Pharmacogenetics of osteoporosis and the prospect of individualized prognosis and individualized therapy (original) (raw)
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Recent Advances in the Genetics of Fractures in Osteoporosis
Frontiers in Endocrinology, 2019
Genetic susceptibility, together with old age, female sex, and low bone mineral density (BMD) are amongst the strongest determinants of fracture risk. Tmost recent large-scale genome-wide association study (GWAS) meta-analysis has yielded fifteen loci. This review focuses on the advances in the research of genetic determinants of fracture risk. We first discuss the genetic architecture of fracture risk, touching upon different methods and overall findings. We then discuss in a second paragraph the most recent advances in the field and focus on the genetics of fracture risk and also of other endophenotypes closely related to fracture risk such as bone mineral density (BMD). Application of state-of-the-art methodology such as Mendelian randzation in fracture GWAS are reviewed. The final part of this review touches upon potential future directions in genetic research of osteoporotic fractures.
Breaking Down Bone Strength: A Perspective on the Future of Skeletal Genetics
Journal of Bone and Mineral Research, 2001
W ITH INCREASING INTENSITY over the past decade, researchers have pursued genetic approaches to understanding the basis of skeletal fragility. This month's issue of the JBMR includes a report by Beamer and associates (1) that identifies quantitative trait loci (QTLs) for femoral and vertebral volumetric bone mineral density (vBMD) and presents us with an opportunity to reflect on recent progress and future directions in bone genetics.
An insight into the paradigms of osteoporosis: From genetics to biomechanics
Bone Reports
Considered as one of the major epidemics of the 21st century, osteoporosis affects approximately 200 million people globally, with significant worldwide impact on rates of morbidity and mortality and massive socioeconomic burdens. Mainly characterized by decreased bone mineral density (BMD) and increased risk of bone fragility/deterioration, this devastating silent epidemic typically has no symptoms until a fracture occurs. The multifactorial disease, osteoporosis is instigated by complex interactions between genetic, metabolic and environmental factors, with severe impact on the biomechanics of the musculoskeletal system. This article provides a review of the epidemiology, genetic and biomechanical aspects of primary osteoporosis. The review begins with a summary of the epidemiology and global prevalence of osteoporosis. Sections 1 and 2 discuss the genetic associations and molecular signaling pathways involved in normal and pathological osteogenesis while Section 3 explores the biomechanics of osteoporosis and its quantitative damaging effects on critical bone mechanical properties, and associated bone remodeling. Overall, this review summarizes the recent findings about osteoporosis and emphasizes the importance of an integrative holistic approach in investigating osteoporosis towards providing better informed, more effective preventive and treatment modalities. Importantly, this work also explores the limited available literature on the various aspects of osteoporosis in the United Arab Emirates (UAE), Gulf Cooperation Council (GCC), and Middle East despite its alarming prevalence in the region, and highlights the need for further research and studies taking into consideration the importance of the vitamin D receptor (VDR) gene influencing the development of osteoporosis.
Osteoporosis genetics: year 2011 in review
BoneKEy Reports, 2012
Increased rates of osteoporotic fractures represent a worldwide phenomenon, which result from a progressing aging in the population around the world and creating socioeconomic problems. This review will focus mostly on human genetic studies identifying genomic regions, genes and mutations associated with osteoporosis (bone mineral density (BMD) and bone loss) and related fractures, which were published during 2011. Although multiple genome-wide association studies (GWAS) were performed to date, the genetic cause of osteoporosis and fractures has not yet been found, and only a small fraction of high heritability of bone mass was successfully explained. GWAS is a successful tool to initially define and prioritize specific chromosomal regions showing associations with the desired traits or diseases. Following the initial discovery and replication, targeted sequencing is needed in order to detect those rare variants which GWAS does not reveal by design. Recent GWAS findings for BMD included WNT16 and MEF2C. The role of bone morphogenetic proteins in fracture healing has been explored by several groups, and new single-nucleotide polymorphisms present in genes such as NOGGIN and SMAD6 were found to be associated with a greater risk of fracture non-union. Finding new candidate genes, and mutations associated with BMD and fractures, also provided new biological connections. Thus, candidates for molecular link between bone metabolism and lactation (for example, RAP1A gene), as well as possible pleiotropic effects for bone and muscle (ACTN3 gene) were suggested. The focus of contemporary studies seems to move toward whole-genome sequencing, epigenetic and functional genomics strategies to find causal variants for osteoporosis.
Genetic factors , osteoporosis and bone fractures
2017
Bone fracture risk is influenced by a number of factors, including bone mineral density (BMD), bone quality parameters and non-skeletal factors affecting the risk of falls. Each of these factors is itself under at least partial genetic control. Several studies suggested that between 50 and 85% of the variance in peak bone mass was genetically determined. It was also presumed that genes contributed significantly to variability in age-related bone loss and other determinants of fracture risk. Candidate genes for osteoporosis were classified according to metabolic or hormonal pathways. It was found that polymorphisms of genes encoding and/or regulating the Wnt/β-catenin signaling pathway, the RANK-RANKL-OPG pathway, vitamin D receptor (VDR) and vitamin D binding protein (DBP), procollagen 1 molecule, and the estrogen receptor α influenced BMD and bone fracture risk.
Endocrine Reviews, 2002
Osteoporosis is a common multifactorial disorder of reduced bone mass. The disorder in its most common form is generalized, affecting the elderly, both sexes, and all racial groups. Multiple environmental factors are involved in the pathogenesis. Genes also play a major role as reflected by heritability of many components of bone strength. Quantitative phenotypes in bone strength in the normal population do not conform to a monogenetic mode of inheritance. The common form of osteoporosis is generally considered to be a polygenic disorder arising from the interaction of common polymorphic alleles at quantitative trait loci, with multiple environmental factors. Finding the susceptibility genes underlying osteoporosis requires identifying specific alleles that coinherit with key heritable phenotypes in bone strength. Because of the close correspondence among mammalian genomes, identification of the genes underlying bone strength in mammals such as the mouse is likely to be of major assistance in human studies. Identification of susceptibility genes for osteoporosis is one of several important approaches toward the long-term goal of understanding the molecular biology of the normal variation in bone strength and how it may be modified to prevent osteoporosis. As with all genetic studies in humans, these scientific advances will need to be made in an environment of legal and ethical safeguards that are acceptable to the general public. (Endocrine Reviews 23: 303-326, 2002)
Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study
Lancet, 2008
Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density. In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone m...