Community-Acquired Pneumonia: Genomics, Epigenomics, Transcriptomics, Proteomics, and Metabolomics

Grant W. Waterer

doi:10.1055/s-0032-1315637

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2012; 33(03): 257-265
DOI: 10.1055/s-0032-1315637

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Community-Acquired Pneumonia: Genomics, Epigenomics, Transcriptomics, Proteomics, and Metabolomics

Grant W. Waterer

¹Department of Medicine, University of Western Australia, Perth, Australia.

²Department of Medicine, Northwestern University, Chicago, Illinois.

› Author Affiliations

Abstract

Community-acquired pneumonia remains a significant health problem with very little progress having been made over the past 2 to 3 decades. Recent technological advances have opened up whole new avenues of exploration in the fields of genomics, epigenomics, transcriptomics, proteomics, and metabolomics. Although data in pneumonia are relatively scant with the exception of genomics due to the early stages of the science, some intriguing insights and clear avenues of application are already emerging. This review discusses recent studies in pneumonia using these new approaches as well as relevant research in sepsis and other diseases. Current and potential future uses of these platforms are discussed, and both key findings and key barriers to further progress are highlighted.

Keywords

pneumonia - genomics - proteomics - metabolomics - epigenomics

Full Text

References

References
1 Hoyert DL, Heron MP, Murphy SL, Kung HC. Deaths:final data for 2003. Natl Vital Stat Rep 2006; 54 (13) 1-120
2 Rello J, Catalán M, Díaz E, Bodí M, Alvarez B. Associations between empirical antimicrobial therapy at the hospital and mortality in patients with severe community-acquired pneumonia. Intensive Care Med 2002; 28 (8) 1030-1035
3 Simpson JC, Macfarlane JT, Watson J, Woodhead MA ; British Thoracic Society Research Committee and Public Health Laboratory Service. A national confidential enquiry into community acquired pneumonia deaths in young adults in England and Wales. Thorax 2000; 55 (12) 1040-1045
4 Mandell LA, Wunderink RG, Anzueto A , et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 (Suppl. 02) S27-S72
5 Rodriguez A, Lisboa T, Blot S , et al; Community-Acquired Pneumonia Intensive Care Units (CAPUCI) Study Investigators. Mortality in ICU patients with bacterial community-acquired pneumonia: when antibiotics are not enough. Intensive Care Med 2009; 35 (3) 430-438
6 Sørensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988; 318 (12) 727-732
7 Burgner D, Jamieson SE, Blackwell JM. Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better?. Lancet Infect Dis 2006; 6 (10) 653-663
8 Murphy PM. Molecular mimicry and the generation of host defense protein diversity. Cell 1993; 72 (6) 823-826
9 Waterer GW. Polymorphism studies in critical illness—we have to raise the bar. Crit Care Med 2007; 35 (5) 1424-1425
10 Temple SE, Cheong KY, Ardlie KG, Sayer D, Waterer GW. The septic shock associated HSPA1B1267 polymorphism influences production of HSPA1A and HSPA1B. Intensive Care Med 2004; 30 (9) 1761-1767
11 Bayley JP, Ottenhoff TH, Verweij CL. Is there a future for TNF promoter polymorphisms?. Genes Immun 2004; 5 (5) 315-329
12 Tan JH, Temple SE, Kee C , et al. Characterisation of TNF block haplotypes affecting the production of TNF and LTA. Tissue Antigens 2011; 77 (2) 100-106
