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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 x 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.

Original languageEnglish
Article numberofaa489
Pages (from-to)ofaa489
Number of pages10
JournalOpen Forum Infectious Diseases
Volume7
Issue number11
DOIs
Publication statusPublished - 1-Nov-2020

Keywords

  • Africa
  • Cryptococcal meningitis
  • genome-wide association study (GWAS)
  • HIV
  • macrophage colony-stimulating factor (M-CSF)
  • MACROPHAGE ANTICRYPTOCOCCAL ACTIVITY
  • EARLY FUNGICIDAL ACTIVITY
  • AMPHOTERICIN-B
  • MENINGITIS
  • DISEASE
  • CSF
  • FLUCYTOSINE
  • FLUCONAZOLE
  • CANDIDIASIS
  • THERAPY

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