title: Genes involved in innate immunity associated with asbestos-related fibrotic changes.
abstract: OBJECTIVE
  To determine whether genetic polymorphisms in several candidate genes related to innate immunity and protease-antiprotease balance modify individual susceptibility to develop asbestos-related fibrotic pleuropulmonary changes.
  
  
  METHODS
  Sixteen polymorphisms from nine genes (NLRP3, CARD8, TNF, TGFB1, GC, MMP1, MMP9, MMP12 and TIMP2) were genotyped from 951 Finnish asbestos-exposed workers. The genotype/haplotype data were compared to signs of fibrosis and pleural thickenings using linear and logistic regression analysis adjusted for potential confounders.
  
  
  RESULTS
  A functional polymorphism (Q705K; rs35829419) in the NLRP3 gene was associated with interstitial lung fibrosis (p=0.013), and the TGFB1 rs2241718 SNP with visceral pleural fibrosis (VPF) (p=0.044). In stratified analysis, the carriage of at least one NLRP3 variant allele conferred a 2.5-fold increased risk for pathological interstitial lung fibrosis (OR 2.44, 95% CI 0.97 to 6.14). Conversely, the carriage of at least one TGFB1 rs2241718 variant allele protected against VPF (OR 0.62, 95% CI 0.39 to 0.98). The TIMP2 rs2277698 SNP and a haplotype consisting of the TGFB1 rs1800469 and rs1800470 SNPs were associated with the degree of pleural thickening calcification (p=0.037 and p=0.035), and the CARD8 rs2043211 SNP with the greatest thickness of pleural plaques (p=0.015).
  
  
  CONCLUSIONS
  Our results support the hypothesis that the NLRP3 inflammasome is important in the development of fibrotic lung disease by associating the NLRP3 rs35829419 variant allele with increased risk of asbestos-related interstitial lung fibrosis, and the TGFB1 rs2241718 variant allele with decreased risk of asbestos-related VPF. Polymorphisms in CARD8 and TIMP2 are proposed to modify the development and/or calcification of pleural thickenings.
authors.affiliation: Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Mari K
authors.initials: MK
authors.lastname: Kukkonen
authors.forename: Tapio
authors.initials: T
authors.lastname: Vehmas
authors.forename: Päivi
authors.initials: P
authors.lastname: Piirilä
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
mesh_terms: D000368:Aged; D000483:Alleles; D001194:Asbestos / Q000009:adverse effects*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D005355:Fibrosis / Q000235:genetics; D005387:Finland; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009784:Occupational Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016273:Occupational Exposure / Q000009:adverse effects*; D009790:Occupations; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D010995:Pleural Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011480:Protease Inhibitors / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; C508960:TGFB1 protein, human; C560823:TIMP2 protein, human; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; D001194:Asbestos; D010447:Peptide Hydrolases