A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma

Our plain-English summary of A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma, by S. Crovella, R.R. Moura, S. Cappellani, et al (Journal of Toxicology and Environmental Health. Part a, 2018).

The study

• Authors: S. Crovella, R.R. Moura, S. Cappellani, F. Celsi, E. Trevisan, M. Schneider, A. Brollo, E.M. Nicastro, F. Vita, L. Finotto, G. Zabucchi, V. Borelli
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2018;81(5):98-105
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos.

In plain English

This genetic association study used autopsy samples from 81 people (73 men, 8 women) from the Monfalcone shipyard area of northeastern Italy. All had confirmed asbestos exposure, mostly in shipbuilding, and died of malignant pleural mesothelioma between 1980 and 1995. The authors tested 86 genetic variants in 10 iron-metabolism genes and 7 variants in two inflammasome genes (NLRP1 and NLRP3). They compared these with the number of asbestos bodies (coated fibers) per gram of dry lung tissue. No significant association was found for the iron-metabolism variants. For the NLRP1 variant rs12150220, people with the A/T genotype had a median of 3,000 asbestos bodies per gram. The median was 27,000 for the A/A genotype and 9,600 for T/T. Only the A/A versus A/T difference was statistically significant (p = 0.0164). The authors noted that the A/T median was still above the 1,000 per gram threshold used to suggest occupational exposure. The authors concluded, while noting the small number of subjects, that NLRP1 may be one of the host genetic factors behind individual differences in asbestos body formation.

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 on archived autopsy tissue (candidate gene variants compared with lung asbestos body counts)
• Who was studied: 81 people (73 men, 8 women, aged 44 to 90) with confirmed asbestos exposure who died of malignant pleural mesothelioma between 1980 and 1995, from the Monfalcone area of northeastern Italy
• Exposure: Occupational exposure data were available for 85% of subjects. For them, exposure was predominantly in shipbuilding (75%). Others worked in the navy and merchant marine or in the textile and construction industries. 75% of the women had household exposure from laundering family members' work clothes.
• Main results:
  • Asbestos bodies were found in all 81 subjects, ranging from 20 to 876,000 per gram of dry lung tissue (median 8000; 25th percentile 1700; 75th percentile 65,000).
  • Energy-dispersive X-ray analysis of random asbestos body samples from the shipyard population showed amosite and crocidolite as the primary fiber cores (data not shown).
  • No significant association was found between the variants in iron-metabolism genes and lung asbestos body burden.
  • For the NLRP1 rs12150220 variant, the median asbestos body count by genotype was: A/T genotype (39 people), 3,000; A/A genotype (24 people), 27,000; T/T genotype (18 people), 9,600.
  • Only the A/A versus A/T comparison was statistically significant (p = 0.0164; significance threshold p lower than 0.017). The other comparisons were not significant: A/A versus T/T, p = 0.6112; A/T versus T/T, p = 0.1541.
  • When results were split by tumor histological type, no marked association was seen between the NLRP1 variant and asbestos body number.
  • The median of 3,000 asbestos bodies per gram in A/T carriers was still above the internationally accepted threshold of 1000 per gram used to define a possibility of occupational exposure.
  • Computer prediction tools (SIFT and Polyphen) predicted the NLRP1 variant to be possibly or probably damaging to the protein.
• The authors' conclusion: The authors postulated that the NLRP1 inflammasome may be one of the host genetic factors contributing to individual variability in how efficiently asbestos fibers become coated to form asbestos bodies.
• Limitations the authors state:
  • The number of individuals enrolled was low, and the inhaled fibers were characterized only indirectly.
  • No biological material was available for gene expression or protein analysis, so the effect of the variant could not be functionally validated.
  • No complete NLRP1 protein structure was available, so the variant's effect on protein shape could not be predicted by computer.
  • Other iron-metabolism gene variants that were not examined cannot be excluded.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Asbestos Body Formation, Pleural Mesothelioma, Asbestos Bodies, Parenchyma, Occupational Exposure.

Related studies

• Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes — F. Celsi, S. Crovella, et al. (2019)
• Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers — S. Crovella, R.R. Moura, et al. (2022)
• The microbial and danger signals that activate Nod-like receptors — S. Benko, D.J. Philpott, et al. (2008)
• MicroRNA expression in lung tissues of asbestos-exposed mice: Upregulation of miR-21 and downregulation of tumor suppressor genes Pdcd4 and Reck — Y. Hiraku, J. Watanabe, et al. (2021)
• A comparison of asbestos burden in lung parenchyma, lymph nodes, and plaques — R.F. Dodson, M.G. Williams, et al. (1991)
• Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma — H. Kohno, V.J. Amatya, et al. (2010)

Browse more research in Journal of Toxicology and Environmental Health. Part a, or return to medical research.