A Novel Polymorphism in the Promoter Region for the Human Osteocalcin Gene: The Possibility of a Correlation with Bone Mineral Density in Postmenopausal Japanese Women

Abstract

We present a polymorphism of the human osteocalcin gene (also known as BGP, for bone Gla protein) due to a 1 base pair (bp) substitution from cytosine to thymine at position 298 nucleotides (nt), which is at position 198 nt upstream from the BGP exon 1. This mutation was detected by single-strand conformation polymorphism analysis after polymerase chain reaction for the osteocalcin gene fragment (326 bp) and sequencing analysis. The cytosine/thymine polymorphism can be defined by restriction fragment length polymorphism analysis using a modified primer pair and the restriction endonuclease HindIII. The osteocalcin genotype was determined in 160 postmenopausal Japanese women (age 48 -80 years). Osteocalcin alleles were designated according to the absence (H) or presence (h) of the HindIII restriction site. There were 12 HH, 49 Hh, and 99 hh individuals, and the allele frequencies were 22.8% for H and 77.2% for h. To determine if genetic variation influences bone mineral density (BMD) and thus can be a determinant of susceptibility to osteoporosis in older women, we examined the association of BMD with the osteocalcin genotypes found in the present study. The subjects with genotype HH had the smallest BMD and those with hh had the greatest BMD among subjects, but these differences did not reach statistical significance. The HindIII genotype showed a significant effect on the prevalence of osteopenia in the subjects, that is, women with genotype HH had a 5.74 times greater risk for osteopenia (p < 0.05) and those with genotype Hh had a 1.59 times greater risk than women with genotype hh. We identified the osteocalcin gene polymorphism, detected with the HindIII genotype, which was suggested to influence bone density and is a possible genetic marker for bone metabolism. (J Bone Miner Res 1998;13:1633-1639)

Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification

“…(38,39) The studies that looked at BMD have yielded variable results. (21)(22)(23)(24)(25)(26)34,39) In this study, we examined the relationships between genetic variation in and around the osteocalcin gene and circulating OC, BMD, and body fat and the implication for prediction of fracture occurrence.…”

“…Because of the absence of tagging singlenucleotide polymorphism (SNP) data at that time, SNPs were selected based on relative position in relation to the gene, minor allele frequency in the white population, and distance between the polymorphisms. In addition to the most commonly reported SNP, rs1800247 (also known as HindIII) at nucleotide 298 in the promoter region of the osteocalcin gene, (10,21,22,25,(32)(33)(34) three additional SNPs were chosen. These SNPs were rs1543294 (C/T) located 3 0 of the osteocalcin gene and close to the PMF1 (polyamine-modulated factor 1) gene; rs2842880 (C/T) located in intron 13, and rs933489 (G/A) located in intron 14 of the EST1B (EST1B-like protein, S-mg5 homologue) gene.…”

“…Furthermore, the relatively few studies that have been performed examining bone-related phenotypes produced conflicting results with respect to BMD and circulating OC levels, explained in some cases by small sample sizes or cohorts of different ethnicities. (21)(22)(23)(24)(25)(26) There are no studies analyzing the relationship between osteocalcin polymorphisms and fracture. Therefore, our objective in this study was to perform a comprehensive evaluation of the association between variations at the osteocalcin locus and levels of serum OC, BMD, fracture, and parameters reflecting adiposity in elderly Swedish women.…”

Associations of Serum Osteocalcin and Polymorphisms of<b> </b>the<b><i> Osteocalcin</i></b> Gene with Bone Mineral Density in Postmenopausal and Elderly Chinese Women

“…Many studies have revealed associations of the osteocalcin gene with BMD in various ethnic populations [23,24,25,26,27,28,29]. Results regarding the association between serum osteocalcin and osteocalcin gene polymorphisms with BMD and bone metabolism markers vary; thus, the main objectives of this study were as follows: (1) to evaluate the association of serum osteocalcin with BMD and markers of bone metabolism in postmenopausal Chinese women and (2) to observe the relationships of single-nucleotide polymorphisms (SNPs) in and around the osteocalcin gene with serum osteocalcin, BMD, and markers of bone metabolism.…”

Osteoporoz Genetiği

“…Yapılan çalışmalarda BGLAP geni promotor bölgesi -298 C/T poliorfizmi osteoporozla ilişkilendirilmiştir (28). Bu kısım maksimum promotor aktivitesine sahiptir, -298T allelinin OS geninin promoter aktivitesini azalttığı bildirilmiştir BGLAP geninin düşük ekspresyonu, kemik organik matriks bileşiminde osteokalsin düzeyini azaltmaktadır (29,30). Kollajen Tip1 allfa 1 (Col1A1) ve (Col1A12) Genleri: Kollajen, memelilerde büyük oranda fibroblast ve osteoblastlar tarafından üretilir.…”