Genetics of osteoporosis in Chinese

Osteoporosis is a common skeletal disease characterized by low bone mineral density (BMD) and deterioration in bone microarchitecture, resulting in increased bone fragility and susceptibility to fractures. As a complex disease, it is determined by both genetic and environmental factors, as well as their interactive effects. Studies have suggested that different genetic determinants may be involved in different ethnic groups. In this paper, we reviewed the genetic studies of osteoporosis in A Chinese population, focusing on the genes affecting BMD, a surrogate phenotype of osteoporosis.     

Plant domestication, a unique opportunity to identify the genetic basis of adaptation

Despite the fundamental role of plant domestication in human history and the critical importance of a relatively small number of crop plants to modern societies, we still know little about adaptation under domestication. Here we focus on efforts to identify the genes responsible for adaptation to domestication. We start from a historical perspective, arguing that Darwin's conceptualization of domestication and unconscious selection provides valuable insight into the evolutionary history of crops and also provides a framework to evaluate modern methods used to decipher the genetic mechanisms underlying phenotypic change. We then review these methods, framing the discussion in terms of the phenotype-genotype hierarchy. Top-down approaches, such as quantitative trait locus and linkage disequilibrium mapping, start with a phenotype of interest and use genetic analysis to identify candidate genes. Bottom-up approaches, alternatively, use population genetic analyses to identify potentially adaptive genes and then rely on standard bioinformatics and reverse genetic tools to connect selected genes to a phenotype. We discuss the successes, advantages, and challenges of each, but we conclude that bottom-up approaches to understanding domestication as an adaptive process hold greater promise both for the study of adaptation and as a means to identify genes that contribute to agronomically important traits.     

Osteoporosis associated with gene mutation

Osteoporosis is the most common metabolic bone disease and caused by multiple nutritional, environmental and genetical factors. Bone mineral density (BMD) is rather strongly under genetical control. A number of candidate genes have been studied with respect to the impact on BMD. Also, gene loci of susceptibility genes for osteoporosis have been identified by family-based association and linkage approaches. In particular, LRP5 is an important molecule involved in the determination of BMD, because its abnormality is associated with osteoporosis-pseudoglioma syndrome or autosomal dominant syndrome characterized by high bone density. These findings may contribute to new strategy to teat patients with osteoporosis.     

Genetics and osteoporosis

Over the past 10 years, many advances have been made in understanding the mechanisms by which genetic factors regulate susceptibility to osteoporosis. It has become clear from studies in man and experimental animals that different genes regulate BMD at different skeletal sites and in men and women. Linkage studies have identified several chromosomal regions that regulate BMD, but only a few causative genes have been discovered so far using this approach. In contrast, significant advances have been made in identifying the genes that cause monogenic bone diseases, and polymorphic variation is some of these genes has been found to contribute to the genetic regulation of BMD in the normal population. Other genes that have been investigated as possible candidates for susceptibility to osteoporosis because of their role in bone biology, such as vitamin D, have yielded mixed results. Many candidate gene association studies have been underpowered, and meta-analysis has been used to try to confirm or refute potential associations and gain a better estimate of their true effect size in the population. Most of the genetic variants that confer susceptibility to osteoporosis remain to be discovered. It is likely that new techniques such as whole-genome association will provide new insights into the genetic determinants of osteoporosis and will help to identify genes of modest effect size. From a clinical standpoint, genetic variants that are found to predispose to osteoporosis will advance our understanding of the pathophysiology of the disease. They could be developed as diagnostic genetic tests or form molecular targets for design of new drugs for the prevention and treatment of osteoporosis and other bone diseases.     

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.     