13 Temple SE, Lim E, Cheong KY , et al. Alleles carried at positions -819 and -592 of the IL10 promoter affect transcription following stimulation of peripheral blood cells with Streptococcus pneumoniae. Immunogenetics 2003; 55 (9) 629-632
14 Fine MJ, Smith MA, Carson CA , et al. Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA 1996; 275 (2) 134-141
15 Waterer GW, Bruns AH. Genetic risk of acute pulmonary infections and sepsis. Expert Rev Respir Med 2010; 4 (2) 229-238
16 Affandi JS, Price P, Waterer G. Can immunogenetics illuminate the diverse manifestations of respiratory infections?. Ther Adv Respir Dis 2010; 4 (3) 161-176
17 Yuan FF, Marks K, Wong M , et al. Clinical relevance of TLR2, TLR4, CD14 and FcgammaRIIA gene polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol 2008; 86 (3) 268-270
18 Yee AM, Ng SC, Sobel RE, Salmon JE. Fc gammaRIIA polymorphism as a risk factor for invasive pneumococcal infections in systemic lupus erythematosus. Arthritis Rheum 1997; 40 (6) 1180-1182
19 Yuan FF, Wong M, Pererva N , et al. FcgammaRIIA polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol 2003; 81 (3) 192-195
20 Solé-Violán J, García-Laorden MI, Marcos-Ramos JA , et al. The Fcγ receptor IIA-H/H131 genotype is associated with bacteremia in pneumococcal community-acquired pneumonia. Crit Care Med 2011; 39 (6) 1388-1393
21 Moens L, Van Hoeyveld E, Verhaegen J, De Boeck K, Peetermans WE, Bossuyt X. Fcgamma-receptor IIA genotype and invasive pneumococcal infection. Clin Immunol 2006; 118 (1) 20-23
22 Khor CC, Davila S, Breunis WB , et al; Hong Kong–Shanghai Kawasaki Disease Genetics Consortium; Korean Kawasaki Disease Genetics Consortium; Taiwan Kawasaki Disease Genetics Consortium; International Kawasaki Disease Genetics Consortium; US Kawasaki Disease Genetics Consortium; Blue Mountains Eye Study. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet 2011; 43 (12) 1241-1246
23 Zuniga J, Buendía-Roldán I, Zhao Y , et al. Genetic variants associated with severe pneumonia in A/H1N1 influenza infection. Eur Respir J 2012; 39 (3) 604-610
24 van der Pol WL, Huizinga TW, Vidarsson G , et al. Relevance of Fcgamma receptor and interleukin-10 polymorphisms for meningococcal disease. J Infect Dis 2001; 184 (12) 1548-1555
25 Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24 (1) 1-8
26 Schaaf BM, Boehmke F, Esnaashari H , et al. Pneumococcal septic shock is associated with the interleukin-10-1082 gene promoter polymorphism. Am J Respir Crit Care Med 2003; 168 (4) 476-480
27 Gallagher PM, Lowe G, Fitzgerald T , et al. Association of IL-10 polymorphism with severity of illness in community acquired pneumonia. Thorax 2003; 58 (2) 154-156
28 Baier RJ, Loggins J, Yanamandra K. IL-10, IL-6 and CD14 polymorphisms and sepsis outcome in ventilated very low birth weight infants. BMC Med 2006; 4 (4) 10-12
29 Stanilova SA, Miteva LD, Karakolev ZT, Stefanov CS. Interleukin-10-1082 promoter polymorphism in association with cytokine production and sepsis susceptibility. Intensive Care Med 2006; 32 (2) 260-266
30 Gong MN, Thompson BT, Williams PL , et al. Interleukin-10 polymorphism in position -1082 and acute respiratory distress syndrome. Eur Respir J 2006; 27 (4) 674-681
31 Shu Q, Fang X, Chen Q, Stuber F. IL-10 polymorphism is associated with increased incidence of severe sepsis. Chin Med J (Engl) 2003; 116 (11) 1756-1759
32 Wattanathum A, Manocha S, Groshaus H, Russell JA, Walley KR. Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis. Chest 2005; 128 (3) 1690-1698
