Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women

Tracy L. Stewart, Huilin Jin, Fiona E. A. McGuigan, Omar M. E. Albagha, Natalia Garcia-Giralt, Amelia Bassiti, Daniel Grinberg, Susana Balcells, David M Reid, Stuart H. Ralston

Research output: Contribution to journalArticle

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Abstract

Context: The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1.
Objective: The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women.
Design: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program.
Main Outcome Measures: BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+ 1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298).
Results: The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LSBMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/-1245G) had increased BMD (P = 0.007 for LSBMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype.
Conclusions: Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.

Original languageEnglish
Pages (from-to)3575-3583
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume91
Issue number9
Early online date27 Jun 2006
DOIs
Publication statusPublished - 1 Sep 2006

Keywords

  • hormone replacement therapy
  • SP1 binding site
  • osteoporotic fractures
  • postmenopausal women
  • in vitro
  • alleles
  • association
  • risk
  • perimenopausal
  • susceptibility

Cite this

Stewart, T. L., Jin, H., McGuigan, F. E. A., Albagha, O. M. E., Garcia-Giralt, N., Bassiti, A., ... Ralston, S. H. (2006). Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women. Journal of Clinical Endocrinology and Metabolism, 91(9), 3575-3583. https://doi.org/10.1210/jc.2005-2651

Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women. / Stewart, Tracy L.; Jin, Huilin; McGuigan, Fiona E. A.; Albagha, Omar M. E.; Garcia-Giralt, Natalia; Bassiti, Amelia; Grinberg, Daniel; Balcells, Susana; Reid, David M; Ralston, Stuart H.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 91, No. 9, 01.09.2006, p. 3575-3583.

Research output: Contribution to journalArticle

Stewart, TL, Jin, H, McGuigan, FEA, Albagha, OME, Garcia-Giralt, N, Bassiti, A, Grinberg, D, Balcells, S, Reid, DM & Ralston, SH 2006, 'Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women', Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 9, pp. 3575-3583. https://doi.org/10.1210/jc.2005-2651
Stewart, Tracy L. ; Jin, Huilin ; McGuigan, Fiona E. A. ; Albagha, Omar M. E. ; Garcia-Giralt, Natalia ; Bassiti, Amelia ; Grinberg, Daniel ; Balcells, Susana ; Reid, David M ; Ralston, Stuart H. / Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women. In: Journal of Clinical Endocrinology and Metabolism. 2006 ; Vol. 91, No. 9. pp. 3575-3583.
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title = "Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women",
abstract = "Context: The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1. Objective: The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women. Design: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program. Main Outcome Measures: BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+ 1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298). Results: The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95{\%} of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LSBMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/-1245G) had increased BMD (P = 0.007 for LSBMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype. Conclusions: Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.",
keywords = "hormone replacement therapy, SP1 binding site, osteoporotic fractures, postmenopausal women, in vitro, alleles, association, risk, perimenopausal, susceptibility",
author = "Stewart, {Tracy L.} and Huilin Jin and McGuigan, {Fiona E. A.} and Albagha, {Omar M. E.} and Natalia Garcia-Giralt and Amelia Bassiti and Daniel Grinberg and Susana Balcells and Reid, {David M} and Ralston, {Stuart H.}",
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T1 - Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women

AU - Stewart, Tracy L.

AU - Jin, Huilin

AU - McGuigan, Fiona E. A.

AU - Albagha, Omar M. E.

AU - Garcia-Giralt, Natalia

AU - Bassiti, Amelia

AU - Grinberg, Daniel

AU - Balcells, Susana

AU - Reid, David M

AU - Ralston, Stuart H.

PY - 2006/9/1

Y1 - 2006/9/1

N2 - Context: The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1. Objective: The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women. Design: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program. Main Outcome Measures: BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+ 1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298). Results: The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LSBMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/-1245G) had increased BMD (P = 0.007 for LSBMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype. Conclusions: Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.

AB - Context: The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1. Objective: The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women. Design: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program. Main Outcome Measures: BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+ 1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298). Results: The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LSBMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/-1245G) had increased BMD (P = 0.007 for LSBMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype. Conclusions: Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.

KW - hormone replacement therapy

KW - SP1 binding site

KW - osteoporotic fractures

KW - postmenopausal women

KW - in vitro

KW - alleles

KW - association

KW - risk

KW - perimenopausal

KW - susceptibility

U2 - 10.1210/jc.2005-2651

DO - 10.1210/jc.2005-2651

M3 - Article

VL - 91

SP - 3575

EP - 3583

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 9

ER -