The genetics of osteoporosis and the search for osteoporosis genes

Osteoporosis represents a major or developing public health problem in most countries around the world. Because fracture, the clinical manifestation of the disease, is a time dependent event, bone mineral density (BMD) is most frequently used as a surrogate phenotype. Each standard deviation decrease in BMD is associated with an approximate twofold increase in fracture risk, which is similar to the magnitude of association between hypertension and cardiovascular disease. Thus, identifying factors that are involved in the determination of BMD is important in osteoporosis research. One of the remarkable features of BMD is that it is normally distributed with a virtually constant variance throughout life. Although BMD shows an age dependent pattern of an initial increase with growth and subsequent decline in later life, twin and family studies have shown that at each stage of life, genetic factors account for up to 70 to 80% of the variance of BMD. However multiple genes appear responsible for determining BMD at various skeletal sites. Two strategies have been used for identifying genes influencing BMD, namely genome‐wide scanning (a top down approach) and candidate genes (a bottom up approach). The latter has been most frequently used to date and two candidate genes have received the most attention, namely the vitamin D receptor and collagen genes. In 1994, a strong association between non‐coding polymorphisms in the vitamin D receptor gene and BMD was reported, although when genotyping errors were later accounted for, the effect was considerably weaker in magnitude. Numerous subsequent studies have reported an association between BMD and VDR genotypes ranging from a similar effect to no effect. In 1997, an association between polymorphisms in the collagen 1a1 gene and BMD was also reported. Again subsequent reports have supported the original findings but also shown no effect in some populations. Other candidate genes reported include the estrogen receptor, apolipoprotein E, TGFβ and IL‐6, all with varying strength of association and controversy. These discrepancies may be due to a variety of problems including inadequate study sample size, selection bias in the populations studies, gene environment effects, linkage dysequilibrium and genotyping errors. Determining the effects of gene–environment interactions on measured phenotypes is particularly complicated if multiple genetic loci are involved, as is likely, and the dose of ‘environmental exposure’ varies, as seems common between populations. For these reasons it is likely that the top down approach, of genome‐wide scanning in appropriate large scale twin or affected sib pair populations, will prove most effective in identifying clinically meaningful osteoporosis genes in the future.     

Studies of natural allele effects in mice can be used to identify genes causing common human obesity

Although genes causing rare Mendelian forms of human obesity have provided much useful information about underlying causes of obesity, these genes do not explain significant proportions of common obesity. This review presents evidence that animal models can be used to uncover subtle genetic effects on obesity and can provide a powerful rigorous compliment to human association studies. We discuss the advantages of animal models of obesity, various approaches to discovering obesity genes, and the future of mapping and isolating naturally occurring alleles of obesity genes. We review evidence that it is important to map naturally occurring obesity genes using quantitative trait locus (QTL) mapping, instead of mutagenesis and knockout models because the latter do not allow study of interactions and because naturally occurring obesity alleles can interfere with cloning from mutagenesis projects. Because a substantial percentage of human obesity results from complex interactions, the underlying genes can only be identified by direct studies in humans, which are still very difficult, or by studies in mice that begin with QTL mapping. Finally, we emphasize that animal model studies can be used to prove that a specific gene, only associated with obesity in humans, can indeed be the underlying cause of obesity in mammals.     

Osteoporosis in Thailand

Osteoporosis is a health problem which is becoming more prevalent in Thailand. A number of differences compared to Caucasian populations, however, exist which include the burden and the diagnosis of osteoporosis, genetics of osteoporosis, vitamin D status and calcium intake. Thai postmenopausal women suffer less hip fractures despite lower bone mineral density (BMD). Other environmental or genetic factor are likely to play modulatory role on the determination of osteoporotic fractures besides BMD. Distal renal tubular acidosis is prevalent in certain parts of Thailand. The disorder in which low BMD is a clinical feature needs to be excluded before the diagnosis of osteoporosis based on bone densitometry can be made. Genetic factors play important role in the determination of osteoporosis and osteoporotic fractures. The cohort of genes involved in osteoporosis and their impact are likely to be different among populations with different ethnic background. Besides genetic factors, environmental factors such as calcium intake and vitamin status are also crucial. Thailand is situated in a geographic area with abundant sunlight exposure and vitamin D deficiency is not commonly found in our elderly who are still active and ambulatory. Due to adequate vitamin D status, favorable vitamin D receptor genotype and less urinary calcium loss because of smaller body built, the optimal calcium in Thais may not be as high as that recommended in Caucasians.     

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.     

