Lack of association of the caspase-12 long allele with community-acquired pneumonia in people of African descent.

Jiwang Chen,Grant W Waterer,Esther S Wilson,Michael W Quasney,Richard G Wunderink,Charles Feldman,Mary K Dahmer,Cordula M Stover

doi:10.1371/journal.pone.0089194

Abstract

Community-acquired pneumonia (CAP) is a common cause of sepsis. Active full-length caspase-12 (CASP12L), confined to the people of African descent, has been associated with increased susceptibility to and mortality from severe sepsis. The objective of this study was to determine whether CASP12L was a marker for susceptibility and/or severity of CAP. We examined three CAP cohorts and two control populations: 241 adult Memphis African American CAP patients, 443 pediatric African American CAP patients, 90 adult South African CAP patients, 120 Memphis healthy adult African American controls and 405 adult Chicago African American controls. Clinical outcomes including mortality, acute respiratory distress syndrome (ARDS), septic shock or severe sepsis, need for mechanical ventilation, and S. pneumoniae bacteremia. Neither in the three individual CAP cohorts nor in the combined CAP cohorts, was mortality in CASP12L carriers significantly different from that in non-CASP12L carriers. No statistically significant association between genotype and any measures of CAP severity was found in any cohort. We conclude that the functional CASP12L allele is not a marker for susceptibility and/or severity of CAP.

Highlights

Even in the antibiotic era, pneumonia remains the most common infectious cause of death worldwide, occurring in all age groups
In the South African adult Community-acquired pneumonia (CAP) cohort of 90 patients, four (4.4%) deaths occurred, five (5.6%) patients required mechanical ventilation, 16 (17.8%) patients had acute hypoxemia, 58 (64.4%) patients had HIV infection, and 41 (45.6%) patients were bacteremic with S. pneumoniae
The frequency of other clinical phenotypes, including shock, need for mechanical ventilation, acute lung injury (ALI)/acute hypoxemia, renal dysfunction and HIV infection, were not significantly different between the CASP12L and the CASP12S groups (Table 5). This analysis is the first to examine any association between human full-length, active caspase-12 [CASP12L] and either susceptibility to or severity of CAP. In both adult and pediatric African American CAP patients, we found no association of CASP12L allele with mortality, need for mechanical ventilation, ALI/acute respiratory distress syndrome (ARDS), septic shock/severe sepsis or S. pneumoniae bacteremia

Summary

Introduction

Even in the antibiotic era, pneumonia remains the most common infectious cause of death worldwide, occurring in all age groups. Among children under five years old, pneumonia is one of the leading causes of death globally accounting for approximately 2 million deaths per year [1]. Pneumonia is the most common source of severe sepsis. Clinical manifestations of pneumonia are mediated largely by cytokines and chemokines, whose production and release are modulated by caspases, including caspase-12 [3]. CASP12L is confined to approximately 20–25% of people of African descent and has been reported to confer hypo-responsiveness to lipopolysaccharide (LPS)-stimulated cytokine production [5]. CASP12L has been associated with increased susceptibility to, and mortality from, severe sepsis [5]. Studies performed in mice suggest that the long form of caspase-12 is associated with mortality as mice without caspase-12 have a significantly higher survival rate in a murine model of polymicrobial peritonitis sepsis [6]

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