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Glycyrrhizic acid conjugates with amino acid methyl esters target the main protease, exhibiting antiviral activity against wild-type and nirmatrelvir-resistant SARS-CoV-2 variants

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Antiviral research 2024年 227卷 105920页

作者： Uyen Nguyen phuong Le Yu-Jen Chang Chih-Hao Lu Yeh Chen Wen-Chi Su Shao-Ting Chao Lia A Baltina Svetlana F Petrova Sin-Rong Li Mien-Chie Hung Michael M C Lai Lidia A Baltina Cheng-Wen Lin Graduate Institute of Biological Science and Technology China Medical University Taichung Taiwan Department of Medical Laboratory Science and Biotechnology China Medical University Taichung Taiwan. The Ph.D. Program of Biotechnology and Biomedical Industry China Medical University Taichung Taiwan. The Ph.D. Program of Biotechnology and Biomedical Industry China Medical University Taichung Taiwan Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Hsinchu Taiwan Department of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu Taiwan. Department of Food Science and Biotechnology National Chung Hsing University Taichung 402 Taiwan. Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan. Ufa Institute of Chemistry Ufa Federal Research Center of the Russian Academy of Sciences Russia. Department of Laboratory Medicine China Medical University Hospital Taichung 404327 Taiwan. Research Center for Cancer Biology China Medical University Taichung 404327 Taiwan Center for Molecular Medicine China Medical University Hospital Taichung 404327 Taiwan. Institute of Molecular Biology Academia Sinica Taipei 115201 Taiwan. Ufa Institute of Chemistry Ufa Federal Research Center of the Russian Academy of Sciences Russia. Electronic address: baltina@anrb.ru. Department of Medical Laboratory Science and Biotechnology China Medical University Taichung Taiwan Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan Department of Medical Laboratory Science and Biotechnology Asia University Taichung Taiwan. Electronic address: cwlin@mail.cmu.edu.tw.

COVId-19 pandemic is predominantly caused by SARS-CoV-2, with its main protease, Mpro, playing a pivotal role in viral replication and serving as a potential target for inhibiting different variants. In this study, potent Mpro inhibitors were identified from glycyrrhizic acid (GL) derivatives with amino acid methyl/ethyl esters. Out of the 17 derivatives semisynthesized, Compounds 2, 6, 9, and 15, with methionine methyl esters, d-tyrosine methyl esters, glutamic acid methyl esters, and methionines in the carbohydrate moiety, respectively, significantly inhibited wild-type SARS-CoV-2 Mpro-mediated proteolysis, with IC50 values ranging from 0.06 μM to 0.84 μM. They also demonstrated efficacy in inhibiting trans-cleavage by mutant Mpro variants (Mpro_P132H, Mpro_E166V, Mpro_P168A, Mpro_Q189I), with IC50 values ranging from 0.05 to 0.92 μM, surpassing nirmatrelvir (IC50: 1.17-152.9 μM). Molecular modeling revealed stronger interactions with Valine166 in the structural complex of Mpro_E166V with the compounds compared to nirmatrelvir. Moreover, these compounds efficiently inhibited the post-entry viral processes of wild-type SARS-CoV-2 single-round infectious particles (SRIPs), mitigating viral cytopathic effects and reducing replicon-driven GFP reporter signals, as well as in vitro infectivity of wild-type, Mpro_E166V, and Mpro_Q189I SRIPs, with EC50 values ranging from 0.02 to 0.53 μM. However, nirmatrelvir showed a significant decrease in inhibiting the replication of mutant SARS-CoV-2 SRIPs carrying Mpro_E166V (EC50: >20 μM) and Mpro_Q189I (EC50: 13.2 μM) compared to wild-type SRIPs (EC50: 0.06 μM). Overall, this study identifies four GL derivatives as promising lead compounds for developing treatments against various SARS-CoV-2 strains, including Omicron, and nirmatrelvir-resistant variants.

