Genes involved in innate immunity associated with asbestos-related fibrotic changes

Our plain-English summary of Genes involved in innate immunity associated with asbestos-related fibrotic changes, by M.K. Kukkonen, T. Vehmas, P. Piirilä, et al (Occupational and Environmental Medicine, 2014).

The study

• Authors: M.K. Kukkonen, T. Vehmas, P. Piirilä, A. Hirvonen
• Journal: Occupational and Environmental Medicine
• Published: 2014;71(1):48-54
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: 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.

In plain English

This Finnish study asked whether common gene variants linked to the body's innate immune response and to tissue repair were associated with fibrotic (scarring-type) changes in the lungs and pleura of asbestos-exposed workers. The authors combined data from two earlier studies (1996–1997 and 2003–2004). They tested 16 variants in nine genes in 951 workers, almost all men and largely construction workers, whose chests had been examined with high-resolution CT. A variant in the NLRP3 gene was associated with interstitial lung fibrosis (p=0.013). Carriers had an odds ratio of 2.44 (95% CI 0.97 to 6.14) for pathological fibrosis, which the authors called only borderline significant. Carriers of a TGFB1 variant (rs2241718) had lower odds of visceral pleural fibrosis (OR 0.62, 95% CI 0.39 to 0.98). A TIMP2 variant and two TGFB1 haplotypes were associated with more calcification of pleural plaques. The authors concluded that their results strengthen the hypothesis that the NLRP3 inflammasome is important in fibrotic lung disease. They cautioned that because many comparisons were made, the findings should be treated with caution until replicated in another population.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic association study of asbestos-exposed workers, combining data from two earlier studies (ASBE and ASSE)
• Who was studied: 951 Finnish asbestos-exposed workers (935 men, 16 women) examined in 1996–1997 (ASBE) or 2003–2004 (ASSE) in Helsinki, Tampere and Turku, with chest high-resolution CT and blood samples
• Exposure: Occupational asbestos exposure, mainly in construction work: installing heat and fire insulation or asbestos-containing walls and ceiling panels, using asbestos paints, putties and fillers, dismantling asbestos materials, or cleaning asbestos areas (ASSE participants were mostly construction workers, cleaners or plumbers). Mean duration of exposure was 23.9 years in the whole group. Fiber types were not specified for this population.
• Main results:
  • Among the 951 workers, the NLRP3 rs35829419 variant was associated with interstitial lung fibrosis (p=0.013), and the TGFB1 rs2241718 variant with visceral pleural fibrosis (p=0.044)
  • Carriers of at least one NLRP3 rs35829419 variant allele had an OR of 2.44 (95% CI 0.97 to 6.14) for pathological interstitial lung fibrosis compared with workers with no changes; the authors described this as only borderline significant
  • Carriers of at least one TGFB1 rs2241718 variant allele had an OR of 0.62 (95% CI 0.39 to 0.98) for visceral pleural fibrosis; the authors described the variant as protective
  • Carriers of at least one TIMP2 rs2277698 variant allele had an OR of 1.90 (95% CI 1.09 to 3.33) for a high degree of pleural plaque calcification
  • Compared with the most common TGFB1 haplotype (GT), the GC haplotype (OR 1.52, 95% CI 1.09 to 2.11) and the AT haplotype (OR 1.95, 95% CI 1.18 to 3.22) were associated with pleural plaque calcification; these counts are of chromosomes
  • The CARD8 rs2043211 variant was associated with the greatest thickness of pleural plaques (p=0.015), but this association was not found in the stratified analysis
  • No associations were found between GC gene haplotypes and the fibrotic or pleural changes studied
• The authors' conclusion: The authors concluded that their results strengthen the hypothesis that the NLRP3 inflammasome is important in the development of fibrotic lung diseases. They proposed that the NLRP3 rs35829419 variant increases the risk of asbestos-related interstitial lung fibrosis, that the TGFB1 rs2241718 variant protects against visceral pleural fibrosis, and that CARD8 and TIMP2 variants may modify the development or calcification of pleural thickenings.
• Limitations the authors state:
  • Four different CT scanners and seven radiologists were used across three cities and two studies
  • Multiple comparisons increase the chance of false-positive associations
  • The results need replication in another study population before they are relied on

Topics

The National Library of Medicine indexes this study under subjects our site covers: Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Fibrosis, Pleural Thickening, Interstitial, Pleural Plaques.

Related studies

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• The microbial and danger signals that activate Nod-like receptors — S. Benko, D.J. Philpott, et al. (2008)
• Tumour necrosis factor-alpha gene polymorphisms in asbestos-induced diseases — S. Helmig, N. Aliahmadi, et al. (2010)
• Pulmonary toxicants and fibrosis: innate and adaptive immune mechanisms — R. Malaviya, H.M. Kipen, et al. (2020)
• Risk of malignant pleural mesothelioma and polymorphisms in genes involved in the genome stability and xenobiotics metabolism — F. Gemignani, M. Neri, et al. (2009)
• Comparison of independent randomised reading of radiographs with direct progression scoring for assessing change in asbestos-related pulmonary and pleural lesions — G.H. McMillan, C.E. Rossiter, et al. (1982)

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