Two research groups independently reported Identifications of genetic variants associated with the loss of bone mineral density and the risk of osteoporosis.

by Michael Smith, North American Correspondent, MedPage Today

LONDON, April 29 — Identifications of genetic variants associated with the loss of bone mineral density and the risk of osteoporosis were reported independently today by two research groups.

In a study led by researchers here, published online in The Lancet, two common genetic variants were shown to increase the risk of osteoporosis — a finding that may open the door to early screening for the conditions.

And in a study from Iceland, published online in the New England Journal of Medicine, variants in eight regions of the genome were shown to be consistently associated with bone mineral density or the risk of fracture, or both.

Action Points

Action Explain to interested patients that osteoporosis is known to have a hereditary component but few convincing genetic links have been made to the disease.

Note that these studies — using genome-wide association scanning techniques — find regions of the genome that are associated with the risk of osteoporosis in one and with bone mineral density in the other.

Both studies used similar techniques — genome-wide association scanning — to look for single nucleotide polymorphisms (SNPs) that were associated with the conditions.

Only one SNP — found on chromosome eight — was identified in both studies.

The British study found that two SNPs, on chromosomes eight and 11, were significantly associated with an increased risk of osteoporosis both singly and together, according to Tim Spector, M.D., of St. Thomas’ Hospital, and colleagues.

The SNPs taken together also significantly increased the risk of osteoporotic fractures, Dr. Spector and colleagues wrote in The Lancet.

The variants can be “measured with near-perfect precision and without bias years before the age at which fractures tend to occur,” the researchers said.

Such early measurement “could provide ample lead-time for preventive measures,” they said.

Dr. Spector and colleagues analyzed more than 314,000 SNPs in a cohort of 2,094 women in a British twin study, looking for associations with osteoporosis and osteoporotic fractures.

Significant associations were then replicated in 6,463 women from three other cohorts in western Europe.

The analysis found:

One SNP, dubbed rs3736228, on chromosome 11 in the gene for low-density lipoprotein-receptor-related protein, which is involved in stimulating bone formation.

Three SNPs on chromosome eight near the gene for osteoprotegerin, which is involved in bone resorption. The researchers concentrated on the SNP most highly associated with osteoporosis, rs4355801.

The chromosome 11 SNP, rs3736228, was associated with a 30% increase in the risk of both osteoporosis and osteoporotic fractures. Both increases were significant, at P=0.002 and P=0.008, respectively.

Among the study participants, 28% had at least one copy of the risk allele at rs3736228.

The lead SNP on chromosome eight, rs4355801, was associated with a 20% increased risk of osteoporosis (significant at P=0.038) but not with the risk of osteoporotic fracture, the researchers found. (For the other two, rs6469792 and rs6469804, the researchers reported only their association with bone mineral density.)

At least one copy of the risk allele of rs4355801 was found in 79% of study participants.

Participants carrying at least one copy of each risk allele — 22% of the study population — had a 50% increased risk of osteoporosis, which was significant at P=0.0026, and a 29% increased risk of osteoporotic fractures (significant at P=0.014).

The study is “an important step toward understanding the genetic basis of osteoporosis,” according to Joseph Zmuda, Ph.D., and Candace Kammerer, Ph.D., both of the University of Pittsburgh, in an accompanying commentary.

However, they noted that more work remains to be done. Follow-up studies are needed to tease out the mechanisms behind the associations, they said.

Also, the study only included Caucasian women, and research in other ethnic and racial groups — as well as in men — will be needed to see if the associations hold up, they said.

They also said that “many more common variants for bone mineral density remain unidentified, and large studies will be needed to detect them.”

The Icelandic study, reported in the New England Journal of Medicine, focused on bone mineral density and — as suggested — found several common variants not seen in the British study.

The methods used were similar — identification of significant associations in 5,861 Icelandic volunteers, followed by replication in three cohorts totaling 7,925 participants.

The Icelandic study was looking at associations with bone mineral density and fracture risk, rather than osteoporosis, according to senior researcher Kari Stefansson, M.D., Ph.D., of DeCODE Genetics, and colleagues.

The analysis found SNPs in five regions were consistently associated with bone mineral density, three of them close to or within genes known to be important for bone. These are the receptor activator of nuclear factor-κB ligand gene (RANKL) on chromosome 13, the osteoprotegerin gene on chromosome eight, and the estrogen receptor 1 gene (ESR1) on chromosome six.

The other regions were near the zinc finger and BTB domain on chromosome 1 and the major histocompatibility complex region on chromosome 6, Dr. Stefansson said.

The researchers also found that the first three were associated with the risk of fractures, as were regions on chromosome 18, near the receptor activator of the nuclear factor-κB gene (RANK), and on chromosomes 2 and 11.

Unlike the British study, the findings are “not clinically useful in the prediction of risk to the individual person,” Dr. Stefansson and colleagues said.

But they added that the variants may be useful in teasing out the biochemical basis of osteoporosis.

The only SNP that was seen in both studies was rs6469804 on chromosome eight. In the British study, it was significantly associated, at P=6.7×10-6, with bone density in the lumbar spine.

In the Icelandic study, the SNP was significantly associated with bone mineral density at either the spine or the hip, at P=7.4×10−15.

The British-led study was supported by the Wellcome Trust, the European Commission, NWO Investments, the Arthritis Research Campaign, the Chronic Disease Research Foundation, the Canadian Institutes of Health Research, the European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Québec, the Canada Research Chairs, the National Health and Medical Research Council of Australia, and the European Union. The researchers said they had no conflicts of interest.

The Icelandic study was supported by DeCODE Genetics. Dr. Stefansson is chief executive officer of the company and holds equity in it. Drs. Zmuda and Kammerer said they had no conflicts.

Additional source: The Lancet

Source reference:

Richards JB, et al “Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study” Lancet 2008; DOI:10.1016/S0140-6736(08)60599-1.

Zmuda JM, Kammerer CM “Snipping away at osteoporosis susceptibility” Lancet 2008; DOI:10.1016/S0140-6736(08)60600-5.


Additional source: New England Journal of Medicine

Source reference:

Styrkarsdottir U, et al “Multiple genetic loci for bone mineral density and fractures” N Engl J Med 2008; 358: DOI: 10.1056/NEJMoa0801197.

Additional articles and resources on this topic:

Reviewed by Zalman S. Agus, MD; Emeritus Professor, University of Pennsylvania School of Medicine.

Published: April 29, 2008

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