33 Nafee TM, Farrell WE, Carroll WD, Fryer AA, Ismail KM. Epigenetic control of fetal gene expression. BJOG 2008; 115 (2) 158-168
34 Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996; 24 (7) 1125-1128
35 De Santa F, Narang V, Yap ZH , et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J 2009; 28 (21) 3341-3352
36 Chan C, Li L, McCall CE, Yoza BK. Endotoxin tolerance disrupts chromatin remodeling and NF-kappaB transactivation at the IL-1beta promoter. J Immunol 2005; 175 (1) 461-468
37 El Gazzar M, Yoza BK, Chen X, Garcia BA, Young NL, McCall CE. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance. Mol Cell Biol 2009; 29 (7) 1959-1971
38 Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics 2011; 6 (3) 273-283
39 Brogdon JL, Xu Y, Szabo SJ , et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 2007; 109 (3) 1123-1130
40 Wen H, Dou Y, Hogaboam CM, Kunkel SL. Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood 2008; 111 (4) 1797-1804
41 Benjamin CF, Hogaboam CM, Lukacs NW, Kunkel SL. Septic mice are susceptible to pulmonary aspergillosis. Am J Pathol 2003; 163 (6) 2605-2617
42 Benjamin CF, Lundy SK, Lukacs NW, Hogaboam CM, Kunkel SL. Reversal of long-term sepsis-induced immunosuppression by dendritic cells. Blood 2005; 105 (9) 3588-3595
43 Mortensen EM, Kapoor WN, Chang CC, Fine MJ. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia. Clin Infect Dis 2003; 37 (12) 1617-1624
44 Waterer GW, Kessler LA, Wunderink RG. Medium-term survival after hospitalization with community-acquired pneumonia. Am J Respir Crit Care Med 2004; 169 (8) 910-914
45 Bermejo-Martin JF, Martin-Loeches I, Rello J , et al. Host adaptive immunity deficiency in severe pandemic influenza. Crit Care 2010; 14 (5) R167
46 Kin NW, Crawford DM, Liu J, Behrens TW, Kearney JF. DNA microarray gene expression profile of marginal zone versus follicular B cells and idiotype positive marginal zone B cells before and after immunization with Streptococcus pneumoniae. J Immunol 2008; 180 (10) 6663-6674
47 Song XM, Connor W, Jalal S, Hokamp K, Potter AA. Microarray analysis of Streptococcus pneumoniae gene expression changes to human lung epithelial cells. Can J Microbiol 2008; 54 (3) 189-200
48 Bootsma HJ, Egmont-Petersen M, Hermans PW. Analysis of the in vitro transcriptional response of human pharyngeal epithelial cells to adherent Streptococcus pneumoniae: evidence for a distinct response to encapsulated strains. Infect Immun 2007; 75 (11) 5489-5499
49 Rogers PD, Thornton J, Barker KS , et al. Pneumolysin-dependent and -independent gene expression identified by cDNA microarray analysis of THP-1 human mononuclear cells stimulated by Streptococcus pneumoniae. Infect Immun 2003; 71 (4) 2087-2094
50 Lee SM, Chan RW, Gardy JL , et al. Systems-level comparison of host responses induced by pandemic and seasonal influenza A H1N1 viruses in primary human type I–like alveolar epithelial cells in vitro. Respir Research 2010; 11: 147
51 Kassim SY, Gharib SA, Mecham BH, Birkland TP, Parks WC, McGuire JK. Individual matrix metalloproteinases control distinct transcriptional responses in airway epithelial cells infected with Pseudomonas aeruginosa. Infect Immun 2007; 75 (12) 5640-5650
52 Zhang H, Su YA, Hu P , et al. Signature patterns revealed by microarray analyses of mice infected with influenza virus A and Streptococcus pneumoniae. Microbes Infect 2006; 8 (8) 2172-2185
53 Chelvarajan RL, Liu Y, Popa D , et al. Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages. J Leukoc Biol 2006; 79 (6) 1314-1327
