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

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Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
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ISSN da Revista
Título do Volume
Editora
OXFORD UNIV PRESS
Autores
GIACCHERINI, Matteo
GORI, Leonardo
GENTILUOMO, Manuel
FARINELLA, Riccardo
CERVENA, Klara
SKIECEVICIENE, Jurgita
DIJK, Frederike
CAPURSO, Gabriele
VEZAKIS, Antonis
ARCHIBUGI, Livia
Citação
CARCINOGENESIS, v.44, n.8-9, p.642-649, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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 x 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 x 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 re-analysis of genome-wide association studies (GWASs) in light of functional data. [GRAPHICS] .
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https://observatorio.fm.usp.br/handle/OPI/58851
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MDR