Elsevier

Gene

Volume 515, Issue 1, 15 February 2013, Pages 167-172
Gene

Association between osteoporosis and polymorphisms of the bone Gla protein, estrogen receptor 1, collagen 1-A1 and calcitonin receptor genes in Turkish postmenopausal women

https://doi.org/10.1016/j.gene.2012.10.041Get rights and content

Abstract

In this study, we have investigated the association between osteoporosis and osteocalcin (BGLAP) 298 C>T, estrogen receptor 1 (ER1) 397 T>C, collagen type1 alpha 1 (Col1A1) 2046 G>T and calcitonin receptor (CALCR) 1340 T>C polymorphisms. Genomic DNA was obtained from 266 persons (158 osteoporotic and 108 healthy controls). Genomic DNA was extracted from EDTA-preserved peripheral venous blood of patients and controls by a salting-out method and analyzed by PCR-RFLP. As a result, there was no statistically significant difference in the genotype and allele frequencies of patients and controls for BGLAP 298 C>T, Col1A1 2046 G>T, ER1 397 T>C and CALCR 1340 T>C polymorphisms. However, ER1 CC genotype compared with TT + TC genotypes was found to increase the two fold the risk of osteoporosis [p = 0.039, OR = 2.156, 95% CI (1.083–4.293)] and CALCR CC genotype compared with TT + TC genotypes was found to have protective effect against osteoporosis [p = 0.045, OR = 0.471, 95% CI (0.237–0.9372)]. In the combined genotype analysis, ER1/CALCR TCCC combined genotype was estimated to have protective effect against osteoporosis [p = 0.0125, OR = 0.323, 95% CI (0.1383–0.755)] whereas BGLAP/Col1A1 CCTT and ER1/CALCR CCTT combined genotypes were estimated as risk factors for osteoporosis in Turkish population (p = 0.027, p = 0.009 respectively).

Highlights

► Understanding the genetics of osteoporosis is important for diagnosis and treatment. ► We examined BGLAP, ER1, COL1A1, CALCR genes in osteoporosis. ► ER1 CC genotype compared with TT + TC genotypes were found risk for osteoporosis. ► ER1/CALCR TCCC genotype was protective against osteoporosis. ► BGLAP/Col1A1 CCTT and ER1/CALCR CCTT combine genotypes were risk for osteoporosis.

Introduction

Osteoporosis (OMIM166710) is a common skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue with increased susceptibility to fracture (Ralston and Uitterlinden, 2010). According to the International Osteoporosis Foundation (IOF), 30–50 % of women and 15–30 % of men will be afflicted in the course of their lives. It affects one in three postmenopausal women and the majority of the elderly. The incidence of osteoporotic fractures increases with age and it is higher in whites than blacks (Choi et al., 2012, Gennari et al., 2005, Lee et al., 2010, Ralston, 2010, Ralston and Uitterlinden, 2010).

The major determinant of bone strength and osteoporotic fracture risk is bone mineral density (BMD), as assessed by dual photon absorptiometry or dual energy X-ray absorptiometry (DEXA). Osteoporosis is a multifactorial disorder with a strong genetic component. Twin and family studies suggest that about 50–85% of the variance in BMD is genetically determined (Ralston, 2010). There are several genes that play a role in the genetic determination of osteoporosis. In this regard, a large number of polymorphisms in multiple candidate genes have been investigated (Ralston, 2010).

Osteocalcin (BGLAP) (also known as bone Gla protein, BGP) is one of the major noncollagenous proteins of bone (Chen et al., 2001). Noncollagenous proteins together with collagen, contribute to structural and mechanical properties of bone (Sroga and Vashishth, 2012). BGLAP also plays a role in bone resorption and remodeling (Wu et al., 2003). BGLAP gene − 298 C>T polymorphic promoter region is important for the controlling expression of the BGLAP gene (containing osteocalcin box) (Wu et al., 2003). Various promoter elements lying less than a kilobase 5′ to the transcription initiation site contribute to basal expression and osteoblast specificity (Ivaska and Kaisa, 2005). − 298 C>T polymorphism in the promoter region has been associated with osteoporosis in postmenopausal women (Chen et al., 2001).