关键词： Glycyrrhizic acid derivative Inhibitor Mpro Nirmatrelvir-resistant variant Omicron SARS-CoV-2

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#1. Acid ceramidase (ASAH1) is a key mediator of drug resistance in relapsed/refractory multiple myeloma

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Journal of Bone Oncology 2024年 45卷 100539-100539页

作者： Ryan T. Bishop Tao Li Raghunandan R. Alugubelli Mostafa Nasr Karl J. Nyman Praneeth Sudalagunta Mark Meads Jeremy Frieling Niveditha Nerlakanti Marilena Tauro Oliver Hampton Bin Fang Steven Grant John Koomen Ariosto Siqueira Silva Kenneth H. Shain Conor C. Lynch Tumor Biology Dept. H. Lee Moffitt Cancer Center and Research Institute Tampa FL USA Collaborative Data Services Core H. Lee Moffitt Cancer Center & Research Institute Tampa FL 33612 USA Cancer Biology Ph.D. Program University of South Florida Tampa FL USA Department of Metabolism and Physiology H. Lee Moffitt Cancer Center and Research Institute Tampa Florida Bioinformatics and Biostatistics Department M2GEN Tampa FL USA Chemical Biology & Molecular Medicine H. Lee Moffitt Cancer Center & Research Institute Tampa FL USA Virginia Commonwealth University (VCU) Massey Cancer Center Richmond VA 23298 USA Department of Molecular Oncology H. Lee Moffitt Cancer Center & Research Institute Tampa FL 33612 USA Department of Malignant Hematology H. Lee Moffitt Cancer Center & Research Institute Tampa FL 33612 USA

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SWEET: a single-sample network inference method for deciphering individual features in disease

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Briefings in bioinformatics 2023年第2期24卷 bbad032页

作者： Hsin-Hua Chen Chun-Wei Hsueh Chia-Hwa Lee Ting-Yi Hao Tzu-Ying Tu Lan-Yun Chang Jih-Chin Lee Chun-Yu Lin Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Hsinchu 300 Taiwan. School of Medical Laboratory Science and Biotechnology College of Medical Science and Technology Taipei Medical University Taipei 110 Taiwan. TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei 110 Taiwan. Ph.D. Program in Medical Biotechnology College of Medical Science and Technology Taipei Medical University Taipei Taiwan. Department of Otolaryngology-Head and Neck Surgery Tri-Service General Hospital National Defense Medical Center Taipei 110 Taiwan. Department of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu 300 Taiwan. Institute of Data Science and Engineering National Yang Ming Chiao Tung University Hsinchu 300 Taiwan. Center for Intelligent Drug Systems and Smart Bio-devices National Yang Ming Chiao Tung University Hsinchu 300 Taiwan. School of Dentistry Kaohsiung Medical University Kaohsiung 807 Taiwan.

Recently, extracting inherent biological system information (e.g. cellular networks) from genome-wide expression profiles for developing personalized diagnostic and therapeutic strategies has become increasingly important. However, accurately constructing single-sample networks (SINs) to capture individual characteristics and heterogeneity in disease remains challenging. Here, we propose a sample-specific-weighted correlation network (SWEET) method to model SINs by integrating the genome-wide sample-to-sample correlation (i.e. sample weights) with the differential network between perturbed and aggregate networks. For a group of samples, the genome-wide sample weights can be assessed without prior knowledge of intrinsic subpopulations to address the network edge number bias caused by sample size differences. Compared with the state-of-the-art SIN inference methods, the SWEET SINs in 16 cancers more likely fit the scale-free property, display higher overlap with the human interactomes and perform better in identifying three types of cancer-related genes. Moreover, integrating SWEET SINs with a network proximity measure facilitates characterizing individual features and therapy in diseases, such as somatic mutation, mut-driver and essential genes. Biological experiments further validated two candidate repurposable drugs, albendazole for head and neck squamous cell carcinoma (HNSCC) and lung adenocarcinoma (LUAd) and encorafenib for HNSCC. By applying SWEET, we also identified two possible LUAd subtypes that exhibit distinct clinical features and molecular mechanisms. Overall, the SWEET method complements current SIN inference and analysis methods and presents a view of biological systems at the network level to offer numerous clues for further investigation and clinical translation in network medicine and precision medicine.

