Genetics of osteoporosis

Genetic factors play an important role in regulating bone mineral density and other phenotypes relevant to the pathogenesis of osteoporosis such as ultrasound properties of bone, skeletal geometry, and bone turnover. Progress has been made in identifying quantitative traits for regulation of bone mineral density by linkage studies in man and mouse, but relatively few causal genes have been identified. Dramatic progress has been made in identifying the genes responsible for monogenic bone diseases and it appears that polymorphisms in many of these genes also play a role in regulating bone mineral density in the general population. Advances in knowledge about the genetic basis of osteoporosis and other bone diseases offer the prospect of developing new markers for assessment of fracture risk and the identification of novel molecular targets for the design of new drug treatments for osteoporosis.     

FokI and BsmI polymorphisms of the vitamin D receptor gene and bone mineral density in a random Bulgarian population sample

Numerous studies on vitamin D receptor (VDR) gene polymorphisms differ with conflicting data in various populations. We studied the association of FokI and BsmI polymorphisms in the gene encoding the vitamin D receptor with bone mineral density (BMD) in 219 persons of Bulgarian nationality. The calculated relative risk (RR) for low bone mineral density is higher for Fokl marker (3.14) compared to BsmI marker (2.44). The etiological factor (EF), which shows association between polymorphisms investigated and illness on populational level, is defined as EF=0.51 for FokI marker and EF=0.42 for BsmI marker. Because of this we conclude that FokI and BsmI polymorphisms are closely related to low BMD at the forearm and lumbar spine. Both polymorphisms are useful genetic markers in determining BMD and osteoporosis risk. Further studies of larger cohorts and in ethnically diverse subgroups are necessary.     

Role of genetic factors in the pathogenesis of osteoporosis

Osteoporosis is a common disease with a strong genetic component characterised by low bone mass, microarchitectural deterioration of bone tissue and an increased risk of fracture. Twin and family studies have shown that genetic factors play an important role in regulating bone mineral density and other determinants of osteoporotic fracture risk, such as ultrasound properties of bone, skeletal geometry and bone turnover. Osteoporosis is a polygenic disorder, determined by the effects of several genes, each with relatively modest effects on bone mass and other determinants of fracture risk. It is only on rare occasions that osteoporosis occurs as the result of mutations in a single gene. Linkage studies in man and experimental animals have defined multiple loci which regulate bone mass but the genes responsible for these effects remain to be defined. Population-based studies and case-control studies have similarly identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, including the vitamin D receptor, oestrogen receptor and collagen type IalphaI gene. The individual contribution of these genes to the pathogenesis of osteoporosis is small however, reflected by the fact that the relationship between individual candidate genes and osteoporosis has been inconsistent in different studies. An important aim of future work will be to define how the genes which regulate bone mass, bone turnover and other aspects of bone metabolism interact with each other and with environmental variables to cause osteoporosis in individual patients. If that aim can be achieved then there is every prospect that preventative therapy could be targeted to those at greatest risk of the osteoporosis, before fractures have occurred.     

Genetic aspects of osteoporosis.

At a given age, bone mass represents the difference between the maximal amount of bone mineral mass gained during growth (peak bone mass) and post-menopausal and/or senile bone loss. Twins and parents-offspring models have shown a strong inheritance of peak bone mass and it is now known that familial resemblance in various bone mass constituents is detectable well before the pubertal growth spurt. Recent developments in the molecular epidemiology of osteoporosis have focused on the association between areal bone mineral density and common polymorphisms in several candidate genes. Among them, vitamin D receptor (VDR), estrogen receptor and collagen-1 -alpha-1 (COL1A1) genes have been the most extensively investigated. Although controversial results have been reported and osteoporosis cannot be predicted by any single polymorphic gene marker, recent advances in this field have emphasized the complexity of bone mineral mass determination, because of gene-gene and gene-environment interactions.     

Molecular epidemiology of osteoporosis

Recently, molecular epidemiological studies have been performed in order to identify genetic factors associated with osteoporosis. Linkage analysis and association study are useful methods in molecular epidemiology. Quantitative trait locus (QTL) analysis, an effective technique of linkage analysis has been performed for loci linked to bone mineral density (BMD). Association studies between bone mass and a number of polymorphisms in candidate genes were carried out, including vitamin D receptor (VDR) gene. However, one problem has been poor reproducibility of the results. Genome-wide linkage screens with a dense set of single nucleotide polymorphism (SNP) markers are currently being conducted.     

Osteoporosis and gene polymorphism

Osteoporosis is a multifactorial disease for which genetic and environmental factors are determinants. We have been conducting a candidate-gene approach in which polymorphisms of many bone metabolism related genes have been examined in the association study with bone mineral density and fracture incidence. However, the contribution of each gene is small and the major genetic determinants of BMD have not elucidated. Recently, a genome-wide systematic approach has been conducted to find the responsible genes using a genome-wide list of single nucleotide polymorphisms (SNPs). So far, several genes with higher statistical power have been screened out with this approach. The accumulating information of genome science will help understand the pathogenesis of osteoporosis and find the useful ways for the prevention and the treatment of this disease.     

Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

Serum thyroid parameters show substantial inter-individual variability, in which genetic variation is a major factor. Findings in patients with subclinical hyper- and hypothyroidism illustrate that even minor alterations in serum thyroid function tests can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate. In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that alter serum thyroid function tests. In this review, we discuss the genetic variation in the TSH receptor and iodothyronine deiodinases. We discuss the possible consequences of these studies for the individual patient and also the new insights in thyroid hormone action that can be obtained from these data.     

Vitamin D receptor,oestrogen receptor-alpha gene and interleukin-1 receptor antagonist gene polymorphisms in Hungarian patients with primary biliary cirrhosis

BACKGROUND : Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis. Oestrogen receptor-alpha gene, vitamin D receptor gene and interleukin-1 receptor antagonist gene are all attractive candidates for osteoporosis susceptibility. We investigated the polymorphisms of the above genes and bone disease in Hungarian patients with primary biliary cirrhosis. PATIENTS AND METHODS : Thirty-three female patients with primary biliary cirrhosis were enrolled (age range, 39-72 years; anti-mitochondrial antibody M2 positive, stage II-IV). Eighty-four healthy and 76 osteoporotic age matched female subjects served as controls. Vitamin D receptor BsmI, interleukin-1 receptor antagonist gene variable- number tandem repeat and oestrogen receptor-alpha PvuII and XbaI polymorphisms were determined. Bone mineral density was measured by dual energy X-ray absorptiometry (XR26, Norland) in lumbar spine and femoral neck. RESULTS : The genotype frequency of vitamin D receptor BsmI (BB, 57.5%; Bb, 33.3%; bb, 9.1%) and oestrogen receptor-alpha PvuII (PP, 18.2%; Pp, 75.6%; pp, 6.2%) and XbaI (XX, 9.1%; Xx, 90.9%; xx, 0%) of the primary biliary cirrhosis patients was different from that of the healthy and osteoporotic control groups (P < 0.03 for each). Osteoporosis (t score < -2.5) was present in 42.4% of the patients. Osteoporotic primary biliary cirrhosis patients were older and had a longer disease history (P = 0.01 for both). No association was found between the polymorphisms and bone mineral density values at either position. CONCLUSIONS : We confirmed previous findings concerning the higher frequency of vitamin D receptor BsmI BB genotype in patients with primary biliary cirrhosis. The oestrogen receptor-alpha PvuII and XbaI Pp and Xx genotypes were more frequent in primary biliary cirrhosis patients, while interleukin-1 receptor antagonist gene variable-number tandem repeat polymorphism was not different. Since none of the polymorphisms was associated with bone mineral density, it is unlikely that these polymorphisms are essential in predicting bone mineral density in primary biliary cirrhosis.     

Insulin-like growth factor I gene microsatellite repeat, collagen type Ialpha1 gene Sp1 polymorphism, and bone disease in primary biliary cirrhosis

BACKGROUND: Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis. Insulin-like growth factor I (IGF-I) gene microsatellite repeat polymorphism was found to be associated with osteoporosis in some studies, and collagen-Ialpha1 (COLIA1) Sp1 s allele was associated with lower bone mineral density in primary biliary cirrhosis. IGF-I treatment restored osteopenia and reduced fibrogenesis in experimental cirrhosis. We investigated IGF-I and COLIA1 gene polymorphisms and bone mineral density in Hungarian primary biliary cirrhosis patients. PATIENTS AND METHODS: Seventy female patients with primary biliary cirrhosis were enrolled (mean age 57.6 years, range 37-76 years; all anti-mitochondrial antibody M2-positive; stage II-IV). One hundred and thirty-nine age-matched female subjects served as controls (mean age 55.9 years, range 43-72 years). COLIA1 and IGF-I polymorphisms were determined by polymerase chain reaction. Bone mineral density was measured by dual-energy X-ray absorptiometry in the lumbar spine and femoral neck. RESULTS: The IGF-I was not different between primary biliary cirrhosis patients and controls. The genotype frequency of COLIA1 polymorphism was also not different between primary biliary cirrhosis patients and controls. However, the s allele was significantly less frequent in patients with primary biliary cirrhosis. Osteoporosis was detected in 22 patients. The IGF-I 192/192 genotype was associated with higher femoral-neck z-scores compared with other genotypes. CONCLUSION: In contrast to previous studies, the s allele was less frequent in patients with primary biliary cirrhosis, and its presence was not associated with bone mineral density. Since IGF-I polymorphism was associated with bone mineral density, it may be hypothesised that not COLIA1 but IGF-I together with other genetic and environmental factors may be involved in the complex regulation of bone mineral density in primary biliary cirrhosis.     