54 Schurr JR, Young E, Byrne P, Steele C, Shellito JE, Kolls JK. Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria. Infect Immun 2005; 73 (1) 532-545
55 Liu M, Fang L, Tan C, Long T, Chen H, Xiao S. Understanding Streptococcus suis serotype 2 infection in pigs through a transcriptional approach. BMC Genomics 2011; 12: 253
56 Seo SU, Kwon HJ, Ko HJ , et al. Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice. PLoS Pathog 2011; 7 (2) e1001304
57 Evans SE, Tuvim MJ, Zhang J , et al. Host lung gene expression patterns predict infectious etiology in a mouse model of pneumonia. Respir Res 2010; 11: 101
58 Mortensen S, Skovgaard K, Hedegaard J, Bendixen C, Heegaard PM. Transcriptional profiling at different sites in lungs of pigs during acute bacterial respiratory infection. Innate Immun 2011; 17 (1) 41-53
59 Wiersinga WJ, Dessing MC, van der Poll T. Gene-expression profiles in murine melioidosis. Microbes Infect 2008; 10 (8) 868-877
60 Rosseau S, Hocke A, Mollenkopf H , et al. Comparative transcriptional profiling of the lung reveals shared and distinct features of Streptococcus pneumoniae and influenza A virus infection. Immunology 2007; 120 (3) 380-391
61 Textoris J, Loriod B, Benayoun L , et al. An evaluation of the role of gene expression in the prediction and diagnosis of ventilator-associated pneumonia. Anesthesiology 2011; 115 (2) 344-352
62 Beutler B. Toll-like receptors: how they work and what they do. Curr Opin Hematol 2002; 9 (1) 2-10
63 Tang BM, McLean AS, Dawes IW, Huang SJ, Cowley MJ, Lin RC. Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients. Crit Care Med 2008; 36 (4) 1125-1128
64 Nau GJ, Richmond JF, Schlesinger A, Jennings EG, Lander ES, Young RA. Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci U S A 2002; 99 (3) 1503-1508
65 Yu SL, Chen HW, Yang PC , et al. Differential gene expression in gram-negative and gram-positive sepsis. Am J Respir Crit Care Med 2004; 169 (10) 1135-1143
66 Feezor RJ, Oberholzer C, Baker HV , et al. Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. Infect Immun 2003; 71 (10) 5803-5813
67 Flacher V, Bouschbacher M, Verronèse E , et al. Human Langerhans cells express a specific TLR profile and differentially respond to viruses and Gram-positive bacteria. J Immunol 2006; 177 (11) 7959-7967
68 Ramilo O, Allman W, Chung W , et al. Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 2007; 109 (5) 2066-2077
69 Pankla R, Buddhisa S, Berry M , et al. Genomic transcriptional profiling identifies a candidate blood biomarker signature for the diagnosis of septicemic melioidosis. Genome Biol 2009; 10 (11) R127
70 Kowalczewska M, Sekeyova Z, Raoult D. Proteomics paves the way for Q fever diagnostics. Genome Med 2011; 3 (7) 50
71 Gonzales DA, De Torre C, Wang H , et al. Protein expression profiles distinguish between experimental invasive pulmonary aspergillosis and Pseudomonas pneumonia. Proteomics 2010; 10 (23) 4270-4280
72 Park SH, Kwon SJ, Lee SJ , et al. Identification of immunogenic antigen candidate for Chlamydophila pneumoniae diagnosis. J Proteome Res 2009; 8 (6) 2933-2943
73 McGarvey PB, Huang H, Mazumder R , et al. Systems integration of biodefense omics data for analysis of pathogen-host interactions and identification of potential targets. PLoS ONE 2009; 4 (9) e7162
74 Ye Y, Mar EC, Tong S , et al. Application of proteomics methods for pathogen discovery. J Virol Methods 2010; 163 (1) 87-95
