Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA ...were identified in a genome-wide association study and meta-analysis.
We sought to investigate genetic susceptibility to PA.
Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations.
An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10−8), whereas SNPs associated with Src kinase–associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase–activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10−6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10−6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10−11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10−6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30.
This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.
Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the ...involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Wittenoom legacy Musk, Arthur W (Bill); Reid, Alison; Olsen, Nola ...
International journal of epidemiology,
04/2020, Letnik:
49, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
The Wittenoom crocidolite (blue asbestos) mine and mill ceased operating in 1966. The impact of this industry on asbestos-related disease in Western Australia has been immense. Use of the ...employment records of the Australian Blue Asbestos Company and records of the Wittenoom township residents has permitted two cohorts of people with virtually exclusive exposure to crocidolite to be assembled and studied. Follow-up of these two cohorts has been conducted through data linkage with available hospital, mortality and cancer records. The evolution of asbestos-related disease has been recorded and, with the establishment of exposure measurements, quantitative exposure–response relationships have been estimated. There has been an ongoing epidemic of mortality from lung cancer and malignant mesothelioma and, less so, from asbestosis. Wittenoom crocidolite was used extensively in asbestos-cement products in Western Australia. As a result, the state has recorded a higher malignant-mesothelioma mortality rate than in any other Australian state and in any defined general population in the world. Thus, the legacy of Wittenoom has extended beyond the mine and the town, and is still evident more than 50 years after the closure of the mine.
Background
Long‐term childhood asthma studies that investigate adult outcomes other than respiratory morbidity are lacking. This study examines the associations of childhood asthma and the occurrence ...of cardiovascular disease (CVD) events and mortality in adulthood.
Methods
A cohort of 4430 school children (aged 17 years) who attended the Busselton Health Study between 1967 and 1983 were analyzed. Self‐reported history of doctor‐diagnosed asthma was determined based on the questionnaire. Subsequent CVD events (hospital admissions or death) up to 2014 were identified using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on CVD events and mortality in adulthood. A subgroup of 2153 participants who re‐attended a survey in young adulthood was also analyzed.
Results
A total of 462 (10%) of the cohort had childhood asthma. During follow‐up, 867 participants experienced a CVD event and 22 participants died from CVD. Childhood asthma was not associated with the risk of CVD events in adulthood (HR, 1.12; 95% CI: 0.91–1.39; p = .2833) and this persisted after adjustment for confounders. Childhood asthma was not associated with coronary heart disease events (HR, 0.72; 95% CI: 0.40–1.30; p = .2761), heart failure events (HR, 0.55; 95% CI: 0.07–4.13; p = .5604) or CVD mortality (HR, 0.91; 95% CI: 0.21–3.89; p = .8987) in adulthood.
Conclusion
Childhood asthma is not associated with the risk of CVD events and mortality in adulthood.
Asbestos exposure is associated with many adverse health conditions including malignant mesothelioma and lung cancer as well as production of autoantibodies. Autoantibodies may serve as biomarkers ...for asbestos exposure in patients with cancer, and autoimmune dysfunction has been linked to increased rates of various cancers. The aim of this study was to examine the hypothesis that autoantibodies are more frequent in asbestos-exposed individuals with either lung cancer or mesothelioma than those without these conditions. Asbestos-exposed individuals from Western Australia who had lung cancer (n = 24), malignant mesothelioma (n = 24), or no malignancy (n = 51) were tested for antinuclear autoantibodies (ANA) using indirect immunofluorescence and specific extractable nuclear autoantibodies (ENA) employing a multiplexed addressable laser bead immunoassay. Contrary to the hypothesis, data demonstrated that individuals without malignancy were more likely to be positive for ANA compared to those with cancer. However, autoantibodies to histone and Ro-60 were found to be associated with lung cancer. These results support a possible predictive value for specific autoantibodies in the early detection of lung cancer and/or in our understanding of the role of autoimmune processes in cancer. However, further studies are needed to identify specific target antigens for the antibodies.