Vitamin D receptor polymorphisms, bone ultrasound and mineral density in post-menopausal women

BACKGROUND AND AIMS: Bone structure, geometry and mineral content represent complex traits with a significant heritable component. However, the specific contributing genes have not been unambiguously identified. The aim of the present cross-sectional study was to analyse an association between heel ultrasound measurements, partly reflecting bone quality, and VDR (Vitamin D receptor) gene polymorphisms in post-menopausal women, and to assess whether these associations differ from those of bone density or not. METHODS: BUA (broadband ultrasound attenuation, dB/MHz) at the right heel and BMD (bone mineral density, g/cm2) at the lumbar spine and hip were measured in 114 post-menopausal women of Caucasian origin (62.4 +/- 9.8 years). All probands were genotyped for common VDR polymorphisms--FokI, BsmI, Apal and TaqI--by restriction analysis of the PCR product. RESULTS: ANCOVA revealed significant associations between calcaneal BUA adjusted for BMI (body mass index) and YSM (years since menopause), and BsmI, Apal and TaqI genotypes in the VDR gene (p < 0.02; p < 0.0003; p < 0.02 ANCOVA, respectively). BMI- and YSM-adjusted BMD was significantly associated with Fokl genotypes in the VDR gene (p < 0.028 at lumbar spine, p < 0.007 at hip). CONCLUSIONS: The present data show that post-menopausal BMD and BUA are determined by different polymorphisms within the VDR gene. Non-coding polymorphisms in the 3' end of the VDR gene (BsmI, Apal, TaqI) are related to heel ultrasound while the FokI polymorphism in exon 2, located at the opposite site of the VDR gene, is associated with BMD measurements. Further studies are required to determine whether different polymorphic markers within a single gene independently determine various components of post-menopausal bone.     

基因多态性与骨密度的相关性

骨密度受遗传因素影响,骨密度测定是诊断骨质疏松的主要依据.维生素D受体、Ⅰ型胶原、雌激素受体、降钙素受体参与骨形成和骨代谢,其基因多态性决定骨密度.研究发现Wnt蛋白、人类白细胞抗原等基因多态性也与骨密度有关.本文就基因多态性与骨密度的相关性进行论述.     

Genetic determinants of osteoporosis

PURPOSE OF REVIEW: Osteoporosis is a common disease with a strong genetic component characterised by reduced bone mass and an increased risk of fragility fractures. Several advances have been made over recent years in understanding the genetic basis of susceptibility to osteoporosis. This paper will review recent developments in this area. RECENT FINDINGS: Twin studies have shown that genetic factors contribute to osteoporosis by influencing bone mineral density and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover. In the normal population, many different genes contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Whereas the effect size of individual genes is small, meta-analysis has been successfully used in many cases to define the role of individual polymorphisms in predisposing to osteoporosis. Linkage studies in humans and experimental animals have identified several quantitative trait loci that regulate osteoporosis-related phenotypes, and many genes that cause monogenic bone diseases have been identified by use of this approach. It has been found that subtle polymorphisms in some of these genes also contribute to regulation of bone mass in the normal population. SUMMARY: Research has recently begun to clarify the genes and genetic variants that predispose to osteoporosis and regulation of bone mass. Clinical applications of this research include the identification of genetic markers for assessment of fracture risk and the identification of novel molecular targets for the design of drugs that can be used to treat bone disease.     

The vitamin d receptor gene and calcium metabolism.

Dietary Ca(2+) is essential for the development and maintenance of bone mineral mass. The vitamin D endocrine system plays a fundamental role in the regulation of Ca(2+) homeostasis, and mutations affecting genes implicated in vitamin D metabolism or vitamin D receptor (VDR) functions are responsible for severe alterations in skeletal growth. In addition, vitamin D is also implicated in the pathophysiology and treatment of adult bone disorders associated with impaired mineralization of bone matrix. Very recently, common polymorphisms in the 3'- and 5'-end region of the VDR gene have been suggested as possible determinants of bone mineral mass and, hence, of the risk of osteoporosis. None of these polymorphisms appear to be associated unequivocally with bone mineral mass or biochemical variables of Ca(2+) and phosphate metabolism, except perhaps VDR 3'-end polymorphisms before puberty. As these associations are so inconsistent, interactions with environmental factors, particularly dietary intake, and with other polymorphisms have to be considered.     

