Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia

Background: Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient’s heterogeneity. Methods: For up to N = 389 genotyped participants of the PROGRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants. Results: 102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10−20), at 17q21.32 (p = 1.51 × 10−9) and at 10p12.1 (p = 2.76 × 10−9) for IL-1β, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10−9), and at 9q34.12 for IL-10 (p = 4.52 × 10−8). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics. Conclusion: This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms

VEGFR2 and VEGFA polymorphisms are not associated with an inferior prognosis in Caucasian patients with aggressive B-cell lymphoma

Purpose Previous published data showed an impact of single‐nucleotide polymorphisms in the VEGF A and VEGFR2 genes on the survival of patients with various malignancies, among others diffuse large B‐cell lymphoma (DLBCL). Patients and Methods We investigated the role of four VEGF‐A and two VEGFR‐2 gene polymorphisms on the outcome of 273 patients with diffuse large B‐cell lymphoma who were treated with R‐CHOP within a prospective, randomized trial of the German High‐Grade Non‐Hodgkin Lymphoma Study Group (DSHNHL). The genomic DNA samples were analyzed using commercial DNA Probes (Applied Biosystems, USA) to detect single‐nucleotide polymorphisms in the VEGF A rs699947, rs1570360, rs2010963, rs3025039 and rs1870377, and rs2305948 in the VEGFR2 receptor. Hundred healthy blood donors served as a control. Results There was no difference between the SNP allele frequencies in lymphoma patients compared to the control group for all investigated SNPs. None of the investigated SNPs was significantly associated with EFS or OS. After adjusting for the International Prognostic Index risk factors in a multivariate analysis, these results could be confirmed. Conclusion Single‐nucleotide polymorphisms of the VEGF and VEGFR2 were not associated with a worse outcome in Caucasian patients with DLBCL

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia

Background: Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient’s heterogeneity. Methods: For up to N = 389 genotyped participants of the PROGRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants. Results: 102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10−20), at 17q21.32 (p = 1.51 × 10−9) and at 10p12.1 (p = 2.76 × 10−9) for IL-1β, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10−9), and at 9q34.12 for IL-10 (p = 4.52 × 10−8). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics. Conclusion: This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms

Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia

Background: Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient’s heterogeneity. Methods: For up to N = 389 genotyped participants of the PROGRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants. Results: 102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10−20), at 17q21.32 (p = 1.51 × 10−9) and at 10p12.1 (p = 2.76 × 10−9) for IL-1β, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10−9), and at 9q34.12 for IL-10 (p = 4.52 × 10−8). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics. Conclusion: This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms

Krueppel-Like Factor 4 Expression in Phagocytes Regulates Early Inflammatory Response and Disease Severity in Pneumococcal Pneumonia

The transcription factor Krueppel-like factor (KLF) 4 fosters the pro-inflammatory immune response in macrophages and polymorphonuclear neutrophils (PMNs) when stimulated with Streptococcus pneumoniae, the main causative pathogen of community-acquired pneumonia (CAP). Here, we investigated the impact of KLF4 expression in myeloid cells such as macrophages and PMNs on inflammatory response and disease severity in a pneumococcal pneumonia mouse model and in patients admitted to hospital with CAP. We found that mice with a myeloid-specific knockout of KLF4 mount an insufficient early immune response with reduced levels of pro-inflammatory cytokines and increased levels of the anti-inflammatory cytokine interleukin (IL) 10 in bronchoalveolar lavage fluid and plasma and an impaired bacterial clearance from the lungs 24 hours after infection with S. pneumoniae. This results in higher rates of bacteremia, increased lung tissue damage, more severe symptoms of infection and reduced survival. Higher KLF4 gene expression levels in the peripheral blood of patients with CAP at hospital admission correlate with a favourable clinical presentation (lower sequential organ failure assessment (SOFA) score), lower serum levels of IL-10 at admission, shorter hospital stay and lower mortality or requirement of intensive care unit treatment within 28 days after admission. Thus, KLF4 in myeloid cells such as macrophages and PMNs is an important regulator of the early proinflammatory immune response and, therefore, a potentially interesting target for therapeutic interventions in pneumococcal pneumonia

Detection of genomic aberrations in molecularly defined Burkitt’s lymphoma by array-based, high resolution, single nucleotide polymorphism analysis

The present findings suggest that uniparental disomies do not play a major role in the pathogenesis of Burkitt's lymphoma, whereas some genes may contribute to the development of this lymphoma through gene dosage effects. Amplifications of the polymerase iota gene may be functionally linked with increased genomic alterations in Burkitt's lymphoma. The pattern and rarity of chromosomal changes detectable, even at the high resolution employed here, together with aberrations of genes regulating MYC activity, support the hypothesis that deregulation of the MYC pathway is the major force driving the pathogenesis of Burkitt's lymphoma, but show that this deregulation is more complex than previously known

Sets of co-expressed genes reproduce the distinction between Burkitt lymphomas and other types of mature aggressive B-cell lymphomas.

<p>Heat maps of 50 CGSs generated in two independent BL/DLBCL data sets: (A) Hummel et al. (2006), n = 220 (GSE4475) and (B) Dave et al. (2006), n = 303 (GSE4732). Each row shows a profile of a gene and genes are grouped into gene sets as indicated by white and black intervals on the vertical bar left. Red represents high expression and blue represents low expression relative to the mean over all samples. Each column corresponds to one sample. Samples are annotated by horizontal color bars above the heat maps. The samples and the gene sets are ordered by the values of their 1^st principal component. Annotations from Hummel et al. (2006): “MOLDIAG”: classification into molecularly defined Burkitt lymphoma (mBL), intermediate cases and non-mBL cases, “GCB/ABC”: cell of origin (molecular classification), “MYC PARTNER”: information about the absence (“Negative”) or presence of <i>MYC</i> breakpoints and about the translocation partner of <i>MYC</i> (IG or non-IG). “CC”: “consensus clusters” <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076287#pone.0076287-Monti1" target="_blank">[3]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076287#pone.0076287-Bentink1" target="_blank">[6]</a>. Annotations from Dave et al. (2006): “BL” diagnosis of Burkitt lymphoma or DLBCL based on gene expression, “PATHO”: pathological diagnosis or molecular diagnosis in case of samples analysed prior to Dave et al. (2006). “PAP”: “pathway activation patterns” <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076287#pone.0076287-Bentink1" target="_blank">[6]</a> (available for both data sets <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076287#pone.0076287-Hummel1" target="_blank">[4]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076287#pone.0076287-Dave1" target="_blank">[5]</a>).</p