Host Genetic Variants Associated with Susceptibility and Severity of Pneumococcal Pneumonia in Adult Patients

Abstract

Abstract Background The aim of the study was to assess the influence of single nucleotide polymorphisms (SNP) within key genes involved in the innate immune response on the susceptibility to pneumococcal community-acquired pneumonia (P-CAP) and to study whether these polymorphic variants were associated with the severity and outcome of the episodes in a cohort of adult Caucasian patients. Methods Seventeen SNPs from 7 genes (IL-R1, IL-4, IL-10, IL-12B, NFKBIA, NFKBIE, NFKBIZ) were analysed. For susceptibility, a case-control study including a cohort of adult patients with CAP and 280 ethnically matched controls was performed. Genetic influence on clinical severity and outcome was evaluated in a prospective observational study including all consecutive adult CAP patients from November 2015 to May 2017. Results The NFKBIA polymorphism rs696 and a haplotype combination were associated with susceptibility to P-CAP (OR = 0.62, p = 0.005 and OR = 0.63, p = 0.008, respectively). The SNP IL4 rs2227284 was associated with severe P-CAP (OR = 2.17, p = 0.04). IL-R1 (rs3917267) and IL-10 (rs3024509) variants were related with respiratory failure (OR = 3.31, p = 0.001 and OR = 0.18, p = 0.003, respectively) as well as several haplotype combinations in NFKBIA, NFKBIZ, IL-R1 and IL-10 (p = 0,02, p = 0,01, p = 0,001, p = 0,03, respectively). CURB-65 values were associated with the IL-10 rs3024509 variant (beta=-0.4, p = 0.04), and with haplotype combinations of NFKBIZ and IL-10 (p = 0.05, p = 0.04, respectively). Genetic variants in IL-10 (rs3024509) and in IL-12B (rs730691) were associated with PSI values (beta=-0.54, p = 0.01, and beta=-0.28, p = 0.04, respectively), as were allelic combinations in IL-R1 (p = 0.02) and IL-10 (p = 0.01). Finally, several polymorphisms in the IL-R1 gene (rs13020778, rs2160227, & rs3917267) were associated with the time elapsed until clinical stability (beta =-0.83, p = 0.03; beta=-1, p = 0.02 and beta = 1.07, p = 0.008, respectively). Conclusions A genetic variant in NFKBIA was associated with susceptibility to P-CAP in adult Caucasian patients and genetic variants from key cytokines of the innate immune response (Il-4, IL-10, IL-R1 and IL-12B) and NF-κB inhibitors were associated with different phenotypes of severe P-CAP. If validated, these SNPs may help to identify people at risk of P-CAP or severe P-CAP on which preventive measures could be applied.