Details

Autor(en) / Beteiligte

• Kannambath, Shichina
• Jarvis, Joseph N
• Wake, Rachel M
• Longley, Nicky
• Loyse, Angela
• Matzaraki, Vicky
• Aguirre-Gamboa, Raúl
• Wijmenga, Cisca
• Doyle, Ronan
• Paximadis, Maria
• Tiemessen, Caroline T
• Kumar, Vinod
• Pittman, Alan
• Meintjes, Graeme
• Harrison, Thomas S
• Netea, Mihai G
• Bicanic, Tihana

Titel

Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans

Ist Teil von

• Open forum infectious diseases, 2020-11, Vol.7 (11), p.ofaa489-ofaa489

Ort / Verlag

US: Oxford University Press

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract 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. In this first GWAS conducted in cryptococcosis, we describe, replicate and functionally validate novel loci upstream of the colony stimulating factor 1 (CSF1) gene encoding macrophage colony-stimulating factor (M-CSF) as associated with susceptibility to cryptococcosis in HIV-infected South Africans.