关键词： drug repurposing gene expression network inference network medicine precision medicine single-sample network

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BTEX exposure and its body burden pose differential risks for asthma and its phenotypic clusters

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Allergy 2023年第7期78卷 2036-2040页

作者： Yuan-Ting Hsu Chao-Chien Wu Chin-Chou Wang Wen-Yu Chung Chau-Chyun Sheu Yi-Hsin Yang Ming-Yen Cheng Ruay-Sheng Lai Sum-Yee Leung Chi-Cheng Lin Yu-Feng Wei Ching-Hsiung Lin Sheng-Hao Lin Jeng-Yuan Hsu Wei-Chang Huang Chia-Cheng Tseng Yung-Fa Lai Meng-Hsuan Cheng Huang-Chi Chen Chih-Jen Yang Chian-Heng Su Chien-Jen Wang Shih-Chang Hsu Chih-Hsing Hung Chon-Lin Lee Ming-Shyan Huang Shau-Ku Huang National Institute of Environmental Health Sciences National Health Research Institutes Miaoli Taiwan. Department of Internal Medicine Division of Pulmonary and Critical Care Medicine Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung Taiwan. Department of Public Health Kaohsiung Medical University Kaohsiung Taiwan. Department of Computer Science and Information Engineering National Kaohsiung University of Science and Technology Kaohsiung Taiwan. Department of Internal Medicine Division of Pulmonary and Critical Care Medicine Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan. Department of Internal Medicine School of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan. National Institute of Cancer Research National Health Research Institutes Tainan Taiwan. Department of Mathematics Hong Kong Baptist University Hong Kong China. Division of Chest Medicine Kaohsiung Veterans General Hospital Kaohsiung Taiwan. Department of Internal Medicine Chest Division Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital Pingtung Taiwan. Department of Internal Medicine E-Da Cancer Hospital I-Shou University Kaohsiung Taiwan. Department of Internal Medicine Division of Chest Medicine Changhua Christian Hospital Changhua Taiwan. Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan. Department of Recreation and Holistic Wellness MingDao University Changhua Taiwan. Department of Medical Research Division of Clinical Research Taichung Veterans General Hospital Taichung Taiwan. Department of Internal Medicine Division of Chest Medicine Taichung Veterans General Hospital Taichung Taiwan. Department of Medical Technology Jen-Teh Junior College of Medicine Nursing and Management Miaoli Taiwan. School of Medicine Chung Shan Medical University Taichung Taiwan. Ph.D. Program in Translational Medicine National Chung Hsing Universi

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Author Correction: Profiling immunoglobulin repertoires across multiple human tissues using RNA sequencing

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Nature communications 2020年第1期11卷 4499页

作者： Igor Mandric Jeremy Rotman Harry Taegyun Yang Nicolas Strauli dennis J Montoya William Van der Wey Jiem R Ronas Benjamin Statz douglas Yao Velislava Petrova Alex Zelikovsky Roberto Spreafico Sagiv Shifman Noah Zaitlen Maura Rossetti K Mark Ansel Eleazar Eskin Serghei Mangul Department of Computer Science University of California Los Angeles 404 Westwood Plaza Los Angeles CA 90095 USA. Department of Clinical Pharmacy School of Pharmacy University of Southern California 1540 Alcazar Street Los Angeles CA 90033 USA. Bioinformatics Interdepartmental Ph.D. Program University of California Los Angeles 611 Charles E. Young Drive East Los Angeles CA 90095-1570 USA. Biomedical Sciences Graduate Program University of California San Francisco 1675 Owens Street Suite 310 San Francisco CA 94143-0523 USA. Department of Molecular Cell and Developmental Biology University of California Los Angeles 610 Charles E. Young Drive South Los Angeles CA 90095 USA. Department of Microbiology Immunology and Molecular Genetics University of California Los Angeles 609 Charles E. Young Drive East Los Angeles CA 90095 USA. Program in Bioinformatics and Integrative Genomics Harvard Medical School 10 Shattuck Street Suite 514 Boston MA 02115 USA. Wellcome Trust Sanger Institute Wellcome Genome Campus Hinxton Cambridge CB10 1SA UK. Department of Computer Science Georgia State University 33 Gilmer Street SE Atlanta GA 30303 USA. The Laboratory of Bioinformatics I.M. Sechenov First Moscow State Medical University Moscow 119991 Russia. Institute for Quantitative and Computational Biosciences University of California Los Angeles 611 Charles E. Young Drive East Los Angeles CA 90095 USA. Department of Genetics The Institute of Life Sciences The Hebrew University of Jerusalem Jerusalem 9190401 Israel. Department of Medicine University of California San Francisco 533 Parnassus Avenue San Francisco CA 94143 USA. Immunogenetics Center Department of Pathology and Laboratory Medicine David Geffen School of Medicine University of California Los Angeles 1000 Veteran Avenue Los Angeles CA 90095-1652 USA. Sandler Asthma Basic Research Center Department of Microbiology and Immunology University of California San Francisco 513 Parnass

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

关键词： Computational biology and bioinformatics Adaptive immunity Immunogenetics B cells

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Erratum for Wang et al., "Clinically Applicable System for Rapidly Predicting Enterococcus faecium Susceptibility to Vancomycin"

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Microbiology spectrum 2022年第1期10卷 e0261021页

作者： Hsin-Yao Wang Chia-Ru Chung Chao-Jung Chen Ko-Pei Lu Yi-Ju Tseng Tzu-Hao Chang Min-Hsien Wu Wan-Ting Huang Ting-Wei Lin Tsui-Ping Liu Tzong-Yi Lee Jorng-Tzong Horng Jang-Jih Lu Department of Laboratory Medicine Chang Gung Memorial Hospitalgrid.413801.f at Linkou Taoyuan City Taiwan. Ph.D. Program in Biomedical Engineering Chang Gung Universitygrid.145695.a Taoyuan City Taiwan. Department of Computer Science and Information Engineering National Central Universitygrid.37589.30 Taoyuan City Taiwan. Graduate Institute of Integrated Medicine China Medical Universitygrid.254145.3 Taichung Taiwan. Proteomics Core Laboratory China Medical Universitygrid.254145.3 Hospital Taichung Taiwan. Graduate Program in Biomedical Information Yuan-Ze University Taoyuan City Taiwan. Department of Information Management Chang Gung Universitygrid.145695.a Taoyuan City Taiwan. Graduate Institute of Biomedical Informatics Taipei Medical University Taipei City Taiwan. Clinical Big Data Research Center Taipei Medical University Hospital Taipei City Taiwan. Graduate Institute of Biomedical Engineering Chang Gung Universitygrid.145695.a Taoyuan City Taiwan. Division of Haematology/Oncology Department of Internal Medicine Chang Gung Memorial Hospitalgrid.413801.f at Linkou Taoyuan City Taiwan. Biosensor Group Biomedical Engineering Research Center Chang Gung Universitygrid.145695.a Taoyuan City Taiwan. Department of Pathology Kaohsiung Chang Gung Memorial Hospitalgrid.413801.f and Chang Gung University College of Medicine Kaohsiung Taiwan. School of Life and Health Sciences The Chinese University of Hong Kong Shenzhen China. Warshel Institute for Computational Biology The Chinese University of Hong Kong Shenzhen China. Department of Bioinformatics and Medical Engineering Asia University Taichung City Taiwan. School of Medicine Chang Gung Universitygrid.145695.a Taoyuan City Taiwan. Department of Medical Biotechnology and Laboratory Science Chang Gung Universitygrid.145695.a Taoyuan City Taiwan.

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Correlating Reiff scores with clinical, functional, and prognostic factors: characterizing noncystic fibrosis bronchiectasis severity: validation from a nationwide multicenter study in Taiwan

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European journal of medical research 2024年第1期29卷 286页

