Genetic variability of immune checkpoints in asbestos-related diseases

Our plain-English summary of Genetic variability of immune checkpoints in asbestos-related diseases, by I. Zeljkovic, K. Goricar, T. Blagus, et al (Radiology and Oncology, 2026).

The study

• Authors: I. Zeljkovic, K. Goricar, T. Blagus, A. Franko, V. Kovac, V. Dolzan
• Journal: Radiology and Oncology
• Published: 2026;60(2):271-281
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Asbestos exposure is associated with asbestos-related diseases such as pleural plaques, asbestosis, lung cancer, malignant mesothelioma (MM), as well as several other types of cancer. Although the exact mechanism underlying the development of asbestos-related diseases is not yet fully understood, the immune system may play an important role. Immune checkpoints such as programmed cell death receptor 1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) regulate immune responses and are crucial for maintaining immune tolerance, while defects in these mechanisms can lead to the development of cancer. The aim of present study was to investigate the association of polymorphisms in the immune checkpoint genes for PD-1 (PDCD1), PD-L1 (CD274), and CTLA-4 (CTLA4) with the risk of asbestos-related diseases.

Subjects And Methods: We conducted a retrospective case-control study. The cases included individuals with asbestosis or pleural plaques and MM patients. The controls were asbestos-exposed subjects who did not develop asbestos-related diseases. All subjects were genotyped for PDCD1 (rs2227982, rs222798, rs10204525), CD274 (rs2297136, rs4143815, rs4742098) and CTLA4 (rs5742909, rs4553808, rs231775) polymorphisms using competitive allele-specific PCR. Statistical analysis was performed using logistic regression.

Results: Our study showed that the CTLA4 rs4553808 polymorphism was associated with a decreased risk of asbestosrelated diseases (OR = 0.34, 95% CI = 0.15-0.74, P = 0.007). Homozygous carriers of polymorphic rs4553808 G allele had a lower risk of developing pleural plaques as well as MM compared to the control group (OR = 0.28, 95% CI = 0.11-0.68, P = 0.01, and OR = 0.38, 95% CI = 0.16 -0.93, P = 0.03, respectively). However, carriers of polymorphic CTLA4 rs231775 GG genotype had a higher risk of developing MM compared to the group of subjects with pleural plaques (OR = 1.79, 95% CI = 1.10-2.89, P = 0.02). The other investigated polymorphisms were not associated with any of the asbestos-related diseases.

Conclusions: CTLA4 polymorphisms may play a role in the susceptibility for asbestos-related diseases. Our results may contribute to a better understanding of the pathogenesis and progression of asbestos-related diseases.

© 2026 Irma Zeljkovic et al.

In plain English

This retrospective case-control study from Slovenia examined inherited variants in three immune checkpoint genes (PDCD1, CD274 and CTLA4) in relation to asbestos-related disease. It included 902 people: 376 with pleural plaques, 151 with asbestosis, 297 with malignant mesothelioma (MM; 263 pleural and 33 peritoneal), and 78 occupationally asbestos-exposed controls who did not develop asbestos-related disease. Nine gene variants were tested. The article did not report fiber types or exposure levels. People with two copies of the G form of CTLA4 rs4553808 (GG genotype) had lower odds than controls of any asbestos-related disease (odds ratio 0.34, 95% CI 0.15-0.74) and of pleural plaques (odds ratio 0.28, 95% CI 0.11-0.68). For MM compared with controls the odds ratio was 0.38 (95% CI 0.16-0.93), but this was no longer statistically significant after adjustment for age. The CTLA4 rs231775 GG genotype was linked to higher odds of MM compared with pleural plaques (odds ratio 1.79, 95% CI 1.10-2.89). No variant was associated with asbestosis. The authors concluded that CTLA4 variants may affect the risk of pleural asbestos diseases. They noted a small control group and an older MM group as limitations.

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: retrospective case-control genetic association study
• Who was studied: 902 subjects in Slovenia: 376 with pleural plaques, 151 with asbestosis and 297 with malignant mesothelioma, plus 78 occupationally asbestos-exposed controls without asbestos-related disease. Non-MM subjects were evaluated by a state board in Ljubljana from 1999 to 2003. MM patients were treated at the Institute of Oncology Ljubljana from 2001 to 2018. Of the MM patients, 263 had pleural and 33 had peritoneal MM.
• Exposure: Occupational asbestos exposure; the article does not report fiber types, products, jobs or doses. The factors analyzed were nine polymorphisms in the PDCD1, CD274 and CTLA4 genes.
• Main results:
  • CTLA4 rs4553808 GG genotype carriers had lower odds of any asbestos-related disease than controls: OR = 0.34, 95% CI = 0.15-0.74, P = 0.007 (age-adjusted OR = 0.32, 95% CI = 0.15-0.72, P = 0.006).
  • CTLA4 rs4553808 GG genotype carriers had lower odds of pleural plaques than controls: OR = 0.28, 95% CI = 0.11-0.68, P = 0.01.
  • For MM versus controls, CTLA4 rs4553808 GG homozygotes had OR = 0.38, 95% CI = 0.16-0.93, P = 0.03. This was no longer statistically significant after age adjustment (Padj = 0.06).
  • CTLA4 rs231775 GG genotype carriers had higher odds of MM compared with subjects with pleural plaques: OR = 1.79, 95% CI = 1.10-2.89, P = 0.02 (age-adjusted OR = 2.1, 95% CI = 1.19-3.56, P = 0.01).
  • None of the investigated polymorphisms was associated with the risk of asbestosis.
  • The CTLA4 haplotype GCA was associated with lower odds of any asbestos-related disease compared with controls: OR = 0.49, 95% CI = 0.31-0.78, P = 0.003.
• The authors' conclusion: The authors concluded that CTLA4 polymorphisms may have an impact on the risk of asbestos diseases of the pleura, such as pleural plaques and MM.
• Limitations the authors state:
  • The control group was small.
  • The MM patients were significantly older than the other groups; the authors adjusted for age.

Topics

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

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Pleural Plaques, Lung Cancer, Mesothelioma, PD-L1, CTLA-4, Case-Control Study.

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