Association Between FCGR Polymorphisms And Cryptococcosis In HIV-uninfected Patients

Background Cryptococcosis, which is caused by Cryptococcus neoformans and C. gattii, often occurs in patients with cellular immunodeficiency, including patients with acquired immune deficiency syndrome (AIDS), transplant recipients who are on longterm immunosuppressants, and patients who receive corticosteroids. The mortality among HIV-uninfected patients with cryptococcal meningitis can reach as high as20%to44%. There are higher proportions of immunocompetent individuals among HIV-uninfected cryptococcosis patients reported in studies from Aisa. The pathogenesis of cryptococcosis has been explored in many previous studies. However, issues such as the underlying mechanism for the propensity of the fungi to infect the central nervous system (CNS), and the susceptible factors for cryptococcosis in apparently immunocompetent patients have not yet been clarified. Fc gamma receptors (FcyRs) belong to a family of recptors which are expressed on the membrane of a wide range of immune cells, and mediate a variety of immune responses after binding to IgG-opsonized pathogens or immune complexes. Functional genetic polymorphisms have been identified in the low-affinity FcyRs. Associations have been found between FCGR polymorphisms and infectious diseases. However, the relationship between FcyR genetic polymorphisms and cryptococcosis has not been elucidated in Chinese patients.Part1Association between FCGR polymorphisms and the susceptibility to cryptococcosisPurpose To describe the distributions of FCGR polymorphisms in HIV-uninfected patients with cryptococcosis in China, and to investigate the association of FCGR polymorphisms with the susceptibility to cryptococcosis.Methods We compared the distributions of4functional polymorphisms including FCGR2A131H/R, FCGR3A158F/V, FCGR3B NA1/NA2, and FCGR2B232I/T, and the phenotypes of these polymorphisms in198cryptococcosis patients with those in190healthy controls. Genotyping of eight SNPs in FCGRs were performed by multiplex SNaPshot technology using DNA extracted from blood samples. Results There were198cases with cryptococcal infection, with a median age of45years. Of these patients,126(64%) were male, and133(67%) were confirmed cases. There were42%(83/198) immunocomprimised patients, with immunocompromising conditions including corticosteroids medication, autoimmune diseases, diabetes mellitus, idiopathic CD4+T lymphocytopenia, etc. Among the198patients, there were117(59%) patients with cryptococcal meningitis, and122(62%) cases with pulmonary cryptococcosis, and41(21%) with both cryptococcal meningitis and pulmonary cryptococcosis. Compared to healthy controls, individuals who carried FCGR2B232T+(232I/T and232T/T) genotypes were less frequently observed in patients with cryptococcal meningitis (OR,0.605,95%CI,0.38-0.98, P=0.039). Among immunocompetent patients, the FCGR2B232T+genotypes also under-represented in patients with cryptococcal meningitis (OR,0.511,95%CI,0.27-0.9, P=0.033). No significant difference was found among FCGR2A131H/R, FCGR3A158F/V, FCGR3B NA1/NA2genotype frequencies between patients and controls. The distributions of FCGR haplotypes were also significantly different between patients with cryptococcosis and controls.Conclusion FCGR2B232I/T is associated with susceptibility to cryptococcal meningitis, individuals earring FCGR2B232T+genotypes may be less susceptible to cryptococcal meningitis.Part2Association between FCGR polymorphisms and the pathogenesis of cryptococcosisPurpose To analyze the association of FCGR polymorphisms with the infectious sites in HIV-uninfected patients with cryptococcosis, and to investigate the role FCGR polymorphisms in host defense against cryptococcal infection.Methods The overall198cryptococcosis patients were first categorized into patients with CNS infection and those without CNS infection. Then classified according to sites of infection into the following3groups:patients with meningitis and no pulmonary involvement; patients with pulmonary cryptococcosis without meningitis; and patients with both meningitis and pulmonary cryptococcosis. These198patients also divided into groups with or without disseminated infection. We compared the genotype distributions of FCGR2A131H/R, FCGR3A158F/V, FCGR3B NA1/NA2, and FCGR2B232I/T in these groups respectively.Results There were117cases with CNS infection and81non-CNS infection cases; and there were65patients with only cryptococcal meningitis,81patients with only pulmonary cryptococcosis, and41patients with both cryptococcal meningitis and pulmonary cryptococcosis. There were47cases with disseminated infection and140patients with localized infection. The genotype of FCGR2A131R/R was over-represented in patients with CNS infection compared with those without CNS infection (OR,3.53,95%CI,1.27-9.73, P=0.011), and the FCGR2B232T+(232I/T and232T/T) genotypes were underpresented in immunocompetent CNS infection patients compared with those non-CNS infection immunocompetent ones (OR,0.403,95%CI,0.19-0.87, P=0.019). The FCGR2B232T+(232I/T and232T/T) genotypes were also less frequently seen in immunocompetent cases who had both cryptococcal meningitis and pulmonary cryptococcosis compared to immunocompetent patients who only had pulmonary cryptococcosis (OR,0.23,95%CI,0.06-0.92, P=0.040). No significant difference was found among FCGR2A131H/R, FCGR3A158F/V, FCGR3B NA1/NA2and FCGR2B232I/T genotype frequencies between patients with disseminated infection and those with localized infection.Conclusions FCGR2A131H/R and FCGR2B232I/T are associated with the susceptibility to cryptococcal CNS infection among cryptococcosis patients. FCGR2A131R/R contributes to the increased incidence of CNS cryptococcal infection, and patients who carry the FCGR2B232T+genotypes have less CNS infection.