75 Drake RR, Deng Y, Schwegler EE, Gravenstein S. Proteomics for biodefense applications: progress and opportunities. Expert Rev Proteomics 2005; 2 (2) 203-213
76 Waterer GW, Rello J, Wunderink RG. Management of community-acquired pneumonia in adults. Am J Respir Crit Care Med 2011; 183 (2) 157-164
77 Slupsky CM, Cheypesh A, Chao DV , et al. Streptococcus pneumoniae and Staphylococcus aureus pneumonia induce distinct metabolic responses. J Proteome Res 2009; 8 (6) 3029-3036
78 Laiakis EC, Morris GA, Fornace AJ, Howie SR. Metabolomic analysis in severe childhood pneumonia in the Gambia, West Africa: findings from a pilot study. PLoS ONE 2010; 5 (9)
79 Lv H, Hung CS, Chaturvedi KS, Hooton TM, Henderson JP. Development of an integrated metabolomic profiling approach for infectious diseases research. Analyst (Lond) 2011; 136 (22) 4752-4763
80 Shin JH, Yang JY, Jeon BY , et al. (1)H NMR-based metabolomic profiling in mice infected with Mycobacterium tuberculosis. J Proteome Res 2011; 10 (5) 2238-2247
81 Godoy MM, Lopes EP, Silva RO , et al. Hepatitis C virus infection diagnosis using metabonomics. J Viral Hepat 2010; 17 (12) 854-858
82 Liu XR, Zheng XF, Ji SZ , et al. Metabolomic analysis of thermally injured and/or septic rats. Burns 2010; 36 (7) 992-998
83 Al-Mubarak R, Vander Heiden J, Broeckling CD, Balagon M, Brennan PJ, Vissa VD. Serum metabolomics reveals higher levels of polyunsaturated fatty acids in lepromatous leprosy: potential markers for susceptibility and pathogenesis. PLoS Negl Trop Dis 2011; 5 (9) e1303
84 Ghannoum MA, Mukherjee PK, Jurevic RJ , et al. Metabolomics reveals differential levels of oral metabolites in hiv-infected patients: toward novel diagnostic targets. OMICS 2011; Jul 13. [Epub ahead of print]
85 Stringer KA, Serkova NJ, Karnovsky A, Guire K, Paine III R, Standiford TJ. Metabolic consequences of sepsis-induced acute lung injury revealed by plasma ¹H-nuclear magnetic resonance quantitative metabolomics and computational analysis. Am J Physiol Lung Cell Mol Physiol 2011; 300 (1) L4-L11
86 Boudonck KJ, Mitchell MW, Német L , et al. Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol Pathol 2009; 37 (3) 280-292
87 D'Avila LC, Albarus MH, Franco CR , et al. Effect of CD14 -260C>T polymorphism on the mortality of critically ill patients. Immunol Cell Biol 2006; 84 (4) 342-348
88 Gibot S, Cariou A, Drouet L, Rossignol M, Ripoll L. Association between a genomic polymorphism within the CD14 locus and septic shock susceptibility and mortality rate. Crit Care Med 2002; 30 (5) 969-973
89 Sutherland AM, Walley KR, Russell JA. Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med 2005; 33 (3) 638-644
90 Hubacek JA, Stüber F, Fröhlich D , et al. The common functional C(-159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality. Genes Immun 2000; 1 (6) 405-407
91 Nakada TA, Hirasawa H, Oda S , et al. Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukine-10 gene polymorphisms on clinical outcome in Japanese critically ill patients. J Surg Res 2005; 129 (2) 322-328
92 de Aguiar BB, Girardi I, Paskulin DD , et al. CD14 expression in the first 24h of sepsis: effect of -260C>T CD14 SNP. Immunol Invest 2008; 37 (8) 752-769
93 Mira JP, Cariou A, Grall F , et al. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 1999; 282 (6) 561-568
94 Nuntayanuwat S, Dharakul T, Chaowagul W, Songsivilai S. Polymorphism in the promoter region of tumor necrosis factor-alpha gene is associated with severe meliodosis. Hum Immunol 1999; 60 (10) 979-983
