IL-4 polymorphism influences susceptibility to Pneumocystis jirovecii pneumonia in HIV-positive patients

Abstract

Objectives: Pneumocystis jirovecii pneumonia (PJP) is an important cause of morbidity and mortality in HIV-positive patients. Polymorphisms in immune genes are increasingly reported to influence susceptibility to fungal infections. We analysed the role of 21 single nucleotide polymorphisms from 19 candidate genes on PJP development in patients from the Swiss HIV Cohort Study.

Design and methods: The analysis included patients with a nadir CD4 T-cell count less than 200 cells/μl, divided into a discovery (N = 1645) and a replication (N = 1861) cohort. The associations were analysed by using cumulative incidence curves as well as competing risk regression over 18 years, starting from the estimated date of HIV infection, considering death a competing risk, with censoring at lost follow-up, and assuming the dominant mode of inheritance.

Results: The minor allele of rs2243250 in IL-4 was associated with the risk of PJP in the discovery cohort (cumulative incidence 0.18 versus 0.12, P = 0.002). This association was replicated in the validation cohort (0.16 versus 0.12, P = 0.02). It was still significant in multivariate models, adjusted for HIV transmission mode, viral load, CD4 T cells slope, age, antiretroviral therapy, tobacco smoking, hepatitis C virus coinfection, year of cohort entry and PJP prophylaxis (global subhazard ratio 1.42, 95% confidence interval 1.17-1.73, P = 0.0004).

Conclusion: Our data suggest rs2243250, a single nucleotide polymorphism known to influence IL-4 production, is associated with susceptibility to PJP in HIV-positive patients.

Fig. 1

Cumulative incidence of Pneumocystis jirovecii pneumonia according to IL-4 rs2243250 in the discovery [(a) n = 1426 patients with available genotypes] and replication [(b) n = 1832] studies.