Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

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Citações na Scopus
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Tipo de produção
article
Data de publicação
2024
DOI
Scopus
Web of Science
PubMed
Dimensions
Título da Revista
ISSN da Revista
Título do Volume
Editora
BMC
Autores
UENAL, Pelin
LU, Ye
BUENO-DE-MESQUITA, Bas
EIJCK, Casper H. J. van
TALAR-WOJNAROWSKA, Renata
SZENTESI, Andrea
GAZOULI, Maria
KREIVENAITE, Edita
TAVANO, Francesca
MALECKA-WOJCIESKO, Ewa
Citação
HUMAN GENOMICS, v.18, n.1, article ID 12, 12p, 2024
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 x 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 x 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 x 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 x 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.
Palavras-chave
Association study, Enhancer, Pancreatic cancer, Single nucleotide polymorphism, Transcription factor binding site
URI
https://observatorio.fm.usp.br/handle/OPI/58853
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MDR