Low-Copy Number Polymorphism in DEFA1/DEFA3 Is Associated with Susceptibility to Hospital-Acquired Infections in Critically Ill Patients

Abstract

DEFA1/DEFA3, genes encoding human neutrophil peptides (HNP) 1–3, display wide-ranging copy number variations (CNVs) and is functionally associated with innate immunity and infections. To identify potential associations between DEFA1/DEFA3 CNV and hospital-acquired infections (HAIs), we enrolled 106 patients with HAIs and 109 controls in the intensive care unit (ICU) and examined their DEFA1/DEFA3 CNVs. DEFA1/DEFA3 copy number ranged from 2 to 16 per diploid genome in all 215 critically ill patients, with a median of 7 copies. In HAIs, DEFA1/DEFA3 CNV varied from 2 to 12 with a median of 6, which was significantly lower than that in controls (2 to 16 with a median of 8, p = 0.017). Patients with lower DEFA1/DEFA3 copy number (CNV < 7) were far more common in HAIs than in controls (52.8% in HAIs versus 35.8% in controls; p = 0.014; OR, 2.010; 95% CI, 1.164–3.472). The area under the receiver operating characteristic (AUROC) of DEFA1/DEFA3 CNV combined with clinical characteristics to predict the incidence of HAIs was 0.763 (95% CI 0.700–0.827), showing strong predictive ability. Therefore, lower DEFA1/DEFA3 copy number contributes to higher susceptibility to HAIs in critically ill patients, and DEFA1/DEFA3 CNV is a significant hereditary factor for predicting HAIs.

Gut Leakage Markers and Cognitive Functions in Patients with Attention-Deficit/Hyperactivity Disorder

“…Our finding of lower DEFA1 levels in the ADHD group compared to controls may not be unsupported. Previous studies found that decreased levels of DEFA1 were associated with several infectious diseases, while increased levels of DEFA1 may protect against the progression of infection [ 46 , 47 ]. DEFA1 is an antimicrobial peptide of the innate immune system.…”

“…Previous study reported that reduced copy numbers of the DEFA1 gene was associated with recurrent urinary tract infections in children [ 49 ]. It was also reported that lower copy numbers of the DEFA1 gene contribute to a higher risk for hospital-acquired infections [ 46 ]. Another study found that a higher secretion of DEFA1 by immature dendritic cells may protect against the progression of HIV infection [ 47 ].…”

“…Another study found that a higher secretion of DEFA1 by immature dendritic cells may protect against the progression of HIV infection [ 47 ]. It was proposed that a lower DEFA1 protein level may contribute to impaired innate defenses and a weaker functioning of antimicrobial activity, and consequently leads to infections [ 46 ]. Therefore, in the current study, we propose that the significantly decreased DEFA1 level found in the ADHD group may be associated with the fragile functioning of autoimmune and antimicrobial activity.…”

Increased Gene Copy Number of DEFA1A3 Is Associated With the Severity of Ulcerative Colitis

“…A previous study showed that patients with more than 8 copies of DEFA1A3 are more susceptible to severe sepsis ( 38 , 39 ). Patients with lower DEFA1A3 copy numbers (fewer than 7 copies) were far more common to have hospital-acquired infections than controls ( 19 ). A lower DEFA1A3 copy number has also been shown to increase the risk of IgA nephropathy and renal dysfunction ( 40 ).…”

“…The expression level of HNPs in neutrophils varies and depends on the CNV of the HNP-encoding gene DEFA1A3 , which has an extensive range of copy numbers ( 17 , 18 ). DEFA1A3 CNV may be associated with susceptibility to severe sepsis and hospital-acquired infection ( 19 ). However, DEFA1A3 CNV and their involvement in UC development have not been well studied.…”