Genetic factors of osteoporosis and fracture and the application of genetic information to the preventive medicine

Osteoporosis is a common disease caused by multi-factors including genetic factor and environmental and life-style factors. The tailor-made prevention and medicine based on the individual data including genetic information for osteoporosis is expected in the post-genomic era. Genetic susceptibility of osteoporosis has been analyzed by linkage and association study. A number of studies have been shown the association between bone mass and polymorphisms in candidate gene, however, these results have been poor reproducible. Some studies have been reported the interaction between genetic factor and life-style factors on bone mass. Those results have suggested the potential application of genetic information to the prevention of osteoporosis by life-style modification. Further studies should be conducted to develop the practical tailor-made prevention.     

Role of genetics in osteoporosis

Osteoporosis is a disease characterized by fragile bones and high susceptibility to low-trauma fractures. It is a serious health problem, especially in elderly women. Bone mineral density (BMD) has been employed most commonly as the index for defining and studying osteoporosis. BMD has high genetic determination, with heritability ranging from 50 to 90%. Various genemapping approaches have been applied to identify specific genes underlying osteoporosis, largely using BMD as the study phenotype. We review here the genetic determination of osteoporosis as defined by BMD and discuss a fundamental issue we encounter in genetic research in osteoporosis: the choice of phenotype(s) to study. We briefly summarize and discuss advantages and disadvantages of various approaches used in genetic studies of osteoporosis. Finally, we review and discuss the current status for mapping and identification of genes for osteoporosis. We focus on linkage studies in humans and quantitative trait loci mapping in mice to supplement the already extensive reviews of association studies made by many investigators for candidate genes.     

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。     

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.     

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.     

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.     

Hearts and bones

Cardiovascular disease (CVD) and osteoporosis (OP) are two common degenerative processes that contribute in great measure to the decline in performance and quality of life of the elderly population. Traditionally, these disorders have been considered as distinct and unrelated entities. However, over the last few years, there has been increasing evidence supporting an important link between CVD and OP. Several genetic association and linkage studies have shown the existence of common genetic determinants for cardiovascular and skeletal diseases. These genes code for several key players on the metabolism of nutrients, such as lipids, calcium and folate, as well as other factors (e.g. sex hormone receptors) that are known to be subject to dietary modulation, suggesting the links at the level of dietary response. Some dietary factors have shown similarities in influencing the risks of both conditions. However, some others act differently in relation with their effects on the development of cardiovascular disease and osteoporosis. We therefore suggest that, any dietary and behavioral recommendations targeting to the 'global health' of the ageing population would take a comprehensive consideration of their potentially diverse effects (beneficial or deleterious) on the risks of various ageing related disorders, and would be tailored to the individual genetic background.     

Progress in chronic obstructive pulmonary disease genetics

Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, suggesting that genetic factors likely influence the variable development of chronic airflow obstruction in response to smoking. A variety of approaches have been used to identify novel COPD susceptibility genes, including association studies, linkage analysis, and rare variant analysis. Future directions for COPD research include genomewide association studies and animal model genetic studies.     

Association studies of genetic polymorphisms in central obesity: a critical review

During the past decade, mutations affecting liability to central obesity have been discovered at a phenomenal rate, and despite few consistently replicated findings, a number of intriguing results have emerged in the literature. Association studies have been proposed to identify the genetic determinants of complex traits such as central obesity. The advantages of the association method include its relative robustness to genetic heterogeneity and the ability to detect much smaller effect sizes than is detectable using feasible sample sizes in linkage studies. However, the current literature linking central obesity to genetic variants is teeming with reports of associations that either cannot be replicated or for which corroboration by linkage has been impossible to find. Explanations for this lack of reproducibility are well rehearsed, and typically include poor study design, incorrect assumptions about the underlying genetic architecture, and simple overinterpretation of data. These limitations create concern about the validity of association studies and cause problems in establishing robust criteria for undertaking association studies. In this article, the current status of the literature of association studies for genetic dissection of central obesity is critically reviewed.     

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.     

1型糖尿病遗传学研究新进展

1型糖尿病是一种遗传因素和环境因素相互作用,共同参与的复杂遗传病.除家系连锁研究和候选基因关联研究发现的5个易感位点外,全基因组关联研究及后续研究已发现30余个新的易感位点.     

