Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans.
Kannambath, Shichina;
Jarvis, Joseph N;
Wake, Rachel M;
Longley, Nicky;
Loyse, Angela;
Matzaraki, Vicky;
Aguirre-Gamboa, Raúl;
Wijmenga, Cisca;
Doyle, Ronan;
Paximadis, Maria;
+7 more...Tiemessen, Caroline T;
Kumar, Vinod;
Pittman, Alan;
Meintjes, Graeme;
Harrison, Thomas S;
Netea, Mihai G;
Bicanic, Tihana;
(2020)
Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans.
Open Forum Infectious Diseases, 7 (11).
ofaa489-.
DOI: https://doi.org/10.1093/ofid/ofaa489
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BACKGROUND: Cryptococcus is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%-10% of patients with HIV/acquired immune deficiency syndrome and profound CD4+ T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans. METHODS: We analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen). RESULTS: Six loci upstream of the colony-stimulating factor 1 (CSF1) gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at P < 10-6 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped CSF1 SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42-0.66; P = 5.96 × 10-8). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against Cryptococcus in HIV-infected patients and healthy, ethnically matched controls. CONCLUSIONS: This first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis.