Functional sequence variants of intergenic long non-coding RNA on Chromosome 17q21 are associated with asthma

Kwei-Yan Liu^{1

2}, Jia-Jyun Sie^{3

2}, Yajing Gao^{4

2}, Yen-Li Lo³, Chao-Chien Wu⁵, Chin-Chou Wang^{5

6}, Chau-Chyun Sheu^{7

8}, Ruay-Sheng Lai⁹, Sum-Yee Leung⁵, Chi-Cheng Lin¹⁰, Yu-Feng Wei¹¹, Ching-Hsiung Lin^{12

13

14}, Sheng-Hao Lin^{12

13

14}, Jeng-Yuan Hsu¹⁵, Wei-Chang Huang^{16

17

18

19

20}, Chia-Cheng Tseng⁵, Yung-Fa Lai²¹, Meng-Hsuan Cheng^{8

22}, Huang-Chi Chen²³, Chih-Jen Yang⁷, Yuan-Ting Hsu¹, Chian-Heng Su^{7

24}, Shih-Chang Hsu^{25

26}, Wen-Yu Chung²⁷, Ming-Tsuen Hsieh²⁸, Li-Chen Chen²⁹, Chih-Hsing Hung^{30

31}, Chon-Lin Lee^{32

28}, Ming-Shyan Huang^{33

21}, Yufeng Zhou^{34

35}, Cathy S J Fann³⁶, Shau-Ku Huang^{1

37

38

2}

Affiliations

¹ National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
² These authors contributed equally to this work.
³ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁴ NHC Key Laboratory of Neonatal Diseases, Department of Critical care Medicine, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁶ Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁹ Division of Chest Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
¹⁰ Chest Division, Department of Internal Medicine, Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Ping-Tung, Taiwan.
¹¹ Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
¹² Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
¹³ Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.
¹⁴ Department of Recreation and Holistic Wellness, MingDao University, Changhua, Taiwan.
¹⁵ Division of Clinical Research, Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
¹⁶ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
¹⁷ Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
¹⁸ School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
¹⁹ Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
²⁰ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
²¹ Division of Chest Medicine, Department of Internal Medicine, E-Da E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan.
²² Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
²³ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
²⁴ Present address: National Taiwan University Health Data Research Center, National Taiwan University, Taipei, Taiwan.
²⁵ Emergency Department, Taipei Municipal Wan-Fang Hospital, Taipei, Taiwan.
²⁶ Department of Emergency, Taipei Medical University School of Medicine, Taipei, Taiwan.
²⁷ Department of Computer Science and Information Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan.
²⁸ Department of Marine Environment and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan.
²⁹ Department of Pediatrics, New Taipei City Municipal Tu-Cheng Hospital.
³⁰ Department of Pediatrics, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³¹ Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
³² Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³³ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³⁴ NHC Key Laboratory of Neonatal Diseases, Department of Critical care Medicine, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³⁵ Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital (Children's Hospital of Fudan University at Xiamen), Xiamen, China.
³⁶ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³⁷ Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan.
³⁸ Department of Respirology and Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen, China.

PMID: 40610054
DOI: 10.1183/13993003.00847-2025

Free article

Functional sequence variants of intergenic long non-coding RNA on Chromosome 17q21 are associated with asthma

Kwei-Yan Liu et al. Eur Respir J. 2025.

Free article

. 2025 Jul 3:2500847.

doi: 10.1183/13993003.00847-2025. Online ahead of print.

Authors

Affiliations

¹ National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
² These authors contributed equally to this work.
³ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁴ NHC Key Laboratory of Neonatal Diseases, Department of Critical care Medicine, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁵ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁶ Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁹ Division of Chest Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
¹⁰ Chest Division, Department of Internal Medicine, Antai Medical Care Cooperation Antai Tian-Sheng Memorial Hospital, Ping-Tung, Taiwan.
¹¹ Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
¹² Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan.
¹³ Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.
¹⁴ Department of Recreation and Holistic Wellness, MingDao University, Changhua, Taiwan.
¹⁵ Division of Clinical Research, Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
¹⁶ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
¹⁷ Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
¹⁸ School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
¹⁹ Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
²⁰ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
²¹ Division of Chest Medicine, Department of Internal Medicine, E-Da E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan.
²² Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
²³ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
²⁴ Present address: National Taiwan University Health Data Research Center, National Taiwan University, Taipei, Taiwan.
²⁵ Emergency Department, Taipei Municipal Wan-Fang Hospital, Taipei, Taiwan.
²⁶ Department of Emergency, Taipei Medical University School of Medicine, Taipei, Taiwan.
²⁷ Department of Computer Science and Information Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan.
²⁸ Department of Marine Environment and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan.
²⁹ Department of Pediatrics, New Taipei City Municipal Tu-Cheng Hospital.
³⁰ Department of Pediatrics, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³¹ Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
³² Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³³ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³⁴ NHC Key Laboratory of Neonatal Diseases, Department of Critical care Medicine, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³⁵ Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital (Children's Hospital of Fudan University at Xiamen), Xiamen, China.
³⁶ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan skhuang1@gmail.com csjfann@ibms.sinica.edu.tw yfzhou1@fudan.edu.cn a0780047@g-mail.nsysu.edu.tw ed110209@edah.org.tw pedhung@gmail.com.
³⁷ Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan.
³⁸ Department of Respirology and Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen, China.

PMID: 40610054
DOI: 10.1183/13993003.00847-2025

Abstract

Background: The genetic and molecular basis of asthma remains unclear and its gene-environment interaction is still enigmatic. In the present study, we aimed to identify asthma-causing genetic variants and their interactions with the environment.

Methods: We performed case-control genome-wide association studies on individuals of Han Chinese descent from the Taiwan biobank (case=4877 and control=(98 218) to identify asthma susceptibility loci, validated in a hospital-based population of subjects (N=2595). The 10- to 15-year exposure of cumulative ambient particulate matter with a diameter of less than 2.5 μm (PM_2.5) and polycyclic aromatic hydrocarbons (PAHs) were assessed for gene-environment relationships. The function of the newly identified long non-coding RNA, lncZPBP2-3, and its interaction with PM_2.5 and PAH exposure were analyzed using RNA immunoprecipitation, RNA pull-down, RT-qPCR, and western blotting.

Findings: Chromosome 17q12-21 was found to be a significant risk region, encompassing variants of lncZPBP2-3 and its neighboring genes, which interacted with increasing exposure to PM_2.5 and its adsorbed PAHs. The expression of lncZPBP2-3 was elevated, correlating with the expression of its neighboring genes, in the peripheral blood of asthmatic individuals compared to that in controls. Unlike non-risk lncZPBP2-3, the risk variant of lncZPBP2-3 disrupted the transcriptional suppression of the risk locus via its interaction with the transcription insulator, CCCTC-binding factor (CTCF), concomitant with the higher expression levels of neighboring genes in individuals with the risk genotype.

Interpretation: An functional variant of lncRNA, lncZPBP2-3, was significantly associated with asthma and inducible by environmental PAH, suggesting a potentially novel genetic and molecular mechanism of asthma.

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Functional sequence variants of intergenic long non-coding RNA on Chromosome 17q21 are associated with asthma

Affiliations

Functional sequence variants of intergenic long non-coding RNA on Chromosome 17q21 are associated with asthma

Authors

Affiliations

Abstract

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