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| |  Increased Osteoporosis Risk Linked to Two Genes, Screening Possible LONDON -- April 30, 2008 -- Two genetic variants of key biological proteins have been identified, which, when present, increase both the risk of osteoporosis and subsequent osteoporotic fractures. Since these variants are present in more than 1 in 5 of the population studied, there is a potential role for screening. These are the conclusions of authors of an article published early online and in this week's issue of The Lancet. Osteoporosis and its main complication, fragility fractures, cause substantial death and disease globally. The public health burden of this disease is US$17 billion every year in direct expenditures, a figure expected to increase dramatically as populations age. Osteoporosis is defined clinically through the measurement of bone mineral density (BMD), which remains the single best predictor of osteoporotic fractures. BMD is highly heritable, with estimates of 78% heritability of density at the lumbar spine and 84% at the femoral neck. Tim Spector, MD, MSc, FRCP, Consultant Rheumatologist, Twin Research and Genetic Epidemiology Unit, St. Thomas' Hospital, and Professor in Genetic Epidemiology, King's College London, London, United Kingdom; Brent Richards, Twin Research and Genetic Epidemiology Unit, King's College London; and colleagues from the Wellcome Trust Sanger Institute, Cambridge, United Kingdom, and from Rotterdam, Netherlands, did a genome-wide association study of 2,094 female twins* and identified the most promising single nucleotide polymorphisms (SNPs) in their genes, from a total of 314,075 possibilities, which could be responsible for conferring a higher risk of osteoporosis. To confirm this supposition, investigators then tested these SNPs in 6,463 people from 3 other studies in Western Europe. They identified evidence for an association between BMD and two SNPs -- in chromosomes 8 and 11. In chromosome 11, the SNP was on the LRP5 (lipoprotein-receptor-related protein) gene, and a variant SNP here was associated with decreased BMD and a 30% increased risk of both osteoporosis and osteoporotic fractures. In chromosome 8, the SNP was close to the TNFRSF11B (osteoprotegerin) gene, and a variant here was found to decrease BMD and increase the risk of osteoporosis by 20%. In the 22% of people who carried both of these risk alleles, the risk of osteoporotic fractures was increased by 30%. And this effect was independent of BMD. Both these genes are important targets for bone therapies, and drugs are already in development. The authors say, "These alleles can be measured with near-perfect precision and without bias years before the age at which fractures tend to occur, which could provide ample lead time for preventive measures. Eventually, a panel of genetic markers could be used in addition to environmental risk factors to identify individuals who are most at risk for osteoporotic fractures." They conclude, "We have identified genetic variants that decrease bone mineral density and predispose people to osteoporosis and osteoporotic fracture. The increase risk of osteoporotic fracture in people who had both risk alleles was independent of the affect of these alleles on BMD. … The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental factors, and they are present in more than 1 in 5 white people, suggesting a potential role in screening." In an accompanying editorial, Joseph Zmuda, PhD, Assistant Professor, Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, and Candace Kammerer, PhD, Associate Professor, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, describe the report as an important step forward toward understanding the genetic basis of osteoporosis. They say that follow-up studies are necessary to identify the genetic mechanisms involved, and, since the paper focuses on mostly white women of European descent, studies of the effects of these 2 SNPs will need to be done in other populations. *The population studied was white European because North European whites are the highest risk group in the world for fractures, especially females. Also, for genetic studies to discover genes, it is necessary to use homogenous, similar populations.
SOURCE: The Lancet
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