Genetics of Community-Acquired Pneumonia

ABSTRACT

The variable clinical presentation of community-acquired pneumonia (CAP) suggests a genetic predisposition. Specific mutations or polymorphisms in host response genes such as pattern recognition molecules (PRMs), inflammatory molecules, and the coagulation system are likely to play a role in this variable response to CAP. Mannose-binding lectin polymorphisms appear to play a more dominant role in CAP than other PRMs, such as the Toll-like receptors (TLRs). The role of tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) polymorphisms remain unclear despite extensive study whereas interleukin (IL)-10 and IL-1 receptor antagonist polymorphisms appear to play an important role in the anti-inflammatory response. Coagulation gene polymorphisms are likely important as well. The real value of these genetic studies in CAP and other severe infections will be when the management of an individual patient can be optimized by therapy based on the individual's genotype for molecules important in outcome.

KEYWORDS

Genetics - community-acquired pneumonia - polymorphism - tumor necrosis factor - lymphotoxin alpha

REFERENCES

• 1 Angus D C, Linde-Zwirble W T, Lidicker J, Clermont G, Carcillo J, Pinsky M R. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.  Crit Care Med. 2001;  29 1303-1310
• 2 Morimoto S, Okaishi K, Onishi M et al.. Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients.  Am J Med. 2002;  112 89-94
• 3 Sorensen T I, Nielsen G G, Andersen P K, Teasdale T W. Genetic and environmental influences on premature death in adult adoptees.  N Engl J Med. 1988;  318 727-732
• 4 Weiss S T. Association studies in asthma genetics.  Am J Respir Crit Care Med. 2001;  164 2014-2015
• 5 Hoyert D L, Arias E, Smith B L, Murphy S L, Kochanek K D. Deaths: final data for 1999.  Natl Vital Stat Rep. 2001;  49 1-113
• 6 Stuber 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;  24 381-384
• 7 Mira J P, 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;  282 561-568
• 8 Temple S E, Lim E, Cheong K Y et al.. Alleles carried at positions -819 and -592 of the IL-10 promoter affect transcription following stimulation of peripheral blood cells with Streptococcus pneumoniae. .  Immunogenetics. 2003;  55 629-632
• 9 Temple S E, Cheong K Y, Almeida C M, Price P, Waterer G W. Polymorphisms in lymphotoxin alpha and CD14 genes influence TNF alpha production induced by gram-positive and gram-negative bacteria.  Genes Immun. 2003;  4 283-288
• 10 Roy S, Knox K, Segal S et al.. MBL genotype and risk of invasive pneumococcal disease: a case-control study.  Lancet. 2002;  359 1569-1573
• 11 Hibberd M L, Sumiya M, Summerfield J A, Booy R, Levin M. Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group.  Lancet. 1999;  353 1049-1053
• 12 O'Keefe G E, Hybki D L, Munford R S. The G→A single nucleotide polymorphism at the -308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after trauma.  J Trauma. 2002;  52 817-825
• 13 Ohkubo T, Chapman N, Neal B, Woodward M, Omae T, Chalmers J. Effects of an angiotensin-converting enzyme inhibitor-based regimen on pneumonia risk.  Am J Respir Crit Care Med. 2004;  169 1041-1045
• 14 Harding D, Baines P B, Brull D et al.. Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism.  Am J Respir Crit Care Med. 2002;  165 1103-1106
• 15 Marshall R P, Webb S, Bellingan G J et al.. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2002;  166 646-650
• 16 Kronborg G, Weis N, Madsen H O 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 1517-1520
• 17 Garred P, Strom J, Quist L, Taaning E, Madsen H O. Association of mannose-binding lectin polymorphisms with sepsis and fatal outcome, in patients with systemic inflammatory response syndrome.  J Infect Dis. 2003;  188 1394-1403
• 18 Yang I A, Seeney S L, Wolter J M et al.. Mannose-binding lectin gene polymorphism predicts hospital admissions for COPD infections.  Genes Immun. 2003;  4 269-274
• 19 Garred P, Pressler T, Madsen H O et al.. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis.  J Clin Invest. 1999;  104 431-437
• 20 Neonato M G, Lu C Y, Guilloud-Bataille M et al.. Genetic polymorphism of the mannose-binding protein gene in children with sickle cell disease: identification of three new variant alleles and relationship to infections.  Eur J Hum Genet. 1999;  7 679-686
• 21 Kiechl S, Lorenz E, Reindl M et al.. Toll-like receptor 4 polymorphisms and atherogenesis.  N Engl J Med. 2002;  347 185-192
• 22 Lorenz E, Mira J P, Frees K L, Schwartz D A. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock.  Arch Intern Med. 2002;  162 1028-1032
• 23 Hawn T R, Verbon A, Lettinga K D 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 1563-1572
• 24 Hubacek J A, Pitha J, Skodova Z et al.. Polymorphisms in the lipopolysaccharide-binding protein and bactericidal/permeability-increasing protein in patients with myocardial infarction.  Clin Chem Lab Med. 2002;  40 1097-1100
• 25 Barber R C, O'Keefe G E. Characterization of a single nucleotide polymorphism in the lipopolysaccharide binding protein and its association with sepsis.  Am J Respir Crit Care Med. 2003;  167 1316-1320
• 26 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;  30 969-973