Sibling pair linkage and association studies between peak bone mineral density and the gene locus for the osteoclast-specific subunit (OC116) of the vacuolar proton pump on chromosome 11p12-13

A major determinant of the risk of osteoporosis is peak bone mineral density (BMD), which has been shown to have substantial heritability. The genes for 3 BMD-related phenotypes (autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessives osteopetrosis) are all in the chromosome 11q12-13 region. We reported linkage of peak BMD in a large sample of healthy premenopausal sister pairs to this same chromosomal region, suggesting that the genes underlying these 3 disorders may also play a role in determining peak BMD within the normal population. To test this hypothesis, we examined the gene responsible for 1 form of autosomal recessive osteopetrosis, TCIRG1, which encodes an osteoclast-specific subunit (OC116) of the vacuolar proton pump. We identified 3 variants in the sequence of TCIRG1, but only one, single nuclear polymorphism 906713, had sufficient heterozygosity for use in genetic analyses. Our findings were consistent with linkage to femoral neck BMD, but not to spine BMD, in a sample of 995 healthy premenopausal sister pairs. However, further analysis, using both population and family-based disequilibrium approaches, did not demonstrate any evidence of association between TCIRG1 and the spine or femoral neck BMD. Therefore, our linkage data suggest that the chromosomal region that contains OC116 harbors a gene that affects peak BMD, but our association results indicate that polymorphisms in the OC116 gene do not affect peak BMD.     

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

We aim to give a comprehensive review, updated to 2002, of the most important and representative molecular genetic studies, performed mainly within the past decade, that aimed to identify the gene(s) involved in osteoporosis. Early reviews were largely confined to association studies in humans, but we review here, separately, the results of both association and linkage studies in humans, and quantitative trait locus (QTL) mapping in animal models. The main results of all the studies are tabulated for comparison and ease of reference, and to provide a comprehensive retrospective view of molecular genetics studies of osteoporosis. The most striking findings and the most representative studies are singled out for comment regarding the immediacy of their influence on present understanding of the genetics of osteoporosis and on the current status of genetic research in osteoporosis. This is particularly relevant for studies on the association of the vitamin D receptor (VDR) gene, for which there has been a large body of studies and reviews published. The format adopted by this review should be ideal for accommodating future new advances and studies in a fairly young field that is still developing rapidly.     

Design and Interpretation of Linkage and Association Studies on Osteoporosis

Osteoporosis is a common disease with strong genetic control. Genetic linkage and association studies are the two most popular methods used to investigate the genetic basis of osteoporosis. Linkage studies have been successfully used to identify quantitative trait loci (QTLs), and association studies have been widely performed to test candidate genes for osteoporosis. In this article, we review the design and interpretation of linkage and association studies on osteoporosis.     

骨质疏松症的遗传流行病学及其临床应用

骨质疏松症是一种重要的复杂疾病,在全球具有高度的流行性。它需要昂贵的医疗成本,是对现代医疗的一大挑战,许多研究正致力于解开其发病机制。骨质疏松症的临床评估通常结合骨质疏松性骨折相关的家族史信息,如果父母曾经髋部骨折,则子女骨折的风险增加3倍。这一发现为骨质疏松症的遗传性提供了有利的证据。骨质疏松症的发病和进展通常由多个遗传和环境因素以及它们的相互作用控制,极少数情况出现由单一基因导致。在尝试确定复杂疾病如骨质疏松症的遗传因子的研究中,科学家已经从传统的连锁图谱研究,转入有高密度遗传标记的全基因组关联(GWA)研究。高通量技术的出现,使对人类基因组中数以百万计的DNA标记进行基因分型和对骨质疏松症的致病基因和位点的鉴定得以实现。本文主要概述在这些基因组连锁和关联研究中的主要发现及其临床应用。     

The skeletal consequences of thyrotoxicosis

Euthyroid status is essential for normal skeletal development and the maintenance of adult bone structure and strength. Established thyrotoxicosis has long been recognised as a cause of high bone turnover osteoporosis and fracture but more recent studies have suggested that subclinical hyperthyroidism and long-term suppressive doses of thyroxine (T4) may also result in decreased bone mineral density (BMD) and an increased risk of fragility fracture, particularly in postmenopausal women. Furthermore, large population studies of euthyroid individuals have demonstrated that a hypothalamic-pituitary-thyroid axis set point at the upper end of the normal reference range is associated with reduced BMD and increased fracture susceptibility. Despite these findings, the cellular and molecular mechanisms of thyroid hormone action in bone remain controversial and incompletely understood. In this review, we discuss the role of thyroid hormones in bone and the skeletal consequences of hyperthyroidism.     