作者： Wen-Chien Cheng Chia-Ling Chang Chau-Chyun Sheu Ping-Huai Wang Meng-Heng Hsieh Ming-Tsung Chen Wei-Fan Ou Yu-Feng Wei Tsung-Ming Yang Chou-Chin Lan Cheng-Yi Wang Chih-Bin Lin Ming-Shian Lin Yao-Tung Wang Ching-Hsiung Lin Shih-Feng Liu Meng-Hsuan Cheng Yen-Fu Chen Chung-Kan Peng Ming-Cheng Chan Ching-Yi Chen Lun-Yu Jao Ya-Hui Wang Chi-Jui Chen Shih-Pin Chen Yi-Hsuan Tsai Shih-Lung Cheng Horng-Chyuan Lin Jung-Yien Chien Hao-Chien Wang Wu-Huei Hsu Division of Pulmonary and Critical Care Medicine Department of Internal Medicine China Medical University Hospital Taichung Taiwan. wcchengdr@***. Critical Medical Center China Medical University Hospital Taichung Taiwan. wcchengdr@***. School of Medicine College of Medicine China Medical University Taichung Taiwan. wcchengdr@***. Department of Internal Medicine National Taiwan University Hospital Hsin-Chu Branch Hsin-Chu Taiwan. Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan. Division of Pulmonary and Critical Care Medicine Department of Internal Medicine Kaohsiung Medical University Hospital Kaohsiung Taiwan. Department of Internal Medicine School of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan. Division of Thoracic Medicine Far Eastern Memorial Hospital Taipei Taiwan. Department of Thoracic Medicine Chang Gung Memorial Hospital at Linkou Taoyuan Taiwan. College of Medicine Chang Gung University Taoyuan Taiwan. Division of Pulmonary and Critical Care Medicine Department of Internal Medicine Tri-Service General Hospital National Defense Medical Center Taipei Taiwan. Division of Chest Medicine Department of Internal Medicine Taichung Veterans General Hospital Taichung Taiwan. Department of Internal Medicine E-Da Cancer Hospital I-Shou University Kaohsiung Taiwan. School of Medicine for International Students College of Medicine I-Shou University Kaohsiung Taiwan. Division of Pulmonary and Critical Care Medicine Chiayi Chang Gung Memorial Hospital Chiayi Taiwan. Division of Pulmonary Medicine Department of Internal Medicine Taipei Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation New Taipei City Taiwan Republic of China. Department of Internal Medicine Cardinal Tien Hospital and School of Medicine College of Medicine Fu Jen Catholic University New Taipei City Taiwan. Division of Pulmonary Medicine Department of Internal Medicine Hualien Tzu Chi Hospital Buddhi

BACKGROUNd:Our study aimed to confirm a simplified radiological scoring system, derived from a modified Reiff score, to evaluate its relationship with clinical symptoms and predictive outcomes in Taiwanese patients with noncystic fibrosis bronchiectasis (NCFB). METHOdS:This extensive multicenter retrospective study, performed in Taiwan, concentrated on patients diagnosed with NCFB verified through high-resolution computed tomography (HRCT) scans. We not only compared the clinical features of various types of bronchiectasis (cylindrical, varicose, and cystic). Furthermore, we established relationships between the severity of clinical factors, including symptom scores, pulmonary function, pseudomonas aeruginosa colonization, exacerbation and admission rates, and HRCT parameters using modified Reiff scores. RESULTS:data from 2,753 patients were classified based on HRCT patterns (cylindrical, varicose, and cystic) and severity, assessed by modified Reiff scores (mild, moderate, and severe). With increasing HRCT severity, a significant correlation was found with decreased forced expiratory volume in the first second (FEV1) (p < 0.001), heightened clinical symptoms (p < 0.001), elevated pathogen colonization (pseudomonas aeruginosa) (p < 0.001), and an increased annual hospitalization rate (p < 0.001). In the following multivariate analysis, elderly age, pseudomonas aeruginosa pneumonia, and hospitalizations per year emerged as the only independent predictors of mortality. CONCLUSION:Based on our large cohort study, the simplified CT scoring system (Reiff score) can serve as a useful adjunct to clinical factors in predicting disease severity and prognosis among Taiwanese patients with NCFB.

