Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density

Authors

  • Carrie M Nielson,

    1. Public Health and Preventive Medicine, Oregon Health & Science University, Portland, OR, USA
    2. Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
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  • Joseph M Zmuda,

    1. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA
    2. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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  • Amy S Carlos,

    1. Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
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  • Wendy J Wagoner,

    1. Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
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  • Emily A Larson,

    1. Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
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  • Eric S Orwoll,

    1. Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
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  • Robert F Klein

    Corresponding author
    1. Bone and Mineral Research Unit, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
    2. Portland Veterans Affairs Medical Center, Portland, OR, USA
    • Bone and Mineral Unit (CR113), Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098.
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Abstract

Alkaline phosphatase (ALP) plays an essential role in the regulation of tissue mineralization, and its activity is highly heritable. Guided by genetic associations discovered in a murine model, we hypothesized a role for rare coding variants in determining serum ALP level and bone mineral density (BMD) in humans. We sequenced the coding regions of the ALP gene (ALPL) in men with low and normal serum ALP activity levels. Single-nucleotide ALPL variants, including 19 rare nonsynonymous variants (minor allele frequency <1%), were much more frequent among the low ALP group (33.8%) than the normal group (1.4%, p = 1 × 10−11). Within the low ALP group, men with a rare, nonsynonymous variant had 11.2% lower mean serum ALP (p = 3.9 × 10−4), 6.7% lower BMD (p = 0.03), and 11.1% higher serum phosphate (p = 0.002) than those without. In contrast, common nonsynonymous variants had no association with serum ALP, phosphate, or BMD. Multiple rare ALPL coding variants are present in the general population, and nonsynonymous coding variants may be responsible for heritable differences in mineralization and thus BMD. © 2012 American Society for Bone and Mineral Research

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