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Shared genetic factors and the interactions with fresh fruit intake contributes to four types squamous cell carcinomas

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机构： [1]Department of Epidemiology & Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China [2]Department of Outpatient Office, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China [3]West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China [4]Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, China [5]State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China [6]Fudan University Taizhou Institute of Health Sciences, Taizhou, Jiangsu, China [7]Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China [8]National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China [9]Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China

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Studies have reported risk factors for a single-squamous cell carcinoma(Single-SCCs). However, the shared common germline genetic factors and environmental factors have not been well elucidated with respect to augmented risk of pan-squamous cell carcinoma(Pan-SCCs). By integrating a large-scale genotype data of 1,928 Pan-SCCs cases and 7,712 age- and sex-matched controls in the UK Biobank cohort, as well as multiple transcriptome and protein databases, we conducted a multi-omics analysis. Genome-wide association analysis (GWAS) was used to identify genetic susceptibility loci of SCCs. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA and tested for association with SCCs. Credible risk variants (CRVs) were combined risk SNPs reported in GWAS Catalog and our study, followed by comprehensive bioinformatics analyses. We identified six novel index SNPs in the progression of SCCs, which were also strongly interacted with fresh fruit intake. Moreover, our study systematically characterize the HLA variants and their relationship to SCCs susceptibility. We identified HLA-A*01 and six HLA-A amino acid position were associated independently with SCCs. Credible risk variants were annotated to 469 target genes, further GO and KEGG Pathway Enrichment Analysis showed that SCCs genes were primarily involved in immune-related pathways, espechially regulated by HLA region. The transcriptome analysis showed that there were 270 differentially expressed genes(DEGs), with the upregulated genes were enriched in the regulation of stem cell differentiation, proliferation, development, and maintenance. The PPI Network and Modular Analysis uncovered the Keratin(KRT) genes may serve as a potential marker in SCCs. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of SCCs, providing not only novel insights into the genetic commonality among SCCs but also a set of plausible gene targets for post-GWAS functional experiments.Copyright: © 2024 Mo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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最新[2023]版：

大类 | 3 区综合性期刊

小类 | 3 区综合性期刊

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第一作者机构： [1]Department of Epidemiology & Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China [2]Department of Outpatient Office, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China

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通讯机构： [1]Department of Epidemiology & Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai, China [5]State Key Laboratory of Genetic Engineering, Zhangjiang Fudan International Innovation Center, Human Phenome Institute, Fudan University, Shanghai, China [7]Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China

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