New genes for osteoporosis may help guide treatment

yahoo.com ^ | Apr 29, 2008 | Michael Kahn and Maggie Fox

[neverdem]

Researchers looking for genes that raise the risk of osteoporosis found seven different sequences associated with the bone-thinning disease, and one team found two that might predict the risk for 20 percent of people.

The studies, published in the New England Journal of Medicine and the Lancet on Tuesday, may also shed light into how osteoporosis develops.

A British team identified two small mutations called SNPs -- single-letter changes in the DNA code -- that predicted thinning bones.

They scanned the genes of 2,094 female twins and identified a link between decreased bone mineral density and changes in genes on chromosomes 8 and 11.

One change raised the risk 30 percent and the other conferred a 20 percent higher risk.

"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," Tim Spector and Brent Richards, researchers at King's College London wrote in their report in the Lancet.

The two genes are important target for treatments, and drugs are already under development, Spector's team said.

"These (genes) can be measured with near perfection and without bias years before the age at which fractures tend to occur -- which could provide ample lead-time for preventative measures," they wrote.

Osteoporosis affects about one in three women and one in five men globally, according to the International Osteoporosis Foundation. Up to 40 percent of women past menopause develop the disease.

Drugs called bisphosphonates can increase bone mass and cut the risk of fractures in patients with osteoporosis. Exercise, a diet rich in calcium and vitamin D and having thicker bones lowers the risk.

For the New England Journal of Medicine study, a team led by Iceland-based Decode Genetics studied 5,800 Icelanders, and compared them to about 8,000 other people in Iceland, Denmark and Australia.

Every volunteer had bone density x-rays and other tests and were asked if they had ever had a fracture.

The researchers found genetic variations in five areas that were associated with bone strength.

"Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone," they wrote. They said the study provided more information on the biology underlying osteoporosis than any value to any one person.

(Reporting by Michael Kahn and Maggie Fox)

[neverdem]

Here's the title and abstract. The link is to a pdf of the article.

Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study

Summary
Background 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.

Methods
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.

Findings
We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10−). 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 mineral density (rs3736228, p=6·3×10− for lumbar spine and p=1·9×10− for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09–1·52, p=0∙002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10− for lumbar spine and p=3·3×10− for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10−). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10−). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density.

Interpretation
Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.

Multiple Genetic Loci for Bone Mineral Density and Fractures

Bona Fide Genetic Associations with Bone Mineral Density

The last two are HTML Freebies from the NEJM. P.S. I hate copying from pdf's.