Genetics of osteoporosis

There is clear evidence of genetic modulation of bone phenotype parameters including bone density, quantitative ultrasound, bone size, and bone turnover. At any particular age and phase of life, genetic factors explain about 70% of the variance in bone phenotype after adjustment for major medical and disease factors. Hormonal factors, diet, and lifestyle interact with those genetic factors over time. Common allelic variation in the VDR was the first of several genes and now chromosomal loci to be implicated in the genetic determination of bone phenotype. The VDR polymorphisms have an effect weaker than originally reported, and part of the allelic effects may be mediated by effects on body size and development and even other hormonal regulators such as PTH or insulin. Irrespective of the strength or mechanism of these associations, these initial findings on the VDR stimulated the field of the genetics of osteoporosis with targeted genetic studies and now genome scan approaches. Intronic polymorphisms of the collagen I alpha 1 gene have been shown to be related to bone density and to fracture risk in several studies, although not all findings concur. Common allelic variations have now been associated with bone density for the estrogen receptor, TGF beta receptor, and TGF beta 1, for the insulin-like growth factor-I pathway, for interleukin-4 and -6 and the interleukin-1 receptor antagonist, for calcitonin and the PTH receptors and for apolipoprotein E. Of considerable interest, chromosomal loci, notably 11q 12-13, have now been linked to bone phenotypes in human and mouse studies. The mouse strain studies seem likely to be powerful tools providing insight to important human loci based on the mouse-human chromosomal synteny. Variability of genetic findings across studies seems to be the rule rather than the exception. This variability may relate to interaction of particular loci with specific environmental or even other genetic loci. The importance of genetic heterogeneity, including ethnicity, as well as environmental and hormonal confounders, such as calcium and vitamin D intake, hormonal status and skeletal and body size, will need to be taken into account in future gene search approaches. Genome scans in relation to bone density and fracture end-points will need to account for such important potential confounders in each target population. Interactions between genetic and environmental factors, including lifestyle, have been investigated initially for the VDR polymorphisms in relation to the response of bone density and turnover to calcium intake and treatment with simple vitamin D and active vitamin D compounds. Gene-gene and gene-environment interactions in human and animal models will be critical targets for future research. Further genes with positive and negative effects on bone phenotype are certain to be identified in the near future. Each of these will need to be evaluated in relation to potential environmental modulators in pharmacogenetic models. Understanding the molecular physiology of such gene effects is likely to lead to more specific treatments and to allow the selection of more appropriate and effective treatment options.     

Genetic control of susceptibility to osteoporosis

Osteoporosis is a common disease with a strong genetic component. Twin studies have shown that genetic factors play an important role in regulating bone mineral density (BMD), ultrasound properties of bone, skeletal geometry, and bone turnover as well as contributing to the pathogenesis of osteoporotic fracture itself. These phenotypes are determined by the combined effects of several genes and environmental influences, but occasionally, osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, caused by inactivating mutations in the lipoprotein receptor-related protein 5 gene and the high bone mass syndrome, caused by activating mutations of the same gene. Genome-wide linkage studies in man have identified loci on chromosomes 1p36, 1q21, 2p21, 5q33-35, 6p11-12, and 11q12-13 that show definite or probable linkage to BMD, but so far, the causative genes remain to be identified. Linkage studies in mice have similarly identified several loci that regulate BMD, and a future challenge will be to investigate the syntenic loci in humans. A great deal of research has been done on candidate genes; among the best studied are the vitamin D receptor and the collagen type I alpha 1 gene. Polymorphisms of vitamin D receptor have been associated with bone mass in several studies, and there is evidence to suggest that this association may be modified by dietary calcium and vitamin D intake. A functional polymorphism affecting an Sp1 binding site has been identified in the collagen type I alpha 1 gene that predicts osteoporotic fractures independently of bone mass by influencing collagen gene regulation and bone quality. An important problem with most candidate gene studies is small sample size, and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis to try and address this issue and gain an accurate estimate of effect size for different polymorphisms in relation to relevant clinical endpoints, such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important, because they offer the prospect of developing genetic markers for the assessment of fracture risk and the opportunity to identify molecules that will be used as targets for the design of new drugs for the prevention and treatment of bone disease.     

Bone mineral mass and calcium and phosphate metabolism in young men: relationships with vitamin D receptor allelic polymorphisms.

