Study Identifies Genes Which Increase Risk Of Osteoporosis And Confirms Potential For Screening

Main Category: Bones / Orthopaedics
Also Included In: Genetics
Article Date: 05 May 2008 - 3:00 PDT

email to a friend   printer friendly   view / write opinions   rate article

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 one in five 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 expenditure, 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.

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 did a genome-wide association study† 2094 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, they then tested these SNPs in 6463 people from three 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 variants (ie, had both 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 one in five white people, suggesting a potential role in screening."

In an accompanying Comment, Dr Joseph Zmuda, D and Dr Candace Kammerer, Graduate School of Public Health, University of Pittsburgh, PA, USA, 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 two SNPs will need to be done in other populations.

Article
"Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study."
JB Richards MD, F Rivadeneira MD, M Inouye MSc, TM Pastinen MD, N Soranzo PhD, SG Wilson PhD, T Andrew PhD, M Falchi PhD, R Gwilliam PhD, KR Ahmadi PhD, AM Valdes PhD, P Arp BSc, P Whittaker BSc, DJ Verlaan PhD, M Jhamai BSc, V Kumanduri MSc, M Moorhouse PhD, JB van Meurs PhD, Prof A Hofman MD, Prof HAP Pols MD, D Hart PhD, G Zhai PhD, BS Kato PhD, BH Mullin BSc, F Zhang PhD, P Deloukas PhD, Prof AG Uitterlinden PhD and Prof TD Spector MD
The Lancet 2008; 371:1505-1512 - DOI:10.1016/S0140-6736(08)60599-1
Click here to view the Summary online

Comment
"Snipping away at osteoporosis susceptibility"
Dr Joseph Zmuda, D and Dr Candace Kammerer
The Lancet - Vol. 371, Issue 9623, 3 May 2008, Pages 1479-1480
Click here to view Full Text (Login required)

www.thelancet.com