title: Influence of genetic variability at the surfactant proteins A and D in community-acquired pneumonia: a prospective, observational, genetic study.
abstract: BACKGROUND
  Genetic variability of the pulmonary surfactant proteins A and D may affect clearance of microorganisms and the extent of the inflammatory response. The genes of these collectins (SFTPA1, SFTPA2 and SFTPD) are located in a cluster at 10q21-24. The objective of this study was to evaluate the existence of linkage disequilibrium (LD) among these genes, and the association of variability at these genes with susceptibility and outcome of community-acquired pneumonia (CAP). We also studied the effect of genetic variability on SP-D serum levels.
  
  
  METHODS
  Seven non-synonymous polymorphisms of SFTPA1, SFTPA2 and SFTPD were analyzed. For susceptibility, 682 CAP patients and 769 controls were studied in a case-control study. Severity and outcome were evaluated in a prospective study. Haplotypes were inferred and LD was characterized. SP-D serum levels were measured in healthy controls.
  
  
  RESULTS
  The SFTPD aa11-C allele was significantly associated with lower SP-D serum levels, in a dose-dependent manner. We observed the existence of LD among the studied genes. Haplotypes SFTPA1 6A(2) (P = 0.0009, odds ration (OR) = 0.78), SFTPA(2) 1A(0) (P = 0.002, OR = 0.79), SFTPA1-SFTPA2 6A2-1A(0) (P = 0.0005, OR = 0.77), and SFTPD-SFTPA1-SFTPA(2)C-6A2-1A(0) (P = 0.00001, OR = 0.62) were underrepresented in patients, whereas haplotypes SFTPA2 1A(10) (P = 0.00007, OR = 6.58) and SFTPA1-SFTPA2 6A(3)-1A (P = 0.0007, OR = 3.92) were overrepresented. Similar results were observed in CAP due to pneumococcus, though no significant differences were now observed after Bonferroni corrections. 1A(10) and 6A-1A were associated with higher 28-day and 90-day mortality, and with multi-organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) respectively. SFTPD aa11-C allele was associated with development of MODS and ARDS.
  
  
  CONCLUSIONS
  Our study indicates that missense single nucleotide polymorphisms and haplotypes of SFTPA1, SFTPA2 and SFTPD are associated with susceptibility to CAP, and that several haplotypes also influence severity and outcome of CAP.
authors.affiliation: Department of Immunology, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria 35010, Spain. jrodgal@gobiernodecanarias.org
authors.forename: M Isabel
authors.initials: MI
authors.lastname: García-Laorden
authors.forename: Felipe
authors.initials: F
authors.lastname: Rodríguez de Castro
authors.forename: Jordi
authors.initials: J
authors.lastname: Solé-Violán
authors.forename: Olga
authors.initials: O
authors.lastname: Rajas
authors.forename: José
authors.initials: J
authors.lastname: Blanquer
authors.forename: Luis
authors.initials: L
authors.lastname: Borderías
authors.forename: Javier
authors.initials: J
authors.lastname: Aspa
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Briones
authors.forename: Pedro
authors.initials: P
authors.lastname: Saavedra
authors.forename: J Alberto
authors.initials: JA
authors.lastname: Marcos-Ramos
authors.forename: Nereida
authors.initials: N
authors.lastname: González-Quevedo
authors.forename: Ithaisa
authors.initials: I
authors.lastname: Sologuren
authors.forename: Estefanía
authors.initials: E
authors.lastname: Herrera-Ramos
authors.forename: José M
authors.initials: JM
authors.lastname: Ferrer
authors.forename: Jordi
authors.initials: J
authors.lastname: Rello
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodríguez-Gallego
mesh_terms: D016022:Case-Control Studies; D017714:Community-Acquired Infections / Q000097:blood / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D020125:Mutation, Missense / Q000235:genetics; D011014:Pneumonia / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics*; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D