A Causal Association Between Alkaline Phosphatase and Natural-Cause Mortality: A Mendelian Randomization Study in East Asians and Europeans.

Authors

• Hung-Lin Chen, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Ping-Hsun Wu, Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
• Yi-Ting Lin, Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
• Amrita Chattopadhyay, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Hsiu-Yin Chiang, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Yu-Ting Lin, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Ya-Chi Lin, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Che-Chen Lin, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Min-Yu Chiang, Big Data Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Hung-Chieh Yeh, Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
• I-Wen Ting, Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Yu-Cyuan Hong, Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
• David Ray Chang, Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
• Jenq-Wen Huang, Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
• Yu-Ting Lin, Atgenomix, Taipei, Taiwan
• Wei-Chi Syu, Atgenomix, Taipei, Taiwan
• Tzu-Pin Lu, Institute of Health Data Analytics and Statistics, Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan
• Yi-Chun Tsai, Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
• Fuu-Jen Tsai, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
• Chin-Chi Kuo, Big Data Center, China Medical University Hospital, China Medical University, Taichung, TaiwanFollow

Abstract

Background: Although observational studies show a positive association between alkaline phosphatase (ALP) levels and mortality, a causal study is not yet available.

Objective: We conducted a retrospective cohort study and a systematic one-sample Mendelian randomization (MR) study to investigate the causality of ALP on natural-cause mortality.

Methods: The study used a hospital-based cohort of Asian patients recruited from the China Medical University Hospital (CMUH) and a community-based cohort of white European participants from the UK Biobank (UKB). Two retrospective cohorts included 43,994 patients from CMUH and 80,941 participants from UKB, all aged 50–55 years, with ALP measurements. For the MR analysis, the study included 114,692 patients from CMUH and 436,583 participants from UKB, with both ALP measurements and genetic data. Natural-cause mortality excluded deaths from suicide, homicide, or accidents.

Results: Compared with patients with normal ALP levels, those with high ALP levels had a significantly increased risk of natural-cause mortality in both the CMUH (adjusted hazard ratio [aHR], 3.43; 95% confidence interval [CI], 2.98–3.95) and UKB (aHR, 2.08; 95% CI, 1.85–2.34) cohorts. A significant dose-response relationship was observed. However, the MR analysis did not provide evidence for causality between elevated ALP levels and natural-cause mortality in either the CMUH or UKB cohorts.

Conclusions: Our study reinforced a dose-dependent relationship between total ALP levels and natural-cause mortality across ancestries. However, MR analyses in both Asian and European populations did not support a causal role of total ALP. Future research should focus on verifying whether these findings are consistent for specific ALP isoforms and disease outcomes.

Recommended Citation

Chen, Hung-Lin; Wu, Ping-Hsun; Lin, Yi-Ting; Chattopadhyay, Amrita; Chiang, Hsiu-Yin; Lin, Yu-Ting; Lin, Ya-Chi; Lin, Che-Chen; Chiang, Min-Yu; Yeh, Hung-Chieh; Ting, I-Wen; Hong, Yu-Cyuan; Chang, David Ray; Huang, Jenq-Wen; Lin, Yu-Ting; Syu, Wei-Chi; Lu, Tzu-Pin; Tsai, Yi-Chun; Tsai, Fuu-Jen; and Kuo, Chin-Chi (2026) "A Causal Association Between Alkaline Phosphatase and Natural-Cause Mortality: A Mendelian Randomization Study in East Asians and Europeans.," BioMedicine: Vol. 16 : Iss. 3 , Article 2.
DOI: 10.37796/2211-8039.1720

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