circulatory inflammatory proteins play a significant role in anti-Candidahost immune defence. However, little is known about the genetic variation that contributes to the variability of inflammatory responses in response toC. albicans. To systematically characterize inflammatory responses inCandidainfection, we profiled 91 circulatory inflammatory proteins in peripheral blood mononuclear cells (PBMCs) stimulated withC. albicansyeast isolated from 378 individuals of European origin from the 500 Functional Genomics (500FG) cohort of the Human Functional Genomics Project (HFGP) and Lifelines Deep cohort. To identify the genetic factors that determine variation in inflammatory protein responses, we correlated genome-wide single nucleotide polymorphism (SNP) genotypes with protein abundance (protein quantitative trait loci, pQTLs) produced by theCandida-stimulated PBMCs. Furthermore, we investigated whether differences in survival of candidaemia patients can be explained by modulating levels of inflammatory proteins. We identified five genome-wide significant pQTLs that modulate IL-8, MCP-2, MMP-1, and CCL3 in response toC. albicans. In addition, our genetic analysis suggested thatGADD45Gfrom rs10114707 locus that reached genome-wide significance could be a potential core gene that regulates a cytokine network uponCandidainfection. Last but not least, we observed that a trans-pQTL marked from SNP rs7651677 at chromosome 3 that influences urokinase plasminogen activator (uPA) is strongly associated with patient survival (P_survival= 3.52 x 10^-5, OR 3). Overall, our genetic analysis showed that genetic variation determines the abundance of circulatory proteins in response toCandidainfection.