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

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.

Variable number of tandem repeats polymorphism in parathyroid hormone-related protein as predictor of peak bone mass in young healthy Finnish males

“…Reduced height, however, has been linked to PTHR1 in Japanese adolescents (35). On the other hand, Hosoi and colleagues studied the association between a polymorphism of PTH recognized by the enzyme BSTB1 in a Japanese population and found evidence of reduced BMD in Bb heterozygotes when compared with BB homozygotes (36).…”

Parathyroid hormone and its receptor gene polymorphisms: implications in osteoporosis and in fracture healing

“…Similarly, Vilarino-Guell et al [39] reported significant associations for the tetranucleotide repeat and for haplotypes of PTHR1 with lumbar spine BMD in the youngest tertile of their population. Minigawa et al [38] also reported a trend toward higher bone mass for subjects with the repeat, but their finding did not achieve statistical significance.…”

“…The human gene encoding PTHR1 located at 3p21-p22 [33][34][35][36][37][38][39] contains three promoters (P1, P2, P3) that control transcription [36,37]. Minigawa et al [38] reported that P3 promoter is GC rich, but it contains an A-rich sequence that includes a polymorphic tetranucleotide repeat (AAAG)n. In (AAAG) n-containing P3 promoter constructs, the size of the AAAG repeats affected promoter activity in osteoblastic cells. Scillitani et al [37] studied 677 young Caucasian women 18-35 years of age and observed a trend toward association between BMD measured at femoral neck and the P3 promoter repeat of PTHR1 gene.…”

Molecular studies of identification of genes for osteoporosis: the 2002 update

“…A series of genes have been newly recognized as related to variation in BMD (Tables 1 and 2) (Dickson et al 1994, Huizenga et al 1998, Tsuji et al 1998, Zmuda et al 1998, Ogawa et al 1999, Sowers et al 1999, Salamone et al 2000, Spotila et al 2000, Tsukamoto et al 2000a,b, Urano et al 2000, Masi et al 2001, Ogata et al 2001, Albagha et al 2002, Arko et al 2002, Eckstein et al 2002, Fontova et al 2002, Gennari et al 2002, Karasik et al 2002d, Kawano et al 2002, Minagawa et al 2002, Prince et al 2002, Suuriniemi et al 2002, Vaughan et al 2002, Wynne et al 2002. For most of these genes, these were the first reports of an association with BMD and there is a need to repeat the findings in independent studies.…”