From: Reuters
Published April 29, 2008 06:02 PM

Multiple gene locations linked to bone density

NEW YORK (Reuters Health) - Two studies released Tuesday report the identification of several genetic mutations that influence the risk of developing the bone-thinning disease osteoporosis and fracturing a bone.

In a study of three populations of European descent, researchers reporting in The New England Journal of Medicine identified five common sequence mutations that are associated with bone mineral density and with the risk of low-trauma fractures, while in The Lancet, two more gene mutations are identified that appear to raise the risk of osteoporosis and related fractures.

Dr. Kari Stefansson, from deCODE Genetics in Reykjavik, Iceland, and colleagues began by looking for associations between 301,019 gene mutations and bone mineral densities of the hip and lower spine in 5,861 Icelandic subjects. Seventy-four variants identified in this group were then tested for an association in 4,165 additional Icelandic subjects as well as in 2,269 Danish individuals and 1,491 Australian subjects.

Gene mutations in five genetic regions were linked to bone mineral density in the initial study group and confirmed in the Danish and Australian groups.


Three of the implicated regions are near genes known to play a key role in the biologic characteristics of bone. Three other genetic regions were linked with osteoporotic fractures, the researchers point out.

"The (mutations) that we have identified provide insights into the biologic pathways that influence osteoporosis. Some of them are common in the population and therefore have a greater influence on population attributable risk than would otherwise be the case," the team states.

Meanwhile, Dr. T. D. Spector, from St. Thomas' Hospital in London, and colleagues conducted a genome-wide association study looking at 314,075 variants in 2,094 women. Mutations with a possible link to osteoporosis and fracture were then tested in 6,463 people from three western European groups.

Like Stefansson's team, Spector's group identified a genetic variation near the "osteoprotegerin" gene (which regulates bone metabolism) that increased the risk of osteoporosis and osteoporotic fracture. In addition, they discovered a variant on chromosome 11 in the lipoprotein-receptor-related protein gene that had a similar effect.

Together, the impact of these risk mutations on fractures is comparable to that of most well-studied environmental risk factors, the authors note. Moreover, they add, screening for these genes may be fruitful since it is estimated that more than one in five whites carry them.

In a related editorial, Dr. Joseph M. Zmuda and Dr. Candace M. Kammerer, from the University of Pittsburgh, comment that while genome-wide association studies can be "very informative," other types of research, like osteoprotegerin expression studies, are needed to determine how the variants actually cause osteoporosis.

Still, the editorialists call the study by Spector's team "an important step osteoporosis toward understanding the genetic basis of osteoporosis."

SOURCE: The New England Journal of Medicine, April 30, 2008; The Lancet April 29, 2008.

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