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 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 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.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Sequências Reguladoras de Ácido Nucleico , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sítios de Ligação/genéticaRESUMO
The consumption of sweet beverages, including sugar-sweetened beverages (SSB), artificial-sweetened beverages (ASB) and fruit juices (FJ), is associated with the risk of different cardiometabolic diseases. It may also be linked to the development of certain types of tumors. We carried out a systematic review and meta-analysis of observational studies aimed at examining the association between sweet beverage intake and cancer risk. Suitable articles published up to June 2020 were sourced through PubMed, Web of Science and SCOPUS databases. Overall, 64 studies were identified, of which 27 were selected for the meta-analysis. This was performed by analyzing the multivariable-adjusted OR, RR or HR of the highest sweet beverage intake categories compared to the lowest one. Random effects showed significant positive association between SSB intake and breast (RR: 1.14, 95% CI: 1.01-1.30) and prostate cancer risk (RR: 1.18, 95% CI: 1.10-1.27) and also between FJs and prostate cancer risk (RR: 1.03, 95% CI: 1.01-1.05). Although the statistically significant threshold was not reached, there tended to be positive associations for the following: SSBs and colorectal and pancreatic cancer risk; FJs and breast, colorectal and pancreatic cancer risk; and ASBs and pancreatic cancer risk. This study recommends limiting sweet beverage consumption. Furthermore, we propose to establish a homogeneous classification of beverages and investigate them separately, to better understand their role in carcinogenesis.
