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

BACKGROUND

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 () gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at  < 10 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42-0.66;  =5.96 × 10). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against 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.