Multiple genetic loci linked to bone mineral density and fractures

NEW YORK (Reuters Health) - Two studies released Tuesday report the identification of several genetic variants that influence the risk of osteoporosis and fractures.

In a study of three populations of European descent, researchers reporting in the April 30th online issue of The New England Journal of Medicine identify five common sequence variants that are associated with bone mineral density (BMD) and with the risk of low-trauma fractures, while in a study in the April 29th online...

NEW YORK (Reuters Health) - Two studies released Tuesday report the identification of several genetic variants that influence the risk of osteoporosis and fractures.

In a study of three populations of European descent, researchers reporting in the April 30th online issue of The New England Journal of Medicine identify five common sequence variants that are associated with bone mineral density (BMD) and with the risk of low-trauma fractures, while in a study in the April 29th online issue of The Lancet, two more gene variants 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 single-nucleotide polymorphisms and BMD of the hip and lumbar spine in 5861 Icelandic subjects. Seventy-four variants identified in this cohort were then tested for an association in 4165 additional Icelandic subjects as well as in 2269 Danish individuals and 1491 Australian subjects.

Variants in five genomic regions were linked to BMD in the initial study group and confirmed in the validation groups.

Three of the implicated regions are near or within genes known to play a key role in the biologic characteristics of bone, including the RANKL (13q14), osteoprotegerin (8q24), and estrogen receptor 1 (6q25) genes. The two other regions are near the major histocompatibility complex region (6p21) and the zinc finger and BTB domain containing 40 gene (1p36).

The 8q24, 6p21, and 1p36 loci were also linked to osteoporotic fractures, the researchers point out.

"The variants 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 single nucleotide polymorphisms in 2094 women. Variants with a possible link to osteoporosis and fracture were then tested in 6463 people from three western European cohorts.

Like Dr. Stefansson's team, Dr. Spector's group identified a genetic variant near the osteoprotegerin gene 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 alleles on fractures is comparable to that of most well-studied environmental risk factors, the authors note. Moreover, they add, screening for these alleles may be fruitful since it is estimated that more than one in five white people 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 Dr. Spector's team "an important step toward understanding the genetic basis of osteoporosis."

N Engl J Med 2008;358.

Lancet 2008.