The genetic bases of peak bone mass determinants are still poorly understood, particularly in males. We investigated the relationship between vitamin D receptor (VDR) 3'- and 5'-gene polymorphisms (as determined by the restriction enzymes BsmI and FokI) and bone mineral mass, and calcium and inorganic phosphate (Pi) metabolism in an homogeneous cohort of young healthy men. In 104 healthy subjects, aged 24.3 +/- 3.1 yr (mean +/- SD; range, 20.7-38.7), standardized bone mineral density (BMD; z-scores) at the levels of lumbar spine and femoral trochanter, i.e. bone mineral content adjusted for age, body size, and bone area, significantly differed between VDR 3'-end alleles (BsmI), whereas crude areal BMD or bone mineral content did not. Among BsmI homozygotes BB, BMD (z-scores) were significantly lower only in subjects also carrying the f allele at the VDR-5' polymorphic site (FokI). Serum PTH levels were significantly higher in the BB genotype at baseline and remained so under either a low or a high calcium-phosphorus diet. Moreover, on the low calcium-phosphorus diet, BB subjects had significantly decreased tubular Pi reabsorptive capacity and plasma Pi levels. Our results underline the importance of identifying multiple single base mutation polymorphisms within candidate genes of bone mineral mass and suggest a role for environmental/dietary factor interactions with VDR gene polymorphisms in peak bone mineral mass in men.     

The genetics of osteoporosis

Osteoporosis is highly influenced by genetic factors. Bone mineral density (BMD) has also been shown to be highly heritable, as are other risk factors for osteoporotic fracture such as bone quality, femoral neck geometry and bone turnover. Susceptibility to osteoporosis is mediated, in all likelihood, by multiple genes each having small effect and a number of different approaches are being employed to identify the genes involved. Study methods include linkage studies in both humans and experimental animals as well as candidate gene and gene expression studies. Linkage studies have identified multiple quantitative trait loci (QTL) for regulation of BMD and, along with twin studies, have indicated that the effects of these loci on BMD are site-dependent and sex-specific. On the whole, the genes responsible for BMD regulation at these QTL have not been identified. Most studies have used the candidate gene approach, based on what is known of bone metabolism. The vitamin D receptor gene (VDR), the collagen type I alpha I gene (COLIA1) and estrogen receptor gene (ER) alpha have been widely investigated and found to play a role in regulating BMD. A recent meta-analysis suggests, however, that VDR plays no significant role, and the effects of the other 2 genes are modest--probably accounting for less than 3% of the genetic contribution to BMD. Cost-effective large scale genetic testing is becoming available and lends itself to combining large multi-national populations for candidate gene analysis, meta-analyses, DNA pooling studies and gene expression studies.     

Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin.

Osteocalcin, the most abundant noncollagenous protein in bone, is a marker of bone turnover in normal and disease states. Its synthesis is induced by calcitriol, the active hormonal form of vitamin D, through the vitamin D receptor and a specific vitamin D-responsive element in the osteocalcin gene promoter. Serum concentrations of osteocalcin are under strong genetic influence. To ascertain whether variability in circulating osteocalcin levels may reflect allelic variation in the vitamin D receptor gene, we have analyzed the relationship between frequent restriction fragment length polymorphisms (RFLPs, detected by endonucleases Bsm I, EcoRV, and Apa I) that define human vitamin D receptor alleles and serum osteocalcin in a cohort of normal subjects. In 91 Caucasian subjects, RFLPs in the vitamin D receptor gene predicted circulating osteocalcin levels (P less than 0.0001) independent of age or menopause effects. Since the osteocalcin gene and the vitamin D receptor gene are encoded on different chromosomes, the interaction between these two genes occurs in trans. Thus, common alleles of this trans-acting factor, the vitamin D receptor, are functionally different and contribute to "normal" physiological variability in osteocalcin levels. Preliminary analysis in monozygotic and dizygotic twin pairs indicates that the greater diversity in lumbar spine density between the dizygotic pairs can be explained by divergence in vitamin D receptor alleles. Variations in this receptor and other transacting factor genes may confound physiological studies of regulation of target genes and will need to be considered in future human and animal studies. This approach to genetic analysis provides a paradigm for the study of functional variation in trans-acting factors and the role such variation may play in the generation and evolution of physiological diversity.     

Bone mineral density,vitamin D receptor (VDR) gene polymorphisms,fracture risk assessment (FRAX), and trabecular bone score (TBS) in rheumatoid arthritis patients: connecting pieces of the puzzle

Clinical Rheumatology - To assess vitamin D receptor (VDR) gene polymorphisms and bone mineral density and to investigate the possible risk factors of osteoporosis and fracture in rheumatoid...