Part of the book: Advances in DNA Repair
It is becoming evident that both environmental/lifestyle and genetic factors may influence the development of many diseases. This chapter highlights the importance of considering gene-environment interactions, which is shown on the example of our studies into asbestosis, one of the most frequent asbestos-related diseases. Asbestos fibres induce generation of reactive oxygen and nitric species (ROS and RNS), and it is generally accepted that ROS and RNS are involved in the pathogenesis of asbestos-related diseases. Human tissues contain specific enzymes that metabolise ROS and RNS, such as superoxide dismutases (SODs), catalase (CAT), glutathione-S-transferases (GSTs) and inducible nitric oxide synthase (iNOS). As these enzymes are encoded by polymorphic genes, genetic variability in an individual’s capacity to detoxify these reactive species may modify the risk for disease. Our previous studies into asbestosis showed that the associations between the risk of asbestosis and MnSOD Ala-9Val polymorphism and between asbestosis and iNOS genotypes were modified by CAT −262C>T polymorphism. A strong interaction was also found between smoking (lifestyle factor) and GSTM1-null polymorphism, between smoking and iNOS (CCTTT)n polymorphism and between cumulative asbestos exposure (environmental factor) and iNOS (CCTTT)n polymorphism. The findings of our studies and other studies indicate that in addition to environmental and/or occupational exposure to different hazards and lifestyle factors, genetic factors as well as the interactions between different genotypes, between genotypes and lifestyle factors and between genotypes and environmental/occupational exposure to hazards may also have an important role on the development of diseases and should be further investigated.
Part of the book: Occupational Health
Psoriasis is a chronic systemic, immune-mediated disorder of unknown aetiology, usually presenting with typical inflammatory skin lesions and/or joint manifestations, but systemic inflammation that may lead to the development of co-morbidities may also be present. First-line therapy encompasses local cutaneous treatment and phototherapy, but with more severe symptoms or systemic course, systemic treatment with methotrexate (MTX), immunosuppressant cyclosporine, retinoid acitretin or biologicals may be used. Treatment response varies between patients in terms of efficacy and/or toxicity, which could, among other reasons, be due to genetic differences between patients. Approximately 10–30% of patients experience adverse drug reactions with MTX treatment, leading to discontinuation of MTX mostly due to hepatotoxicity. Around 15% of patients experience adverse events when treated with biologicals; however, the most frequent reason for discontinuation is inefficacy or loss of the initially favourable response over time. Inefficacy or occurrence of adverse drug reactions cannot be predicted, so genetic biomarkers of drug response in combination with clinical data could be helpful in treatment planning. Several polymorphic genes have already been associated with treatment outcome, most of them involved in drug metabolism, transport and target pathways. Genetic biomarkers could be helpful in personalized care of psoriasis patients in order to prevent adverse events or predict inefficacy of a certain drug.
Part of the book: Psoriasis
Parkinson’s disease (PD) is a chronic progressive neurodegenerative brain disorder presenting with motor signs and symptoms, such as akinesia, rest tremor, rigidity, and later in disease progression postural instability. However, nonmotor symptoms may harm patients’ quality of life even more than the motor ones. The etiopathogenesis is not clear yet. PD may develop due to a combination of genetic and environmental factors. It is treated symptomatically with dopaminergic drugs. The gold standard of PD management is L-Dopa, however also other drugs are frequently used, such as dopamine agonists, MAOB inhibitors, COMT inhibitors, and occasionally amantadine and anticholinergic drugs. Many patients experience several adverse events of L-Dopa treatment, such as different motor complications. Furthermore, nonmotor adverse events of dopaminergic treatment may occur. The efficacy of drugs varies between patients as well. Several polymorphic genes have already been associated with treatment outcome in PD, such as metabolic enzymes, transport and receptor genes, and might serve as treatment outcome prediction factors. As gene-environment interactions were also shown to contribute to PD development, they might also be able to predict treatment response. Such genetic biomarkers could be helpful in personalized care of PD patients to prevent adverse events and inefficacy of a certain drug.
Part of the book: Parkinson's Disease
Several pleural diseases have been associated with asbestos exposure. Asbestos exposure may lead to the development of benign pleural diseases, such as pleural plaques, diffuse pleural thickening, and pleural effusion, as well as to the development of malignant mesothelioma, a highly aggressive tumour of the pleura. Asbestos exposure related to pleural diseases may be occupational or environmental. Although the causal relationship between asbestos-related pleural diseases and asbestos exposure has been well confirmed, the role of genetic factors in the development of these diseases needs to be further investigated and elucidated. The results of the studies performed so far indicate that in addition to asbestos exposure, genetic factors as well as the interactions between genetic factors and asbestos exposure may have an important impact on the risk of asbestos-related pleural diseases, especially malignant mesothelioma. This chapter aims to present how the risk of developing asbestos-related pleural diseases may be influenced by asbestos exposure, genetic factors, interactions between different genetic factors, as well as interactions between different genetic factors and asbestos exposure.
Part of the book: Diseases of Pleura
Asbestos-related diseases, including asbestosis, benign pleural diseases, lung cancer, other types of cancer, and especially malignant mesothelioma (MM), still represent an enormous problem all over the world and are among the most investigated occupational diseases. Considering that MM is a highly aggressive and severe malignant cancer of pleura, peritoneum and other serosal surfaces, new blood biomarkers for earlier diagnosis, following response to treatment and disease progression, have been intensively investigated. Several studies suggested that soluble mesothelin-related peptides, fibulin-3, survivin, osteopontin, vimentin, calretinin, and many others could be helpful in diagnosis, detecting the progression of MM and evaluating tumour response to treatment; however, these biomarkers have not been validated in clinical practice. Therefore, search for novel better stand-alone or composite biomarkers is under way. The aim of this chapter is to present the importance of blood biomarkers in evaluating the risk of developing asbestos-related diseases, early diagnosis, following the response to treatment and progression of these diseases, with special emphasis on MM.
Part of the book: Asbestos-related Diseases
The established treatments in malignant mesothelioma are based on trimodality approach including surgery, radiation and chemotherapy. Such approach has proved to clinically benefit mesothelioma patients, however the current treatments seem to have reached a limit regarding the survival and disease control. One approach to overcome the limitations of current treatments is focused on finding appropriate serum or genetic biomarkers that could support personalized medicine and improve outcomes with established treatment modalities in mesothelioma patients. The other approach is exploiting better understanding of molecular and genetic characteristics of mesothelioma to search for new treatment modalities. Immunotherapy with anti PD-1, PD-L1 and CTLA-4 agents is a new frontier in mesothelioma treatment. As in many solid tumors, CAR-T cell therapy is emerging from the field of hematological malignancies. Immunomodulatory approaches seem to be a new perspective in treatment of malignant mesothelioma. This chapter aims to explore possible new therapeutic approaches in mesothelioma.
Part of the book: Mesothelioma