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Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: The Nagahama Study

Journal of Human Genetics volume 65, pages 337–343 (2020)Cite this article

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Abstract

Although alkaline phosphatase (ALP) activity is relatively low in carriers of recessive type hypophosphatasia (HPP), most are asymptomatic and therefore do not undergo medical evaluations. We analyzed the association of ALP-encoding ALPL variants with serum ALP and bone traits in the general Japanese population. Study participants (n = 9671) were from the Nagahama Study, which was a longitudinal cohort study of an apparently healthy general Japanese population. ALPL variants were analyzed by whole-genome sequencing or TaqMan probe assays using DNA extracted from peripheral blood samples. The speed of sound in calcaneal bone was assessed by quantitative ultrasound (QUS) and used as surrogate measures of bone mineral density. We identified 13 ALPL variants. Minor allele frequencies of three variants were higher than expected. Variant c.529G > A has been reported as a possible pathogenic variant for adult type HPP. Variants c.979C > T and c.1559delT are reported as pathogenic variants for perinatal severe HPP or infantile HPP. The allele frequencies of c.529G > A, c.979C > T, and c.1559delT were 0.0107, 0.0040, and 0.0014, respectively. Serum ALP activity was significantly lower and differed among the three variants (P < 0.001), as well as between individuals with and without any of the three variants (P < 0.001). Serum ALP activity was inversely associated with QUS values, although no direct association was observed between the ALPL variants and QUS values. An association between serum ALP activity and QUS was confirmed; however, we failed to detect an association between ALPL variants and bone traits in the general Japanese population.

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Acknowledgements

We are extremely grateful to the Nagahama City Office and the non-profit organization Zeroji Club for their assistance in analyzing the Nagahama Study. The Nagahama Study was supported by a University grant, the Center of Innovation Program, the Global University Project, and Grant-in-Aid for Scientific Research (25293141, 26670313, 26293198, 17H04182, 17H04126, 17H04123, and 18K18450) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Practical Research Project for Rare/Intractable Diseases (ek0109070, ek0109070, ek0109196, and ek0109348), the Comprehensive Research on Aging and Health Science Research Grants for Dementia R&D (dk0207006, dk0207027), the Program for an Integrated Database of Clinical and Genomic Information (kk0205008), the Practical Research Project for Lifestyle-related Diseases including Cardiovascular Diseases and Diabetes Mellitus (ek0210066, ek0210096, and ek0210116), and the Research Program for Health Behavior Modification by Utilizing IoT (le0110005) from Japan Agency for Medical Research and Development (AMED); the Takeda Medical Research Foundation; Mitsubishi Foundation; Daiwa Securities Health Foundation; and Sumitomo Foundation. This study was also supported by Research on Rare and Intractable Diseases, Health, Labor and Welfare Sciences Research Grants [H28-Nanchitou (Nan)-Ippan-017 and 19FC1006].

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Authors and Affiliations

  1. Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Sakyo-ku, Kyoto, Japan

    Miho Nagata, Hidenori Kawasaki, Takahito Wada, Takahiro Yamada & Shinji Kosugi

  2. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan

    Kazuya Setoh, Meiko Takahashi, Takahisa Kawaguchi, Yasuharu Tabara & Fumihiko Matsuda

  3. Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, Japan

    Koichiro Higasa

  4. Division of Clinical Genetics, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan

    Atsushi Watanabe

  5. Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

    Hideaki Sawai

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  1. Miho Nagata
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  2. Kazuya Setoh
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Correspondence to Yasuharu Tabara or Takahiro Yamada.

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Nagata, M., Setoh, K., Takahashi, M. et al. Association of ALPL variants with serum alkaline phosphatase and bone traits in the general Japanese population: The Nagahama Study. J Hum Genet 65, 337–343 (2020). https://doi.org/10.1038/s10038-019-0712-3

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