High prevalence and correlates of low bone mineral density in young adults with sickle cell disease

Sickle cell disease (SCD) is a prevalent genetic disorder in which sickle hemoglobin leads to tissue hypoxia and adverse effects on bone. Published studies suggest that children with SCD often have undiagnosed osteopenia or osteoporosis. Minimal data exist on the prevalence of low bone mineral density (BMD) in adults. Our objective was to describe the prevalence of osteopenia and osteoporosis in adults with SCD and to identify patient or disease characteristics associated with low BMD. We conducted a cross-sectional study of adults with SCD. Through questionnaires, we collected data about disease course and osteoporosis risk factors. Patients underwent dual X-ray absorptiometry (DXA) measurement of BMD at the hip, spine, and forearm and sampling of blood and urine for markers of bone turnover, sickle cell disease severity, and secondary causes of osteoporosis. Our main outcome measure was prevalence of osteopenia and osteoporosis as defined by WHO criteria. Of 32 adults with SCD (14 men and 18 women) with a mean age of 34 years, 72% (95% confidence interval 53-86%) had low BMD at one or more anatomic sites. Thirteen patients were classified as osteoporotic and 10 as osteopenic. The prevalence of low BMD was greatest in the lumbar spine (66% of patients). Significant correlates of decreased BMD included low BMI (P < 0.01), male sex (P = 0.02), and low serum zinc concentrations (P < 0.01). The prevalence of osteopenia and osteoporosis in young adults with SCD is extremely high. Further research is needed to address fracture risk and therapeutic interventions.     

Haplotype thinking in lung disease

To identify the genetic etiology of a disease of interest, disease-related characteristics (phenotypes) are often tested for association with genetic variants (genotypes). Although genetic association studies of single genetic variants have been widely performed, there has been increasing interest in studies of multiple adjacent genetic variants on one chromosome, known as a haplotype. In this review, we will provide background about the origin of haplotypes and why they can be useful in genetic studies; we will discuss approaches to determining haplotypes and performing haplotype-based genetic association studies; and we will compare single variant and haplotype-based approaches.     

Genetic basis of atherosclerosis: insights from mice and humans

Atherosclerosis is a complex and heritable disease involving multiple cell types and the interactions of many different molecular pathways. The genetic and molecular mechanisms of atherosclerosis have, in part, been elucidated by mouse models; at least 100 different genes have been shown to influence atherosclerosis in mice. Importantly, unbiased genome-wide association studies have recently identified a number of novel loci robustly associated with atherosclerotic coronary artery disease. Here, we review the genetic data elucidated from mouse models of atherosclerosis, as well as significant associations for human coronary artery disease. Furthermore, we discuss in greater detail some of these novel human coronary artery disease loci. The combination of mouse and human genetics has the potential to identify and validate novel genes that influence atherosclerosis, some of which may be candidates for new therapeutic approaches.     

Osteoporosis as an Hereditary Disease

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that bone mineral density (BMD) and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover have a significant heritable component. Osteoporotic fractures also have a genetic component but heritability reduces dramatically with increasing age. Many different genetic variants contribute to the regulation of these phenotypes; most are common variants of small effect size, but there is evidence that rare variants of large effect size also contribute in some individuals. Genome wide association studies have recently been successfully employed to identifying genes that predispose to osteoporosis, although some of these had already been identified through the study of rare bone diseases. Although there has been extensive progress in understanding the genetic basis of osteoporosis over the past 10 years, most of the genetic variants that regulate bone mass remained to be discovered.