Medicine Lessons and articles

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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