The association of genetic factors with serum calretinin levels in asbestos-related diseases

Our plain-English summary of The association of genetic factors with serum calretinin levels in asbestos-related diseases, by C. Zupanc, A. Franko, D. Strbac, et al (Radiology and Oncology, 2023).

The study

• Authors: C. Zupanc, A. Franko, D. Strbac, V. Kovac, V. Dolzan, K. Goricar
• Journal: Radiology and Oncology
• Published: 2023;57(4):473-486
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Asbestos exposure is associated with different asbestos-related diseases, including malignant mesothelioma (MM). MM diagnosis is confirmed with immunohistochemical analysis of several markers, including calretinin. Increased circulating calretinin was also observed in MM. The aim of the study was to determine if CALB2 polymorphisms or polymorphisms in genes that can regulate calretinin expression are associated with serum calretinin levels or MM susceptibility.

Subjects And Methods: The study included 288 MM patients and 616 occupationally asbestos-exposed subjects without MM (153 with asbestosis, 380 with pleural plaques and 83 without asbestos-related disease). Subjects were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1 and SEPTIN7 genes using competitive allele-specific polymerase chain reaction (PCR). Serum calretinin was determined with ELISA in 545 subjects. Nonparametric tests, logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis.

Results: Carriers of at least one polymorphic CALB2 rs889704 allele had lower calretinin levels (P = 0.036). Carriers of two polymorphic MIR335 rs3807348 alleles had higher calretinin (P = 0.027), while carriers of at least one polymorphic NRF1 rs13241028 allele had lower calretinin levels (P = 0.034) in subjects without MM. Carriers of two polymorphic E2F2 rs2075995 alleles were less likely to develop MM (odds ratio [OR] = 0.64, 95% confidence interval [CI] = 0.43-0.96, P = 0.032), but the association was no longer significant after adjustment for age (P = 0.093). Optimal serum calretinin cut-off values differentiating MM patients from other subjects differed according to CALB2, NRF1, E2F2, and MIR335 genotypes.

Conclusions: The results of presented study suggest that genetic variability could influence serum calretinin levels. These findings could contribute to a better understanding of calretinin regulation and potentially to earlier MM diagnosis.

© 2023 Cita Zupanc et al., published by Sciendo.

In plain English

This retrospective study from Slovenia asked whether inherited DNA variants (polymorphisms) in CALB2, the calretinin gene, and in four genes thought to regulate it were linked to blood (serum) calretinin levels or to malignant mesothelioma (MM). It included 288 MM patients and 616 occupationally asbestos-exposed people without MM: 153 with asbestosis, 380 with pleural plaques and 83 without asbestos-related disease. Serum calretinin was measured in 545 subjects. Median levels were 0.52 ng/ml in MM patients and 0.12 to 0.18 ng/ml in the other groups. Across all subjects, carriers of at least one variant CALB2 rs889704 allele had lower calretinin (P = 0.036). Among subjects without MM, two variant MIR335 rs3807348 alleles were linked to higher calretinin (P = 0.027), and a variant NRF1 rs13241028 allele was linked to lower calretinin (P = 0.034). Carrying two variant E2F2 rs2075995 alleles was linked to lower odds of MM (odds ratio 0.64, 95% CI 0.43 to 0.96). This was no longer statistically significant after adjusting for age. The best calretinin cut-off for separating MM patients from others differed slightly by genotype. The authors concluded that genetic variability could influence serum calretinin levels.

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 genetic association study comparing MM patients with asbestos-exposed subjects without MM
• Who was studied: 904 subjects in Slovenia. 288 had MM (pleural or peritoneal; 33 peritoneal) and were treated at the Institute of Oncology Ljubljana between November 2001 and March 2019. 616 occupationally asbestos-exposed subjects without MM (153 with asbestosis, 380 with pleural plaques, 83 without asbestos-related disease) were evaluated by the State Board for the Recognition of Occupational Asbestos Diseases between September 1998 and April 2007.
• Exposure: Occupational asbestos exposure; fiber types, products, jobs and doses are not reported. The factors studied were seven genetic polymorphisms in the CALB2, E2F2, MIR335, NRF1 and SEPTIN7 genes.
• Main results:
  • Median serum calretinin differed among groups (P < 0.001): 0.52 ng/ml in MM patients (N = 163), 0.13 ng/ml with asbestosis (N = 117), 0.18 ng/ml with pleural plaques (N = 195) and 0.12 ng/ml without disease (N = 70).
  • In all subjects, carriers of at least one variant CALB2 rs889704 allele had lower calretinin (P = 0.036). The difference was not significant when subjects without MM and MM patients were analysed separately (P = 0.069 and 0.441).
  • In subjects without MM, carriers of two variant MIR335 rs3807348 alleles had higher calretinin (P = 0.027).
  • In subjects without MM, carriers of at least one variant NRF1 rs13241028 allele had lower calretinin (P = 0.034). No significant difference was seen in MM patients.
  • Compared with all subjects without MM, carriers of two variant E2F2 rs2075995 alleles were less likely to have MM (OR = 0.64, 95% CI = 0.43 to 0.96, P = 0.032). After adjustment for age this was not significant (OR = 0.68, 95% CI = 0.44 to 1.07, P = 0.093).
  • Compared only with subjects without any asbestos-related disease, carriers of two variant E2F2 rs2075995 alleles were less likely to have MM (OR = 0.35, 95% CI = 0.16 to 0.78, P = 0.010). The association remained after age adjustment (OR = 0.35, 95% CI = 0.14 to 0.84, P = 0.019).
  • Compared with subjects with asbestosis, carriers of two variant MIR335 rs3807348 alleles were more likely to have MM (OR = 1.82, 95% CI = 1.05 to 3.16, P = 0.033).
  • Serum calretinin distinguished MM patients from all other subjects. In the whole group the area under the curve was 0.825 (95% CI 0.781 to 0.868), and a cut-off of 0.32 ng/ml gave sensitivity 0.681 and specificity 0.887.
  • Optimal calretinin cut-offs differed by genotype, but the authors noted that the differences were small.
  • CALB2 haplotypes (combinations of the three CALB2 variants) were not significantly associated with MM (TCC haplotype P = 0.061) or with serum calretinin.
• The authors' conclusion: The authors concluded that genetic variability could influence serum calretinin levels. They wrote that this could contribute to understanding calretinin regulation and potentially to earlier MM diagnosis.
• Limitations the authors state:
  • Serum calretinin was available only for a subgroup of participants (545 of 904).
  • Other polymorphisms in the studied genes, and other factors, could also affect calretinin.
  • The results need validation in an independent population.

Topics

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

Medical terms in this study, explained in our Lexicon: Calretinin, Asbestos Exposure, Mesothelioma, Pleural Plaques, Odds Ratio, confidence interval.

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• Calretinin Functions in Malignant Mesothelioma Cells Cannot Be Replaced by the Closely Related Ca2+-Binding Proteins Calbindin-D28k and Parvalbumin — J. Wörthmüller, A. Oberson, et al. (2018)
• Serum levels of soluble mesothelin-related peptides in malignant and nonmalignant asbestos-related pleural disease: relation with past asbestos exposure — J.A. Rodríguez Portal, E. Rodríguez Becerra, et al. (2009)
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• Serum Calretinin as a Biomarker in Malignant Mesothelioma — C. Zupanc, A. Franko, et al. (2021)

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