Association between hot spring residency and dry eye disease: a crossover gene-environment interaction (GxE) study in Taiwan

Hsin-Yu Wu^#^{1

2}, Kao-Jung Chang^#^{1

3

4

5}, Wei Chiu^#^{1

2}, Ching-Yun Wang^#⁶, Yi-Chen Lin⁷, Yu-Tien Hsu⁸, Yuan-Chih Wen^{2

9

10}, Pin-Hsuan Chiang^{1

7

11}, Yu-Hsiang Chen^{1

2}, He-Jhen Dai^{1

2}, Chia-Hsin Lu^{1

2}, Yi-Cheng Chen^{1

2}, Han-Ying Tsai^{1

7

11}, Yu-Chun Chen^{2

12

13}, Chih-Hung Hsu^{14

15}, Shih-Hwa Chiou^{1

4

16}, Yi-Ping Yang^{1

17}, Ai-Ru Hsieh^#¹⁸, Chih-Chien Hsu^{19

20

21}

Affiliations

¹ Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
² School of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
³ Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
⁴ Department of Ophthalmology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
⁵ Department of Medical Education, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
⁶ Department of Medical Education, Taichung Veterans General Hospital, No. 1650, Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan.
⁷ Department of Statistics, Tamkang University, No. 151, Yingzhuan Rd., Tamsui District, New Taipei, 251301, Taiwan.
⁸ Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.
⁹ Department of Occupational Medicine and Clinical Toxicology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
¹⁰ Institute of Environmental and Occupational Health Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹¹ Big Data Center, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
¹² Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹³ Department of Family Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
¹⁴ Department of Environmental Medicine, Women's Hospital, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, No. 866, Yuhangtang Rd., Hangzhou, 310058, China.
¹⁵ International School of Medicine, Hangzhou 310006 Institute of Genetics, Zhejiang University School of Medicine, Zhejiang University, No. 866, Yuhangtang Rd., Hangzhou, 310058, China.
¹⁶ Institute of Pharmacology, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹⁷ Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹⁸ Department of Statistics, National Taipei University, No151, University Rd., San Shia District, 23741, New Taipei City, Taiwan.
¹⁹ Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan. chihchienym@gmail.com.
²⁰ School of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan. chihchienym@gmail.com.
²¹ Department of Ophthalmology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan. chihchienym@gmail.com.

^# Contributed equally.

PMID: 41126362
DOI: 10.1186/s40246-025-00824-8

Association between hot spring residency and dry eye disease: a crossover gene-environment interaction (GxE) study in Taiwan

Hsin-Yu Wu et al. Hum Genomics. 2025.

. 2025 Oct 22;19(1):120.

doi: 10.1186/s40246-025-00824-8.

Authors

Affiliations

¹ Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
² School of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
³ Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
⁴ Department of Ophthalmology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
⁵ Department of Medical Education, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
⁶ Department of Medical Education, Taichung Veterans General Hospital, No. 1650, Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan.
⁷ Department of Statistics, Tamkang University, No. 151, Yingzhuan Rd., Tamsui District, New Taipei, 251301, Taiwan.
⁸ Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.
⁹ Department of Occupational Medicine and Clinical Toxicology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
¹⁰ Institute of Environmental and Occupational Health Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹¹ Big Data Center, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
¹² Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹³ Department of Family Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan.
¹⁴ Department of Environmental Medicine, Women's Hospital, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, No. 866, Yuhangtang Rd., Hangzhou, 310058, China.
¹⁵ International School of Medicine, Hangzhou 310006 Institute of Genetics, Zhejiang University School of Medicine, Zhejiang University, No. 866, Yuhangtang Rd., Hangzhou, 310058, China.
¹⁶ Institute of Pharmacology, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹⁷ Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan.
¹⁸ Department of Statistics, National Taipei University, No151, University Rd., San Shia District, 23741, New Taipei City, Taiwan.
¹⁹ Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan. chihchienym@gmail.com.
²⁰ School of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St. Beitou District, Taipei, 112304, Taiwan. chihchienym@gmail.com.
²¹ Department of Ophthalmology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan. chihchienym@gmail.com.

^# Contributed equally.

PMID: 41126362
DOI: 10.1186/s40246-025-00824-8

Abstract

Background/aims: The advent of genetic biobanking has powered gene-environment interaction (GxE) studies in various disease contexts. Therefore, we aimed to discover novel GxE effects that address hot spring residency as a risk to inconspicuous disease association.

Methods: A complete genetic and demographic registry comprising 129,451 individuals was obtained from Taiwan Biobank (TWB). After geographical disease prevalence was analyzed to identify putative disease association with hot-spring residency, multivariable regression and logistic regression were rechecked to exclude socioeconomic confounders in geographical-disease association. Genome-wide association study (GWAS), gene ontology (GO), and protein-protein interaction (PPI) analysis identified predisposing genetic factors among hotspring-associated diseases. Lastly, a polygenic risk score (PRS) model was formulated to stratify environmental susceptibility in accord with their genetic predisposition.

Results: After socioeconomic covariate adjustment, prevalence of dry eye disease (DED) was significantly associated with hot spring distribution. Through single nucleotide polymorphisms (SNPs) discovery and subsequent PPI pathway aggregation, CDKL2 kinase pathways were significantly enriched in hot-spring specific DED functional SNPs. Notably, PRS predicted disease well in hot spring regions (AUC = 0.9168). Hot spring and discovered SNPs contributed to crossover GxE effect on DED (relative risk (RR)_G+E-= 0.99; RR_G-E+ = 0.35; RR_G+E+ = 2.04).

Conclusion: We identified hot-spring exposure as a modifiable risk in the PRS-predicted GxE context of DED.

Keywords: Dry eye disease; Gene–environment association; Genome-wide association study; Hot spring; Polygenic risk score; Taiwan biobank.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Ethical approvals were obtained from the Institutional Review Board (IRB) of the Taipei Veterans General Hospital with reference numbers 2023-01-006AC. All participants provided written informed consent. This study was conducted in compliance with the Helsinki Declaration. Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research. Competing interests: The authors declare no competing interests.

References

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Association between hot spring residency and dry eye disease: a crossover gene-environment interaction (GxE) study in Taiwan

Affiliations

Association between hot spring residency and dry eye disease: a crossover gene-environment interaction (GxE) study in Taiwan

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

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