Searches for the genes determining bone mineral density with gene polymorphisms

The genes determining bone mineral density have been searched by association and linkage studies using gene polymorphisms. Candidate gene approaches as well as genome-wide studies with single nucleotide polymorphisms have produced many products. In addition, rare mutations causing monogenic hereditary bone diseases gave novel aspects for the genes contributing the variation in bone mineral density. Furthermore, studies of functional SNPs would explain the variation in bone mineral density and basic pathophysiology of osteoporosis.     

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.     

Genetic determinants of bone mass

PURPOSE OF REVIEW: This review examines recent advances in the analysis of genetic determinants of bone mass. It addresses both human and animal linkage studies as well as genetic manipulations in animals, inbred mouse models, and candidate gene analyses. RECENT FINDINGS: Recent studies have implicated novel regulatory pathways in bone biology including both the neuroendocrine system and metabolic pathways linked to lipid metabolism. Variations in the lipoprotein receptor-related protein 5 (LRP5), part of the Wnt-frizzled pathway, were independently identified by linkage in high and low bone mass families. Subsequently, other high bone mass syndromes have been shown to have mutations in this gene. Neural studies have shown the skeletal regulatory activity of leptin and neuropeptide Y receptors via the hypothalamus. Subsequently, the beta-adrenergic pathway has been implicated, with important changes in bone mass. The lipoxygenase 12/15 pathway, identified through inbred mouse models and through pharmacologic studies with specific inhibitors, has also been shown to have important effects on bone mass. These studies exemplify the value of genetic models both to identify and then confirm pathways by mutational study and pharmacologic interventions. Continuing candidate gene studies often performed with multiple loci complement such discoveries. However, these studies have not focused on the clinical endpoint of fracture and few have included large enough groups to engender confidence in the associations reported, as such studies may require thousands of individuals. Interestingly, results often differ by ethnicity, age, or gender. A small proportion have examined whether relevant genes influence response to treatment. SUMMARY: The combinations of human and animal genetic linkage studies have advanced understanding of the regulation of bone mass. Studies ranging from linkage to pharmacology provide optimism for new targets and treatments for osteoporosis.     

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.     

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.     

Genome studies and linkage in primary osteoarthritis

Genetic epidemiologic studies have demonstrated that primary OA has a major genetic component that segregates in families in a complex manner. Some of these studies suggest that genetic susceptibility may be more relevant to female OA than to male OA and that genes may have a greater role in OA development and progression at certain joint groups compared with others. These observations are not universal, however, and discrepancies between different studies may simply serve to highlight the complex nature of the transmittance of OA susceptibility. The numerous OA linkage studies that have now been performed have revealed a number of regions of the human genome that are likely to harbor genes predisposing to OA. Several of these regions, particularly those identified in genome-wide scans of ASPs, have relatively low LOD scores; as a result, their reliability must be questioned. Nevertheless, a few of these regions have already been linked in more than one study, and these linkages can be considered as more robust. Such confirmation is a prerequisite to finer linkage mapping, which should narrow the linkage intervals to a point at which comprehensive association analysis of DNA sequence variants can be undertaken.     

Genetic factors in lung disease: Atopy and bronchial asthma

Abstract Atopy defined as high IgE responsiveness has now been subject to genetic studies at the molecular level owing to the development of a great number of DNA markers over the human genome. Either by linkage analysis or by association study strong candidate genes of atopy have been proposed to be located on chromosomes 11q13 and 5q31 where high-affinity IgE Fc receptor β subunit and allergy-associated cytokines, respectively, have been mapped. Meanwhile, we found a novel association between one of alleles of D11S97, an anonymous DNA marker on 11g13, and high total serum IgE in a large number of Japanese general population and atopic family members. However, failure to replicate linkage or association studies by different investigators suggest polygenic nature of atopy. In addition to the genes regulating IgE synthesis, the requirement of local (pulmonary) genetic factors in the development of bronchial asthma have been speculated. Linkage analysis suggested possible existence of gene(s) regulating susceptibility and/or clinical characteristics of bronchial asthma also on chromosome 5q. One of the candidate is β2-adrenergic receptor gene polymorphism. Mutated gene transfection studies suggested functional significance of some polymorphisms and clinical evaluations have revealed their contribution to airway responsiveness and severity of asthma.     

Genetics of chronic obstructive pulmonary disease

Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.