Variants at the promoter of the interleukin-6 gene are associated with severity and outcome of pneumococcal community-acquired pneumonia.

PURPOSE: Conflicting results about the role of genetic variability at IL6, particularly the -174 G/C single nucleotide polymorphism (SNP), in sepsis have been reported. We studied the genetic variability at IL6 in patients with community-acquired pneumonia (CAP) and pneumococcal CAP (P-CAP). METHODS: This was a multicenter, prospective observational study. IL6 -174 was analyzed in 1,227 white Spanish patients with CAP (306 with P-CAP). IL6 1753 C/G (N = 750), 2954 G/C (N = 845), and haplotypes defined by these SNPs were also studied. RESULTS: In CAP patients the genotype -174 GG were associated with protection against acute respiratory distress syndrome (ARDS) (p = 0.008, OR = 0.4, 95% CI 0.2-0.8). No other significant associations were observed. However, in patients with P-CAP multivariate analysis adjusted for age, gender, co-morbidity, hospital of origin, and severity (pneumonia severity index, PSI) showed that the IL6 -174 GG genotype was protective against the development of ARDS (p = 0.002, OR = 0.25, 95% CI 0.07-0.79), septic shock (p = 0.006, OR = 0.46, 95% CI 0.18-0.79), and multiple organ dysfunction syndrome (p = 0.02, OR = 0.53, 95% CI 0.27-0.89). P-CAP patients homozygous for IL6 -174 G also showed a higher survival in a logistic regression analysis adjusted for age, gender, co-morbidity, hospital of origin, and PSI (p = 0.048, OR = 0.27, 95% CI 0.07-0.98). CONCLUSIONS: Our results indicate that the IL-6 -174 GG genotype is associated with lower severity and mortality in patients with P-CAP. This effect was higher than that observed in patients with CAP irrespective of the causal pathogen involved. Our results highlight the importance of the causal pathogen in genetic epidemiological studies in sepsis.

The Fcγ receptor IIA-H/H131 genotype is associated with bacteremia in pneumococcal community-acquired pneumonia.

OBJECTIVE: To assess the potential association of the functional polymorphism rs1801274 in the receptor IIa for the Fc portion of immunoglobin G (FcγRIIa) gene (FCGR2A-H131R) with the susceptibility to and the severity of community-acquired pneumonia (CAP). DESIGN: Multicenter prospective and observational study. SETTING: Four university hospitals in Spain. PATIENTS: FCGR2A-H131R polymorphism was determined in 1,262 patients with CAP and in 1,224 in the subject control group. MEASUREMENTS AND MAIN RESULTS: Severe sepsis was recorded in 366 patients. No significant differences in genotype or allele frequencies were seen among patients with CAP or pneumococcal CAP (PCAP) and controls. Patients with bacteremic PCAP (B-PCAP) had significantly higher frequencies of FCGR2A-H/H131 genotypes than those with nonbacteremic PCAP (p = .00016, odds ratio = 2.9, 95% confidence interval 1.58-5.3). The differences remained significant when adjusting for pneumonia severity index, hospital of origin, and intensive care unit admission (p = .0012, odds ratio = 2.83, 95% confidence interval 1.51-5.32). B-PCAP was associated with a significantly higher severity of the disease, evaluated as sepsis severity (p = .000007, odds ratio = 4.40, 95% confidence interval 2.31-8.39), multiorgan dysfunction syndrome (0.00048, odds ratio = 3.29, 95% confidence interval 1.69-6.41), intensive care unit admission, acute renal failure, and acute respiratory distress syndrome. CONCLUSIONS: Our results do not support a role of FCGR2A-H131R polymorphism in susceptibility to CAP or PCAP. However, we provide the insight that homozygosity for FCGR2A-H131 predisposes B-PCAP, which was associated with higher severity in our study.

Genetic variability in the severity and outcome of community-acquired pneumonia.

BACKGROUND: Several studies have investigated single nucleotide polymorphisms (SNP) in candidate genes associated with susceptibility, severity or outcome in patients with community-acquired pneumonia (CAP) with conflicting results. METHODS: Multi-centre, prospective observational study. We studied 1162 white Spanish patients with CAP and 1413 controls. Severe forms of sepsis were recorded in 325 patients. Subjects were genotyped for the following polymorphisms: TNF -238 and -308, LTA +252, IL6 -174, IL1RN 86bp variable number of tandem repeats and TNFRSF1B+676 (TNFR2 M196R). RESULTS: No significant differences in genotype or allele frequencies were seen among patients and controls. We did not find any association between TNF, LTA, IL6 and IL1RN polymorphisms with disease severity or outcome. Analysis of 28-day mortality showed a significant difference in the distribution of TNFRSF1B+676 G/T genotypes (p=0.0129). Sequential Kaplan-Meier survival analysis of TNFRSF1B+676 G/T polymorphism showed a protective role of the GT genotype. Cox regression analysis adjusted for age, gender, hospital of origin and comorbidities showed that patients with GT genotypes had lower mortality rates compared to patients with GG or TT genotypes (p=0.02; HR 0.53; 95% CI 0.31-0.90 for 90-day survival; p=0.01; HR 0.41; 95% CI 0.21-0.81 for 28-day survival and p=0.049; HR 0.48; 95% CI 0.23-0.997 for 15-day survival). CONCLUSIONS: Our study does not support a role for the controversial studied polymorphisms of the TNF, LTA, IL6 and IL1RN genes in the susceptibility or outcome of CAP. A protective role of heterozygosity for the functionally relevant TNFRSF1B+676 polymorphism in the outcome of CAP was observed.