95 Stüber F, Petersen M, Bokelmann F, Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996; 24 (3) 381-384
96 Stuber F, Udalova IA, Book M , et al. -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm 1995; –1996 46 (1) 42-50
97 Waterer GW, Quasney MW, Cantor RM, Wunderink RG. Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med 2001; 163 (7) 1599-1604
98 Solé-Violán J, de Castro F, García-Laorden MI , et al. Genetic variability in the severity and outcome of community-acquired pneumonia. Respir Med 2010; 104 (3) 440-447
99 Shu Q, Shi CC, Zhang XH , et al. Interleukin 10.G microsatellite in the promoter region of the interleukin-10 gene in severe sepsis. Chin Med J (Engl) 2006; 119 (3) 197-201
100 Chen QX, Wu SJ, Wang HH , et al. Protein C -1641A/-1654C haplotype is associated with organ dysfunction and the fatal outcome of severe sepsis in Chinese Han population. Hum Genet 2008; 123 (3) 281-287
101 Wurfel MM, Gordon AC, Holden TD , et al. Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 2008; 178 (7) 710-720
102 Pino-Yanes M, Corrales A, Casula M , et al; GRECIA and GEN-SEP Groups. Common variants of TLR1 associate with organ dysfunction and sustained pro-inflammatory responses during sepsis. PLoS ONE 2010; 5 (10) e13759
103 Moens L, Verhaegen J, Pierik M , et al. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in invasive pneumococcal disease. Microbes Infect 2007; 9 (1) 15-20
104 Brenmoehl J, Herfarth H, Glück T , et al. Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Intensive Care Med 2007; 33 (9) 1541-1548
105 Everett B, Cameron B, Li H , et al. Polymorphisms in Toll-like receptors-2 and -4 are not associated with disease manifestations in acute Q fever. Genes Immun 2007; 8 (8) 699-702
106 Yoon HJ, Choi JY, Kim CO , et al. Lack of Toll-like receptor 4 and 2 polymorphisms in Korean patients with bacteremia. J Korean Med Sci 2006; 21 (6) 979-982
107 Hawn TR, Verbon A, Lettinga KD , et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J Exp Med 2003; 198 (10) 1563-1572
108 Schlüter B, Raufhake C, Erren M , et al. Effect of the interleukin-6 promoter polymorphism (-174 G/C) on the incidence and outcome of sepsis. Crit Care Med 2002; 30 (1) 32-37
109 Sutherland AM, Walley KR, Manocha S, Russell JA. The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Intern Med 2005; 165 (1) 75-82
110 Stassen NA, Leslie-Norfleet LA, Robertson AM, Eichenberger MR, Polk Jr HC. Interferon-gamma gene polymorphisms and the development of sepsis in patients with trauma. Surgery 2002; 132 (2) 289-292
111 Goubar A, Bitar D, Cao WC, Feng D, Fang LQ, Desenclos JC. An approach to estimate the number of SARS cases imported by international air travel. Epidemiol Infect 2009; 137 (7) 1019-1031
112 Ma P, Chen D, Pan J, Du B. Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients [in Chinese]. Zhonghua Yi Xue Za Zhi (Taipei) 2002; 82 (18) 1237-1241
113 Yan SB, Nelson DR. Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Crit Care Med 2004; 32 (5, Suppl) S239-S246
114 Khor CC, Chapman SJ, Vannberg FO , et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 2007; 39 (4) 523-528
115 Waterer GW, ElBahlawan L, Quasney MW, Zhang Q, Kessler LA, Wunderink RG. Heat shock protein 70-2+1267 AA homozygotes have an increased risk of septic shock in adults with community-acquired pneumonia. Crit Care Med 2003; 31 (5) 1367-1372
116 Yende S, Angus DC, Ding J , et al; for the Health ABC Study. 4G/5G plasminogen activator inhibitor-1 polymorphisms and haplotypes are associated with pneumonia. Am J Respir Crit Care Med 2007; 176 (11) 1129-1137
