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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

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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 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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Acknowledgements

We are grateful to R. Dulbecco, A. Albertini, P. Raineri and L. Rossi Bernardi for their encouragement. The technical assistance of L. Susani, E MacLeod and G Taylor is thankfully acknowledged. This work was partially supported by grants from MIUR-FIRB to P.V.; an MRC co-operative group grant to SHR and DMR; an Integrated Clinical Arthritis Centre grant from the Arthritis Research Campaign to DMR and SHR and a grant from the Grampian Osteoporosis Trust to SHR and DMR. This work is manuscript no. 59 of the Genoma 2000/ITBA Project funded by CARIPLO.

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Authors and Affiliations

  1. Instituto di Tecnologie Biomediche, CNR, Via Fratelli Cervi, 93, 20090 Segrate, Milano, Italy

    C. Sobacchi, P. Vezzoni, A. Frattini, M. Mirolo, A. Musio & A. Villa

  2. Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD Scotland, UK

    D. M. Reid, F. E. A. McGuigan, O. M. E. Albhaga & S. H. Ralston

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  1. C. Sobacchi
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  2. P. Vezzoni
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  3. D. M. Reid
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  4. F. E. A. McGuigan
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  5. A. Frattini
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  6. M. Mirolo
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  7. O. M. E. Albhaga
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  8. A. Musio
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  9. A. Villa
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  10. S. H. Ralston
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Correspondence to S. H. Ralston.

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Sobacchi, C., Vezzoni, P., Reid, D. et al. Association Between a Polymorphism Affecting an AP1 Binding Site in the Promoter of the TCIRG1 Gene and Bone Mass in Women . Calcif Tissue Int 74, 35–41 (2004). https://doi.org/10.1007/s00223-002-0004-2

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  • DOI: https://doi.org/10.1007/s00223-002-0004-2

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