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Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

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Nature communications 2023年第1期14卷 3043页

作者： Jianxin Shi Kouya Shiraishi Jiyeon Choi Keitaro Matsuo Tzu-Yu Chen Juncheng dai Rayjean J Hung Kexin Chen Xiao-Ou Shu Young Tae Kim Maria Teresa Landi dongxin Lin Wei Zheng Zhihua Yin Baosen Zhou Bao Song Jiucun Wang Wei Jie Seow Lei Song I-Shou Chang Wei Hu Li-Hsin Chien Qiuyin Cai Yun-Chul Hong Hee Nam Kim Yi-Long Wu Maria Pik Wong Brian douglas Richardson Karen M Funderburk Shilan Li Tongwu Zhang Charles Breeze Zhaoming Wang Batel Blechter Bryan A Bassig Jin Hee Kim demetrius Albanes Jason Y Y Wong Min-Ho Shin Lap Ping Chung Yang Yang She-Juan An Hong Zheng Yasushi Yatabe Xu-Chao Zhang Young-Chul Kim Neil E Caporaso Jiang Chang James Chung Man Ho Michiaki Kubo Yataro daigo Minsun Song Yukihide Momozawa Yoichiro Kamatani Masashi Kobayashi Kenichi Okubo Takayuki Honda dean H Hosgood Hideo Kunitoh Harsh Patel Shun-Ichi Watanabe Yohei Miyagi Haruhiko Nakayama Shingo Matsumoto Hidehito Horinouchi Masahiro Tsuboi Ryuji Hamamoto Koichi Goto Yuichiro Ohe Atsushi Takahashi Akiteru Goto Yoshihiro Minamiya Megumi Hara Yuichiro Nishida Kenji Takeuchi Kenji Wakai Koichi Matsuda Yoshinori Murakami Kimihiro Shimizu Hiroyuki Suzuki Motonobu Saito Yoichi Ohtaki Kazumi Tanaka Tangchun Wu Fusheng Wei Hongji dai Mitchell J Machiela Jian Su Yeul Hong Kim In-Jae Oh Victor Ho Fun Lee Gee-Chen Chang Ying-Huang Tsai Kuan-Yu Chen Ming-Shyan Huang Wu-Chou Su Yuh-Min Chen Adeline Seow Jae Yong Park Sun-Seog Kweon Kun-Chieh Chen Yu-Tang Gao Biyun Qian Chen Wu daru Lu Jianjun Liu Ann G Schwartz Richard Houlston Margaret R Spitz Ivan P Gorlov Xifeng Wu Ping Yang Stephen Lam Adonina Tardon Chu Chen Stig E Bojesen Mattias Johansson Angela Risch Heike Bickeböller Bu-Tian Ji H-Erich Wichmann david C Christiani Gadi Rennert Susanne Arnold Paul Brennan James McKay John K Field Sanjay S Shete Loic Le Marchand Geoffrey Liu Angeline Andrew Lambertus A Kiemeney Shan Zienolddiny-Narui Kjell Grankvist Mikael Johansson Angela Cox Fiona Taylor Jian-Min Yuan philip Lazarus Matthew B Schabath Melinda C Aldrich Hyo-Sung Jeon Shih Sheng Jiang Jae Sook Sung C Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA. jianxin.shi@nih.gov. Division of Genome Biology National Cancer Research Institute Tokyo Japan. Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA. Division of Cancer Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan. Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan. Department of Epidemiology School of Public Health Nanjing Medical University Nanjing China. Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Cancer Medicine Nanjing Medical University Nanjing China. Prosserman Centre for Population Health Research Lunenfeld-Tanenbaum Research Institute Sinai Health Toronto ON Canada. Department of Epidemiology and Biostatistics National Clinical Research Center for Cancer Key Laboratory of Molecular Cancer Epidemiology of Tianjin Tianjin Medical University Cancer Institute and Hospital Tianjin Medical University Tianjin China. Division of Epidemiology Department of Medicine Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center Nashville TN USA. Cancer Research Institute Seoul National University College of Medicine Seoul Republic of Korea. Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology Cancer Institute and Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China. Department of Epidemiology School of Public Health China Medical University Shenyang China. Department of Clinical Epidemiology and Center of Evidence Based Medicine The First Hospital of China Medical University Shenyang China. Department of Oncology Shandong Cancer Hospital and Institute Shandong Academy of Medical Sciences Jinan China. Ministry of Education Key Laboratory of Contemporary Anthropology School of Life Sciences Fudan University Shanghai China. S

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FAdS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

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