Genes Identified That Significantly Increase Risk Of Osteoporosis And Could Serve Potential Screening Function

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Main Category: Bones / Orthopaedics
Also Included In: Women's Health / Gynecology;  Genetics
Article Date: 29 Apr 2008 - 16:00 PDT

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Two genetic variants of important biological proteins have been singled out as increasing the risk of osteoporosis as well as resulting osteoporotic fractures. Additionally, these genetic variants have a high enough incidence in the population to potentially be screens for the disease. This was published in an article released on April 29, 2008 in The Lancet.

Osteoporosis is a bone disease characterized by an increased risk of fracture. Clinically, it is defined by measurement of bone mineral density (BMD,) and this measurement is the current standard for predicting osteoporotic fractures. Between osteoporosis and osteoporotic fractures, the global health burden is US$17 billion every year in direct expenditure. As it is a disorder that largely effects the elderly, this number is only expected to increase as populations age. Someone's BMD is highly heritable, with estimates as high as 78% heritability of the density of the lumbar spine, and 84% at the femoral neck.

To examine heritable characteristics of osteoporosis, Professor Tim Spector and Dr Brent Richards, Department of Twin Research and Genetic Epidemiology, King's College London, UK and colleagues from the Wellcome Trust Sanger Institute, UK, and Rotterdam performed a genome-wide association study of 2094 female twins and identified the most promising single nucleotide polymorphisms (SNPs). These were selected based on potential for responsibility for conferring a higher risk of osteoporosis from a set of 314,075 potential sites. To confirm, these SNPs were examined in 6463 people from three other studies in Western Europe.

There was evidence for an association between BMD and two different SNPs. The first, on chromosome 11, is on the lipoprotein-receptor-related protein (LRP5) gene, and is associated with a decreased BMD as well as a 30% incrased risk of osteoporosis and osteoporotic fractures. The second, on chromosome 8, is very close to the osteoprotegerin gene (TNFRSF11B) and was found to decrease BMD and increase the risk of osteoporosis by 20%.

Of the people tested, 22% had both of the risk alleles, and for this sub-group the risk of osteoporotic fractures was increased by 30%. This effect, notably, was independents of the person's BMD. Both of these genes are important targets for bone therapies, and drugs are already in development to capitalize on this association.

The authors note that this is a great tool to identify osteoporosis early and take preventative measures. "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, summarizing and pointing out the success of the study. "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 one in five white people, suggesting a potential role in screening."

Dr Joseph Zmuda, D and Dr Candace Kammerer, Graduate School of Public Health, University of Pittsburgh, PA, USA, contributed an accompanying Comment in which they describe this report as an important milestone moving toward understanding the genetic basis of osteoporosis. They point out that follow-up studies are now promising to identify the genetic mechanisms involved in the disease. Additionally, they mention that further study should be done in other populations, as this one focused on white women of European descent.

Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study
J B Richards, F Rivadeneira, M Inouye, T M Pastinen, N Soranzo, S G Wilson, T Andrew, M Falchi, R Gwilliam, K R Ahmadi, A M Valdes, P Arp, P Whittaker, D J Verlaan, M Jhamai, V Kumanduri, M Moorhouse, J B van Meurs, A Hofman, H A P Pols, D Hart, G Zhai, B S Kato, B H Mullin, F Zhang, P Deloukas, A G Uitterlinden, T D Spector
The Lancet, April 29, 2008
DOI:10.1016/S0140-6736(08)60599-1
Click Here For Abstract

Snipping away at osteoporosis susceptibility
Joseph M Zmuda, Candace M Kammerer
The Lancet, April 29, 2008
DOI:10.1016/S0140- 6736(08)60600-5
Click Here For Journal

Written by Anna Sophia McKenney
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