• 27 Roy S, Hill A V, Knox K, Griffiths D, Crook D. Research pointers: association of common genetic variant with susceptibility to invasive pneumococcal disease.  BMJ. 2002;  324 1369
• 28 Yee A M, Phan H M, Zuniga R, Salmon J E, Musher D M. Association between FcgammaRIIa-R131 allotype and bacteremic pneumococcal pneumonia.  Clin Infect Dis. 2000;  30 25-28
• 29 Yuan F F, Wong M, Pererva N et al.. FcgammaRIIA polymorphisms in Streptococcus pneumoniae infection.  Immunol Cell Biol. 2003;  81 192-195
• 30 Bredius R G, Derkx B H, Fijen C A et al.. Fc gamma receptor IIa (CD32) polymorphism in fulminant meningococcal septic shock in children.  J Infect Dis. 1994;  170 848-853
• 31 van der Pol W L, Huizinga T W, Vidarsson G et al.. Relevance of Fcgamma receptor and interleukin-10 polymorphisms for meningococcal disease.  J Infect Dis. 2001;  184 1548-1555
• 32 Bone R C. Sir Isaac Newton, sepsis, SIRS, and CARS.  Crit Care Med. 1996;  24 1125-1128
• 33 Beutler B, Cerami A. The biology of cachectin/TNF-a primary mediator of the host response.  Annu Rev Immunol. 1989;  7 625-655
• 34 Grove J, Daly A K, Bassendine M F, Day C P. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis.  Hepatology. 1997;  26 143-146
• 35 Knight J C, Udalova I, Hill A V et al.. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria.  Nat Genet. 1999;  22 145-150
• 36 Tang G J, Huang S L, Yien H W et al.. Tumor necrosis factor gene polymorphism and septic shock in surgical infection.  Crit Care Med. 2000;  28 2733-2736
• 37 McGuire W, Hill A V, Allsopp C E, Greenwood B M, Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria.  Nature. 1994;  371 508-510
• 38 Nadel S, Newport M J, Booy R, Levin M. Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease.  J Infect Dis. 1996;  174 878-880
• 39 Fang X M, Schroder S, Hoeft A, Stuber F. Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis.  Crit Care Med. 1999;  27 1330-1334
• 40 Waterer G W, Quasney M W, Cantor R M, Wunderink R G. Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations.  Am J Respir Crit Care Med. 2001;  163 1599-1604
• 41 Schaaf B M, 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;  168 476-480
• 42 Read R C, Camp N J, di Giovine F S et al.. An interleukin-1 genotype is associated with fatal outcome of meningococcal disease.  J Infect Dis. 2000;  182 1557-1560
• 43 McArthur J A, Zhang Q, Quasney M W. Association between the A/A genotype at the lymphotoxin-alpha +250 site and increased mortality in children with positive blood cultures.  Pediatr Crit Care Med. 2002;  3 341-344
• 44 Majetschak M, Flohe S, Obertacke U et al.. Relation of a TNF gene polymorphism to severe sepsis in trauma patients.  Ann Surg. 1999;  230 207-214
• 45 Waterer G W, ElBahlawan L, Quasney M W, Zhang Q, Kessler L A, Wunderink R G. 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 1367-1372
• 46 Ma P, Chen D, Pan J, Du B. Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients.  Crit Care Med. 2002;  30 1046-1050
• 47 Arnalich F, Lopez-Maderuelo D, Codoceo R et al.. Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis.  Clin Exp Immunol. 2002;  127 331-336
• 48 Read R C, Cannings C, Naylor S C et al.. Variation within genes encoding interleukin-1 and the interleukin-1 receptor antagonist influence the severity of meningococcal disease.  Ann Intern Med. 2003;  138 534-541
• 49 Gallagher P M, Lowe G, Fitzgerald T et al.. Association of IL-10 polymorphism with severity of illness in community acquired pneumonia.  Thorax. 2003;  58 154-156
• 50 Reid C L, Perrey C, Pravica V, Hutchinson I V, Campbell I T. Genetic variation in proinflammatory and anti-inflammatory cytokine production in multiple organ dysfunction syndrome.  Crit Care Med. 2002;  30 2216-2221
• 51 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 1756-1759
• 52 Schluter 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 32-37
• 53 Sutherland A M, Walley K R, Manocha S, Russell J A. The association of interleukin 6 haplotype clades with mortality in critically ill adults.  Arch Intern Med. 2005;  165 75-82
• 54 Quasney M W, Waterer G W, Dahmer M K 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 1115-1119
• 55 Lin Z, Pearson C, Chinchilli V et al.. Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS.  Clin Genet. 2000;  58 181-191
• 56 Gong M N, Wei Z, Xu L L, Miller D P, Thompson B T, Christiani D C. Polymorphism in the surfactant protein-B gene, gender, and the risk of direct pulmonary injury and ARDS.  Chest. 2004;  125 203-211
• 57 Jaber B L, Rao M, Guo D et al.. Cytokine gene promoter polymorphisms and mortality in acute renal failure.  Cytokine. 2004;  25 212-219
• 58 Holmes C L, Russell J A, Walley K R. Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy.  Chest. 2003;  124 1103-1115
• 59 Haralambous E, Hibberd M L, Hermans P W, Ninis N, Nadel S, Levin M. Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children.  Crit Care Med. 2003;  31 2788-2793
• 60 Westendorp R G, Hottenga J J, Slagboom P E. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock.  Lancet. 1999;  354 556-600
• 61 Yan S B, Nelson D R. Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C.  Crit Care Med. 2004;  32(Suppl 5) S239-S246
• 62 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709