The other important and widely studied candidate gene for osteoporosis is estrogen receptor 1 (ER1). ER1 gene encodes ligand-activated transcription factor estrogen receptor alpha which belongs to nuclear receptor superfamily. Estrogen deficiency plays a major role in the pathogenesis of postmenopausal osteoporosis (Ivaska and Kaisa, 2005, Jeedigunta et al., 2010). The skeletal effects of estrogens are mediated by its binding to specific estrogen receptors. While many polymorphisms have been described in ESR1, the most widely studied are T397C and C351G polymorphisms located in the first intron. It is noted that the T>C transition associated with loss of the PvuII site results in a potential binding site for myb transcription factors. Thus, in some settings, the presence of the T allele might amplify ESR1 transcription (Gennari et al., 2005).

Another important candidate gene for predisposition to osteoporosis is the collagen type1 alpha 1 (COL1A1) gene, which encodes the 1(I) protein chain of type I collagen. It makes up 90% of the organic matrix that has a role in bone mineralization and gives flexibility to the bone (Erdogan et al., 2010). It is a heterotrimer protein consisting of two α1 chains and one α2 chain of type 1 collagen. The Sp1 transcription factor binding site is located in the first intron of the COL1A1 gene, an important region for the regulation of collagen transcription (Hubacek et al., 2006). This is a single nucleotide polymorphism affecting the recognition site of the transcription factor Sp1. Presence of the T allele leads to abnormal production of the α-1collagen chain in comparison to the α-2 collagen chain, which has an adverse effect on bone composition and mechanical strength (Hubacek et al., 2006).

The 1340 T>C polymorphism among human calcitonin receptor (CALCR) (also named CTR) gene polymorphism has generated interest precisely because of this single nucleotide polymorphism (SNP) in the coding region. It has been suggested that this locus modulates the susceptibility of postmenopausal women to osteoporotic phenotypes (Lee et al., 2010). CALCR is a member of the transmembrane receptor family and a point mutation polymorphism (1340 T>C) (codon 447) has been identified in the 3-region of the calcitonin receptor gene which included a Pro  Leu shift in the third intracellular domain of the protein (Masi and Brandi, 2007). This change may play a role in G-protein coupling and signal transduction (Wolfe et al., 2003). The absence of the proline residue could alter the secondary structure of the calcitonin receptor (Wolfe et al., 2003).

The aim of this study is to investigate if there is an association between BGLAP 298 C>T, ESR1 397 T>C, Col1A1 2046 G>T and CALCR 1340 T>C gene polymorphisms and osteoporosis risk in a Turkish population.

Section snippets

Subjects

266 postmenopausal women with a mean age of 61.60 ± 8.51 years were included in the study. Among them, a total of 158 had osteoporosis (T score <  2.5, mean age 63.65 ± 8.62 years) and 108 had normal BMD (T score>−1, mean age 58.81 ± 7.97 years). Subjects with a history of bone disease, metabolic or endocrine disorders such as hyperthyroidism and hyperparathyroidism, diabetes mellitus, liver disease, renal disease, and medications known to affect bone metabolism (e.g., corticosteroids, anticonvulsants,

Results

Clinical and laboratory findings of the patients and controls were given in Table 2. In power analysis, the power of ER1/CALCR CCTT genotype comparison between patients and controls was 82% in 95% confidence interval. The results of the genotype and allele frequencies of BGLAP 298 C>T, ER1 397 T>C, Col1A1 2046 G>T and CALCR 1340 T>C for osteoporosis patients and control groups are presented in Table 3. The genotype frequencies of the BGLAP, Col1A1 and CALCR polymorphisms in the control group

Discussion

The results of the present study showed that polymorphic genotypes of BGLAP, ER1, Col1A1 and CALCR genes are not associated with osteoporosis in single form but associated in combined forms.

In the present study, there was no statistically significant difference in the genotype and allele frequencies of patients and controls for BGLAP 298 C>T, Col1A1 2046 G>T, ER1 397 T>C and CALCR 1340 T>C polymorphisms. However, ER1 CC genotype compared with TT + TC genotypes was found to increase two fold the

Conflicts of interest

None.

Acknowledgments

This study was presented as poster in European Human Genetics Conference Amsterdam RAI, The Netherlands, May 28–31, 2011. Additionally, this study was completely supported by Ondokuz Mayis University (Project No. T-593).

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