Asbestos-Related Pleural Diseases: The Role of Gene-Environment Interactions

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

Gene-Environment Interactions: The Case of Asbestosis

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

Asbestos-Related Diseases and Blood Biomarkers

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

Expression of miRNA and Occurrence of Distant Metastases in Patients with Hürthle Cell Carcinoma

Background. Hürthle cell thyroid carcinoma (HCTC) is a rare type of thyroid carcinoma. In the present study, we investigated whether the expression of miRNAs of interest is associated with the occurrence of metastases in patients with HCTC. Materials and Methods. In 39 patients with HCTC (22 with nonmetastatic and 17 with regional or distant metastatic disease), the expression levels of six miRNAs (miR-138, miR-183, miR-221, miR-222, miR-768-3p, and miR-885-5p) and U6 snRNA as endogenous control were determined in FFPE samples of primary tumor and normal thyroid tissue using TaqMan miRNA assays. Results. In patients with HCTC, miR-138 and miR-768-3p were downregulated in tumor samples compared to normal tissue (p=0.013 and p=0.010, resp.). These two miRNAs were also significantly downregulated in tumor samples of patients with metastatic disease (p=0.030 and p=0.048, resp.) but not in patients with nonmetastatic disease (p=0.249 and p=0.101, resp.). In patients with nonmetastatic disease, miR-221 and miR-885-5p were slightly, albeit significantly, upregulated in tumorous compared to normal tissue (p=0.042 and p=0.027, resp.). Conclusion. Expression of miRNA (miR-183, miR-221, and miR-885-5p) in tumor tissue is associated with the occurrence of distant metastases in patients with HCTC

Educating the Next Generation of Pharmacogenomics Experts: Global Educational Needs and Concepts

Personalised Therapeutic

Variants in the 14q32 miRNA cluster are associated with osteosarcoma risk in the Spanish population

Association studies in osteosarcoma risk found significant results in intergenic regions, suggesting that regions which do not codify for proteins could play an important role. The deregulation of microRNAs (miRNAs) has been already associated with osteosarcoma. Consequently, genetic variants affecting miRNA function could be associated with risk. This study aimed to evaluate the involvement of all genetic variants in pre-miRNAs described so far in relationship to the risk of osteosarcoma. We analyzed a total of 213 genetic variants in 206 pre-miRNAs in two cohorts of osteosarcoma patients (n = 100) and their corresponding controls (n = 256) from Spanish and Slovenian populations, using Goldengate Veracode technology (Illumina). Four polymorphisms in pre-miRNAs at 14q32 miRNA cluster were associated with osteosarcoma risk in the Spanish population (rs12894467, rs61992671, rs58834075 and rs12879262). Pathway enrichment analysis including target genes of these miRNAs pointed out the WNT signaling pathways overrepresented. Moreover, different single nucleotide polymorphism (SNP) effects between the two populations included were observed, suggesting the existence of population differences. In conclusion, 14q32 miRNA cluster seems to be a hotspot for osteosarcoma susceptibility in the Spanish population, but not in the Slovenian, which supports the idea of the existence of population differences in developing this disease.Special thanks to Slovenian Osteosarcoma Study Group for their collaboration in sample collection. The "Slovenian Osteosarcoma Study Group" is conformed by Katja Goricar from the Institute of Biochemistry, Faculty of Medicine of Ljubljana, Viljem Kovac from the Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine of University of Ljubljana, Janez Jazbec from the Institute of Oncology Ljubljana, Janez Lamovec from the Oncology and Hematology Unit, University Children's Hospital, University Medical Centre of Ljubljana and Prof. Vita Dolzan included in the authorship of this article. The authors would like to thank Leire Iparraguirre for her technical assistance with figures. This study was funded by the Basque Government (IT661-13, IT989-16), UPV/EHU (UFI11/35)

Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia

Background. Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods. Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTPI (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results. Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the noncarriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rsl 138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions. Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients

Involvement of SNPs in miR-3117 and miR-3689d2 in Childhood Acute Lymphoblastic Leukemia Risk

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Numerous studies have shown that microRNAs (miRNAs) could play a role in this disease. Nowadays, more than 2500 miRNAs have been described, that regulate more than 50% of genes, including those involved in B-cell maturation, differentiation and proliferation. Genetic variants in miRNAs can alter their own levels or function, affecting their target gene expression, and then, may affect ALL risk. Therefore, the aim of this study was to determine the role of miRNA genetic variants in B-ALL susceptibility. We analyzed all variants in pre-miRNAs (MAF > 1%) in two independent cohorts from Spain and Slovenia and inferred their functional effect by in silico analysis. SNPs rs12402181 in miR-3117 and rs62571442 in miR-3689d2 were associated with ALL risk in both cohorts, possibly through their effect on MAPK signalling pathway. These SNPs could be novel markers for ALL susceptibility

Dual Role of PTPN22 but Not NLRP3 Inflammasome Polymorphisms in Type 1 Diabetes and Celiac Disease in Children

Genetic polymorphisms in genes coding for inflammasome components nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) and caspase recruitment domain-containing protein 8 (CARD8) have been associated with autoinflammatory and autoimmune diseases. On the other hand several studies suggested that NLRP3 inflammasome contributes to maintenance of gastrointestinal immune homeostasis and that activation of NLRP3 is regulated by protein tyrosine phosphatase non-receptor 22 (PTPN22). PTPN22 polymorphism was implicated in the risk for various autoimmune diseases including type 1 diabetes (T1D) but not for celiac disease (CD). The aim of our study was to evaluate the role of inflammasome related polymorphisms in subjects with either T1D or CD as well as in subjects affected by both diseases. We examined PTPN22 rs2476601 (p.Arg620Trp), NLRP3 rs35829419 (p.Gln705Lys), and CARD8 rs2043211 (p.Cys10Ter) in 66 subjects with coexisting T1D and CD, 65 subjects with T1D who did not develop CD, 67 subjects diagnosed only with CD and 127 healthy unrelated Slovenian individuals. All results were adjusted for clinical characteristic and human leukocyte antigen (HLA) risk. PTPN22 rs2476601 allele was significantly more frequent among subjects with T1D (Padj = 0.001) and less frequent in subjects with CD (Padj = 0.039) when compared to controls. In patients with coexisting T1D and CD this variant was significantly less frequent compared to T1D group (Padj = 0.010). Protective effect on CD development in individuals with T1D was observed only within the low risk HLA group. On the other hand, we found no association of NLRP3 rs35829419 and CARD8 rs2043211 with the development of T1D, CD or both diseases together. In conclusion PTPN22 rs2476601polymorphism was significantly associated with the risk of developing T1D in Slovenian population, while no associations of proinflammatory NLRP3 and CARD8 polymorphisms with T1D and CD were observed. Interestingly, the same PTPN22 variant protected from CD. We hypothesize that this effect may be mediated through the NLRP3 inflammasome activation

Replication Study Of Polymorphisms Associated With Response To Methotrexate In Patients With Rheumatoid Arthritis

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as.DAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to.DAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response