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A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma
M. Giaccherini, L. Gori, M. Gentiluomo, R. Farinella, K. Cervena, J. Skieceviciene, F. Dijk, G. Capurso, A. Vezakis, L. Archibugi, R. Chammas, T. Hussein, F. Tavano, P. Hegyi, M. Lovecek, JR. Izbicki, H. Brenner, B. Mohelnikova-Duchonova, G....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články
Grantová podpora
Fondazione Arpa
NV19-08-00113
Fondazione Tizzi
NV19-03-00097
Ministry of Health of the Czech Republic
NLK
Free Medical Journals
od 1996 do Před 1 rokem
Open Access Digital Library
od 1996-01-01
Medline Complete (EBSCOhost)
od 1996-01-01 do Před 1 rokem
PubMed
37670727
DOI
10.1093/carcin/bgad056
Knihovny.cz E-zdroje
- MeSH
- celogenomová asociační studie MeSH
- DNA MeSH
- duktální karcinom slinivky břišní * genetika MeSH
- genetická predispozice k nemoci MeSH
- genom lidský MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- nádory slinivky břišní * genetika patologie MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.
Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic
Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Children's Hospital Florence Italy
Carol Davila University of Medicine and Pharmacy Bucharest Romania
Center for Translational Medicine Semmelweis University Budapest Hungary
Departamento de Radiologia e Oncologia Instituto Do Câncer Do Estado de São Paulo São Paulo Brazil
Department of Biology University of Pisa Pisa Italy
Department of Biomedical Sciences Humanitas University Milan Italy
Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland
Department of General Surgery University of Heidelberg Heidelberg Germany
Department of Medicine Centre for Translational Medicine University of Szeged Szeged Hungary
Department of Surgery 1 University Hospital Olomouc Olomouc Czech Republic
Department of Surgery Erasmus MC University Medical Center Rotterdam The Netherlands
Department of Surgery Oncology and Gastroenterology DiSCOG University of Padova Padua Italy
Digestive and Liver Disease Unit S Andrea Hospital Sapienza University of Rome Rome Italy
Division of General and Transplant Surgery Pisa University Hospital Pisa Italy
Division of Pancreatic Diseases Heart and Vascular Center Semmelweis University Budapest Hungary
Division of Preventive Oncology German Cancer Research Center Heidelberg Germany
Endoscopic Unit Department of Gastroenterology IRCCS Humanitas Research Milan Italy
Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany
German Cancer Consortium Heidelberg Germany
Institute for Translational Medicine Medical School University of Pécs Pécs Hungary
Pancreatic Unit IRCCS Humanitas Research Hospital Milan Italy
Citace poskytuje Crossref.org
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- $a Giaccherini, Matteo $u Department of Biology, University of Pisa, Pisa, Italy $1 https://orcid.org/0000000203636632
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- $a A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma / $c M. Giaccherini, L. Gori, M. Gentiluomo, R. Farinella, K. Cervena, J. Skieceviciene, F. Dijk, G. Capurso, A. Vezakis, L. Archibugi, R. Chammas, T. Hussein, F. Tavano, P. Hegyi, M. Lovecek, JR. Izbicki, H. Brenner, B. Mohelnikova-Duchonova, G. Dell'Anna, J. Kupcinskas, S. Ermini, MN. Aoki, JP. Neoptolemos, M. Gazouli, C. Pasquali, R. Pezzilli, R. Talar-Wojnarowska, M. Oliverius, M. Al-Saeedi, M. Lucchesi, N. Furbetta, S. Carrara, CHJ. van Eijck, A. Maleckas, AC. Milanetto, RT. Lawlor, B. Schöttker, U. Boggi, L. Morelli, L. Ginocchi, R. Ponz de Leon Pisani, C. Sperti, A. Zerbi, PG. Arcidiacono, FG. Uzunoglu, S. Bunduc, B. Holleczek, D. Gioffreda, E. Małecka-Wojciesko, M. Kiudelis, A. Szentesi, HWM. van Laarhoven, P. Soucek, M. Götz, B. Erőss, GM. Cavestro, D. Basso, F. Perri, S. Landi, F. Canzian, D. Campa
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- $a Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.
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