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

Carrie Nielson, Joseph M. Zmuda, Amy S. Carlos, Wendy J. Wagoner, Emily A. Larson, Eric Orwoll, Robert Klein

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 -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.

Original languageEnglish (US)
Pages (from-to)93-103
Number of pages11
JournalJournal of Bone and Mineral Research
Volume27
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Bone Density
Alkaline Phosphatase
Serum
Phosphates
Gene Frequency
Nucleotides
Population
Genes

Keywords

  • ALKALINE PHOSPHATASE
  • GENETICS
  • HEREDITY
  • OSTEOPOROSIS

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density. / Nielson, Carrie; Zmuda, Joseph M.; Carlos, Amy S.; Wagoner, Wendy J.; Larson, Emily A.; Orwoll, Eric; Klein, Robert.

In: Journal of Bone and Mineral Research, Vol. 27, No. 1, 01.2012, p. 93-103.

Research output: Contribution to journalArticle

@article{9d0f2e2a2515440286f317e771550bdd,
title = "Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density",
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 -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.",
keywords = "ALKALINE PHOSPHATASE, GENETICS, HEREDITY, OSTEOPOROSIS",
author = "Carrie Nielson and Zmuda, {Joseph M.} and Carlos, {Amy S.} and Wagoner, {Wendy J.} and Larson, {Emily A.} and Eric Orwoll and Robert Klein",
year = "2012",
month = "1",
doi = "10.1002/jbmr.527",
language = "English (US)",
volume = "27",
pages = "93--103",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density

AU - Nielson, Carrie

AU - Zmuda, Joseph M.

AU - Carlos, Amy S.

AU - Wagoner, Wendy J.

AU - Larson, Emily A.

AU - Orwoll, Eric

AU - Klein, Robert

PY - 2012/1

Y1 - 2012/1

N2 - 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 -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.

AB - 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 -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.

KW - ALKALINE PHOSPHATASE

KW - GENETICS

KW - HEREDITY

KW - OSTEOPOROSIS

UR - http://www.scopus.com/inward/record.url?scp=84555195697&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84555195697&partnerID=8YFLogxK

U2 - 10.1002/jbmr.527

DO - 10.1002/jbmr.527

M3 - Article

C2 - 21956185

AN - SCOPUS:84555195697

VL - 27

SP - 93

EP - 103

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 1

ER -