Malignant mesothelioma Robinson, Bruce WS; Musk, Arthur W; Lake, Richard A
Lancet,
07/2005, Letnik:
366, Številka:
9483
Journal Article, Book Review
Recenzirano
Malignant mesothelioma is an aggressive, treatment-resistant tumour, which is increasing in frequency throughout the world. Although the main risk factor is asbestos exposure, a virus, simian virus ...40 (SV40), could have a role. Mesothelioma has an unusual molecular pathology with loss of tumour suppressor genes being the predominant pattern of lesions, especially the
P16
INK4A
, and
P14
ARF
, and
NF2 genes, rather than the more common
p53 and
Rb tumour suppressor genes. Cytopathology of mesothelioma effusions or fine-needle aspirations are often sufficient to establish a diagnosis, but histopathology is also often required. Patients typically present with breathlessness and chest pain with pleural effusions. Median survival is now 12 months from diagnosis. Palliative chemotherapy is beneficial for mesothelioma patients with high performance status. The role of aggressive surgery remains controversial and growth factor receptor blockade is still unproven. Gene therapy and immunotherapy are used on an experimental basis only. Patterns identified from microarray studies could be useful for diagnosis as well as prognostication.
Mesothelioma in Australia: a review Musk, Arthur (Bill) W; Klerk, Nicholas; Brims, Fraser J
Medical journal of Australia,
11/2017, Letnik:
207, Številka:
10
Journal Article
Recenzirano
The incidence of malignant mesothelioma in Australia is among the highest in the world as a result of widespread use of asbestos by industry and in construction throughout the 20th century.
The ...risk of developing malignant mesothelioma after asbestos exposure is dose‐related; a transient, low dose exposure confers a correspondingly very low risk of disease.
Malignant mesothelioma is a heterogeneous disease, partly explaining the limited role of biomarkers in screening and diagnosis.
The prognosis remains poor, and early advice on medico‐legal compensation and a collaborative team approach to managing malignant mesothelioma are both essential.
Chemotherapy can have a modest treatment effect in some people. New therapies, such as immunotherapy, do not yet have a defined role in the treatment of malignant mesothelioma.
As treatment options for malignant mesothelioma are limited and no cure is available, there is no established role for early detection or screening of at risk populations.
A multidisciplinary approach to caring for patients with malignant mesothelioma and their carers is vital.
To the Editor: Previously, we identified the HLA region as a risk factor for peanut allergy (PA); this observation is supported further by 2 independent genome-wide association studies (GWASs).1,2 ...The HLA class II genes (including HLA-DR, HLA-DQ, and HLA-DP) encode molecules involved in presentation of extracellular antigens, such as peanut allergens, to T lymphocytes, which in turn mediates B-cell antibody production. Detailed methods, including PA inclusion criteria (see Table E1 in this article's Online Repository at www.jacionline.org), quality control, and imputation, were published previously (see Figs E1 and E2 in this article's Online Repository at www.jacionline.org).4 In addition to the CanPAR GWAS, 6 additional studies were included in a meta-analysis of the HLA region: 2 American studies (the Chicago Food Allergy study n = 2,197; 316 PA cases)1 and the Genetic Epidemiology Research on Aging (GERA) cohort (n = 29,053; 5108 self-reported food allergy),5 the Australian HealthNuts study (n = 221; 73 PA cases),2 and the German Understanding Food Allergy study (n = 2,592; 205 PA cases).2 Genotyping for HLA SNPs was conducted in Dutch subjects from 2 studies: IDEAL and GENEVA (n = 1,512; 138 PA cases). Both the IDEAL and GENEVA studies include cases of general food allergy.6 See Table E2 in this article's Online Repository at www.jacionline.org for study and phenotype descriptions.4 Fixed- and random-effects models evaluate heterogeneity and require point estimates. Because the Chicago Food Allergy and Understanding Food Allergy studies provided P value and sample sizes only, for meta-analyses, P values were obtained by using the Stouffer weighted z score. The presence of genetic risk factors for multiple atopic conditions within HLA, all at genome-wide significance, and our results demonstrating that HLA-DQB1 SNPs identified in CanPAR are independent of asthma and numerous eQTLs identified in the region suggest that this region is associated with the cause of several allergic phenotypes.
Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced ...levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling.
miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets.
PDF
