Association between osteoporosis and polymorphisms of the bone Gla protein, estrogen receptor 1, collagen 1-A1 and calcitonin receptor genes in Turkish postmenopausal women
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).
References (39)
Association of estrogen receptor α gene polymorphisms with BMD and their affect on estradiol levels in pre- and postmenopausal women in south Indian population from Andhra Pradesh
Clin. Chim. Acta
(2010)- et al.
Association of estrogen receptor a gene polymorphisms with bone mineral density in postmenopausal Indian women
Mol. Genet. Metab.
(2006) In vitro characterization of a human calcitonin receptor gene polymorphism
Mutat. Res.
(2003)- et al.
Osteocalcin gene HindIII C/T polymorphism is a biomarker for prostate cancer and responsiveness to hormone therapy
Eur. Urol.
(2003) - et al.
Association between bone mineral density and polymorphism of the VDR, ERalpha, COL1A1 and CTR genes in Spanish postmenopausal women
J. Endocrinol. Invest.
(2005) COL1A1, ESR1, VDR and TGFB1 polymorphisms and haplotypes in relation to BMD in Spanish postmenopausal women
Osteoporos. Int.
(2007)- et al.
Relation of polymorphism in the promoter region for the human osteocalcin gene to bone mineral density occurrence of osteoporosis in postmenopausal Chinese women in Taiwan
J. Clin. Lab. Anal.
(2001) - et al.
The prevalence of osteoporosis in Korean adults aged 50 years or older and the higher diagnosis rates in women who were beneficiaries of a national screening program: The Korea National Health and Nutrition Examination Survey 2008–2009
J. Bone Miner. Res.
(2012) - et al.
Open Source Epidemiologic Statistics for Public Health, Version 2.3.1
A novel polymorphism in the promoter region for human osteocalcin gene: the possibility of a correlation with bone mineral density in postmenopausal Japanese women
J. Bone Miner. Res.
(1998)
Genetic polymorphism of the calcitonin receptor gene and bone mineral density in Polish population of postmenopausal women
Ginekol. Pol.
Association of estrogen receptor alpha and collagen type I alpha 1 gene polymorphisms with bone mineral density in postmenopausal women
Osteoporos. Int.
Estrogen receptor gene polymorphisms and the genetics of osteoporosis. A HuGE review
Am. J. Epidemiol.
Reduced bone density and osteoporosis associated with a polymorphic sp1 site in the collagen type I alpha 1 gene
Nat. Genet.
Genetic polymorphisms of TGF-beta, PAI-1, and COL1A-1, and determination of bone mineral density in Caucasian females
J.Endocrinol. Regul.
Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis
J. Bone Miner. Res.
Novel insights into the use of osteocalcin as a determinant of bone metabolism. Osteocalcin
No evidence of association of the osteocalcin gene HindIII polymorphism with bone mineral density in Chinese women
J. Musculoskelet. Neuronal Interact.
Association of bone mineral density with polymorphism of the estrogen receptor gene in post-menopausal women
J. Bone Miner. Res.
Cited by (23)
Association of ESR1 and ESR2 Polymorphisms with Osteoporosis: A Meta-Analysis from 36 Studies
2022, Journal of Clinical DensitometryCitation Excerpt :The detailed procedure of selection process is illustrated in Fig. 1. We found a total of 36 studies covering 12507 cases and 18487 controls were eligible on the association of ESR1 and ESR2 polymorphisms with osteoporosis (10-12,18-50). Among them, there were 22 studies with 4162 cases and 5235 controls concerning ESR1 XbaI polymorphism, 26 studies with 4760 cases and 6237 controls concerning ESR1 PvuII polymorphism, 5 studies with 294 cases and 1350 controls concerning ESR1 G2014A polymorphism, 6 studies with 1691 cases and 3017 controls concerning ESR2 AluI polymorphism, 6 studies with 1600 cases and 2648 controls concerning ESR2 RsaI polymorphism.
Association of the Sp1 binding site and -1997 promoter variations in COL1A1 with osteoporosis risk: The application of meta-analysis and bioinformatics approaches offers a new perspective for future research
2020, Mutation Research - Reviews in Mutation ResearchCollagens and elastin genetic variations and their potential role in aging-related diseases and longevity in humans
2020, Experimental GerontologyCitation Excerpt :Another important potential modulator of clinical aging phenotypes is the effect of combined genotypes. For example, some studies have shown that collagen polymorphisms were not associated with bone or joint outcomes when considered individually, but only when combined as haplotypes within a same gene (Falcon-Ramirez et al., 2016; Liu et al., 2004) or with different genes (Balla et al., 2008; Tural et al., 2013; Zhai et al., 2004). Indeed, haplotype mapping may give more refined information when information from more than one SNP locus is considered either by identifying the effects of un assayed markers or by identifying genetic interactions of linked variants (Shirali et al., 2018).
Combined effects of collagen type I alpha1 (COL1A1) Sp1 polymorphism and osteoporosis risk factors on bone mineral density in Turkish postmenopausal women
2014, GeneCitation Excerpt :Previous studies have shown associations between COL1A1 Sp1 polymorphism, low BMD, osteoporosis (Falcón-Ramírez et al., 2011; Gerdhem et al., 2004; Grant et al., 1996; Haris et al., 2000; MacDonald et al., 2001; Uitterlinden et al., 1998; Yazdanpanah et al., 2007) and increased fracture risk (Keen et al., 1999a; Mann and Ralston, 2003; McGuigan et al., 2001; Mezquita-Raya et al., 2002; Uitterlinden et al., 2001), while some have not reached statistical significance (Ashford et al., 2001; Hubacek et al., 2006; Lidén et al., 1998; Wynne et al., 2002). Studies regarding the association of collagen gene variations with BMD values in Turkish postmenopausal women are scarce (Efesoy et al., 2011; Erdogan et al., 2011; Simsek et al., 2008; Tural et al., 2013). Many potential risk factors for osteoporosis such as low body mass index (BMI) and age at menopause, smoking and family history of osteoporosis have also been identified in several studies.