This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Minagawa, M. Articles by Kohno, Y. Search for Related Content PubMed PubMed Citation Articles by Minagawa, M. Articles by Kohno, Y.

Association between AAAG Repeat Polymorphism in the P3 Promoter of the Human Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene and Adult Height, Urinary Pyridinoline Excretion, and Promoter Activity

Department of Pediatrics, Chiba University Graduate School of Medicine (M.M., T.Y., T.W., K.M., Y.T., Y.K.), Inohana, Chuo-ku, Chiba 260-8670, Japan; Department of Pediatrics, National Chiba Hospital (T.Y.), Tsubakimori, Chuo-ku, Chiba 260-8606, Japan; Departments of Physiology and Medicine (D.G., J.H.W., G.N.H.) and Human Genetics (G.N.H.), McGill University, Montréal, Québec, Canada H3G 1Y6; and Calcium Research Laboratory, McGill University, Royal Victoria Hospital (D.G., G.N.H.), Montréal, Québec, Canada H3A 1A1

Address all correspondence and requests for reprints to: Toshiyuki Yasuda, M.D., Department of Pediatrics, National Chiba Hospital, Tsubakimori, Chuo-ku, Chiba 260-8606, Japan. E-mail: . toshi{at}chiba.hosp.go.jp

Abstract

The PTH/PTHrP receptor (PTHR1) plays an essential role in skeletal development and mediates many other functions of PTH and PTHrP. Human PTHR1 gene transcription is controlled by three promoters, P1–P3. The most proximal promoter, P3, is active in bone and osteoblast-like cell lines and accounts for the majority of renal transcripts in adults. We have identified a tetranucleotide repeat (AAAG)n polymorphism in the P3 promoter. In 214 unrelated Japanese, the repeat number (n) ranged from 3–8, with the AAAG5 allele being the most frequent (59%). In 55 unrelated Caucasians, n ranged from 5–7, and the frequency of the AAAG5 allele was 78%. The most frequent genotypes in a cohort of 85 young (18–20 yr) female Japanese were 5/5, 5/6, and 6/6. The 6/6 genotype was associated with greater height (5/5 vs. 6/6; P < 0.02) and lower urinary deoxypyridinoline and pyridinoline (P < 0.02), which are markers of bone resorption. The height of an additional 71 healthy female Japanese subjects, aged 14–17 yr, having genotype 5/5, 5/6, or 6/6 was also in the order of genotype 5/5 < 5/6 < 6/6 (5/5 vs. 6/6, P < 0.05). There was no significant difference in lumbar and femoral bone mineral density between genotypes. Likewise, there was no difference in circulating intact PTH levels between groups. The activity of P3 promoter-luciferase reporter constructs in transcription assays in 2 human osteoblast-like cell-lines varied according to repeat number, with AAAG6 being the least active. In conclusion, the P3 promoter (AAAG)n polymorphism is frequent in both Japanese and Caucasians and has potential as a linkage marker for the PTHR1 locus. In addition, it may influence the expression of the receptor in target tissues and have functional consequences on the developing skeleton.

This article has been cited by other articles:

				A. Gupta, V.-V. Valimaki, M. J Valimaki, E. Loyttyniemi, M. Richard, P. L Bukka, D. Goltzman, and A. C Karaplis Variable number of tandem repeats polymorphism in parathyroid hormone-related protein as predictor of peak bone mass in young healthy Finnish males Eur. J. Endocrinol., May 1, 2008; 158(5): 755 - 764. [Abstract] [Full Text] [PDF]

				Y.-Z. Liu, Y.-F. Guo, P. Xiao, D.-H. Xiong, L.-J. Zhao, H. Shen, Y.-J. Liu, V. Dvornyk, J.-R. Long, H.-Y. Deng, et al. Epistasis between Loci on Chromosomes 2 and 6 Influences Human Height J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3821 - 3825. [Abstract] [Full Text] [PDF]