117 Sapru A, Hansen H, Ajayi T , et al. 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with mortality in intensive care unit patients with severe pneumonia. Anesthesiology 2009; 110 (5) 1086-1091
118 Yende S, Angus DC, Kong L , et al. The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia. FASEB J 2009; 23 (8) 2403-2411
119 Kleiman DA, Calvano JE, Coyle SM, Macor MA, Calvano SE, Lowry SF. A single nucleotide polymorphism in the Mdm2 promoter and risk of sepsis. Am J Surg 2009; 197 (1) 43-48
120 Hubacek JA, Stüber F, Fröhlich D , et al. Gene variants of the bactericidal/permeability increasing protein and lipopolysaccharide binding protein in sepsis patients: gender-specific genetic predisposition to sepsis. Crit Care Med 2001; 29 (3) 557-561
121 Chen Q, Zhou H, Wu S , et al. Lack of association between TREM-1 gene polymorphisms and severe sepsis in a Chinese Han population. Hum Immunol 2008; 69 (3) 220-226
122 Payton A, Payne D, Mankhambo LA , et al. Nitric oxide synthase 2A (NOS2A) polymorphisms are not associated with invasive pneumococcal disease. BMC Med Genet 2009; 10: 28
123 Gordon AC, Waheed U, Hansen TK , et al. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock 2006; 25 (1) 88-93
124 Garred P, Strøm J, Quist L, Taaning E, Madsen HO. Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome. J Infect Dis 2003; 188 (9) 1394-1403
125 Kronborg G, Weis N, Madsen HO , et al. Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients. J Infect Dis 2002; 185 (10) 1517-1520
126 Endeman H, Herpers BL, de Jong BA , et al. Mannose-binding lectin genotypes in susceptibility to community-acquired pneumonia. Chest 2008; 134 (6) 1135-1140
127 Herpers BL, Yzerman EP, de Jong BA , et al. Deficient mannose-binding lectin-mediated complement activation despite mannose-binding lectin-sufficient genotypes in an outbreak of Legionella pneumophila pneumonia. Hum Immunol 2009; 70 (2) 125-129
128 Roy S, Knox K, Segal S , et al; Oxford Pneumoccocal Surveillance Group. MBL genotype and risk of invasive pneumococcal disease: a case-control study. Lancet 2002; 359 (9317) 1569-1573
129 Moens L, Van Hoeyveld E, Peetermans WE, De Boeck C, Verhaegen J, Bossuyt X. Mannose-binding lectin genotype and invasive pneumococcal infection. Hum Immunol 2006; 67 (8) 605-611
130 Garcia-Laorden MI, Sole-Violan J, Rodriguez de Castro F , et al. Mannose-binding lectin and mannose-binding lectin-associated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults. J Allergy Clin Immunol 2008; 122 (2) 368-374 , 374.e1–2
131 Arcaroli J, Silva E, Maloney JP , et al. Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis. Am J Respir Crit Care Med 2006; 173 (12) 1335-1341
132 Chapman SJ, Khor CC, Vannberg FO , et al. IkappaB genetic polymorphisms and invasive pneumococcal disease. Am J Respir Crit Care Med 2007; 176 (2) 181-187
133 Chapman SJ, Khor CC, Vannberg FO , et al. NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations. Genes Immun 2010; 11 (4) 319-325
134 Ku CL, Picard C, Erdös M , et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet 2007; 44 (1) 16-23
135 Chen QX, Lv C, Huang LX , et al. Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population. Genes Immun 2007; 8 (5) 439-443
136 Quasney MW, Waterer GW, Dahmer MK , et al. Association between surfactant protein B+1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia. Crit Care Med 2004; 32 (5) 1115-1119