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Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women

Sobacchi, C; Vezzoni, P; Reid, D M; McGuigan, F E A LU ; Frattini, A; Mirolo, M; Albhaga, O M E; Musio, A; Villa, A and Ralston, S H (2004) In Calcified Tissue International 74(1). p.35-41
Abstract

The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has shown that inactivating mutations of the TCIRG1 cause autosomal recessive osteopetrosis. In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women. Five common polymorphisms were identified: two in the promoter, a conservative change within exon 4, one within intron 4 and one within intron 11. One of the promoter polymorphisms (G-1102A) lay within a consensus recognition site for the AP1 transcription factor. There was a significant... (More)

The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has shown that inactivating mutations of the TCIRG1 cause autosomal recessive osteopetrosis. In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women. Five common polymorphisms were identified: two in the promoter, a conservative change within exon 4, one within intron 4 and one within intron 11. One of the promoter polymorphisms (G-1102A) lay within a consensus recognition site for the AP1 transcription factor. There was a significant association between the G-1102A genotype and BMD at the lumbar spine ( P = 0.01) and femoral neck ( P = 0.03). The association remained significant after correcting for age, weight, height, menopausal status/HRT use and smoking ( P = 0.008 for spine BMD and P = 0.03 for hip BMD), and homozygotes for the -1100 "G" allele had BMD values significantly higher than individuals who carried the -1100 "A" allele at both spine ( P = 0.007) and hip ( P = 0.047). Subgroup analysis showed that the association between G-1102A and BMD was restricted to premenopausal women who comprised 50.6% of the study group. None of the other polymorphisms or haplotypes were significantly associated with BMD in the study group as a whole or in any subgroup. Functional studies will need to be performed to determine the mechanisms that underlie this association, but we conclude that, in this relatively large population, allelic variation at the G-1102A site of TCIRG1 accounts for part of the heritable component of BMD in Scottish women, possibly by affecting peak bone mass.

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publication status
published
keywords
Alleles, Binding Sites, Bone Density, Cohort Studies, Female, Genetic Variation, Haplotypes, Humans, Middle Aged, Molecular Sequence Data, Polymorphism, Genetic, Premenopause, Promoter Regions, Genetic, Retrospective Studies, Scotland, Transcription Factors, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
in
Calcified Tissue International
volume
74
issue
1
pages
7 pages
publisher
Springer
external identifiers
  • scopus:0842283935
ISSN
0171-967X
DOI
10.1007/s00223-002-0004-2
language
English
LU publication?
no
id
5191db41-8ad9-45a2-b4e5-fd0da2a4a96b
date added to LUP
2018-01-02 11:11:50
date last changed
2018-11-21 21:36:56
@article{5191db41-8ad9-45a2-b4e5-fd0da2a4a96b,
  abstract     = {<p>The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has shown that inactivating mutations of the TCIRG1 cause autosomal recessive osteopetrosis. In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women. Five common polymorphisms were identified: two in the promoter, a conservative change within exon 4, one within intron 4 and one within intron 11. One of the promoter polymorphisms (G-1102A) lay within a consensus recognition site for the AP1 transcription factor. There was a significant association between the G-1102A genotype and BMD at the lumbar spine ( P = 0.01) and femoral neck ( P = 0.03). The association remained significant after correcting for age, weight, height, menopausal status/HRT use and smoking ( P = 0.008 for spine BMD and P = 0.03 for hip BMD), and homozygotes for the -1100 "G" allele had BMD values significantly higher than individuals who carried the -1100 "A" allele at both spine ( P = 0.007) and hip ( P = 0.047). Subgroup analysis showed that the association between G-1102A and BMD was restricted to premenopausal women who comprised 50.6% of the study group. None of the other polymorphisms or haplotypes were significantly associated with BMD in the study group as a whole or in any subgroup. Functional studies will need to be performed to determine the mechanisms that underlie this association, but we conclude that, in this relatively large population, allelic variation at the G-1102A site of TCIRG1 accounts for part of the heritable component of BMD in Scottish women, possibly by affecting peak bone mass.</p>},
  author       = {Sobacchi, C and Vezzoni, P and Reid, D M and McGuigan, F E A and Frattini, A and Mirolo, M and Albhaga, O M E and Musio, A and Villa, A and Ralston, S H},
  issn         = {0171-967X},
  keyword      = {Alleles,Binding Sites,Bone Density,Cohort Studies,Female,Genetic Variation,Haplotypes,Humans,Middle Aged,Molecular Sequence Data,Polymorphism, Genetic,Premenopause,Promoter Regions, Genetic,Retrospective Studies,Scotland,Transcription Factors,Comparative Study,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {1},
  pages        = {35--41},
  publisher    = {Springer},
  series       = {Calcified Tissue International},
  title        = {Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women},
  url          = {http://dx.doi.org/10.1007/s00223-002-0004-2},
  volume       = {74},
  year         = {2004},
}