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Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density
Author(s) -
Nielson Carrie M,
Zmuda Joseph M,
Carlos Amy S,
Wagoner Wendy J,
Larson Emily A,
Orwoll Eric S,
Klein Robert F
Publication year - 2012
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.527
Subject(s) - alkaline phosphatase , bone mineral , hypophosphatasia , chemistry , medicine , endocrinology , biochemistry , enzyme , osteoporosis
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