The scientists identified 207 extended families with multiple affected individuals and conducted a genome-wide linkage scan to look for genomic areas shared by family members with low BMD and osteoporotic fractures. They found significant linkage to the short arm of Chromosome 20, an area that contains six known genes, including four genes involved in bone formation and osteoblast (bone-forming cell) differentiation. To winnow the list of most likely candidate genes, Styrkársdóttir et al. screened the genomes of 705 individuals with osteoporosis in a case-control study, using closely spaced genetic markers within the region of interest. This analysis pointed to BMP2 as the most likely candidate--an enticing finding, because BMP2 (bone morphogenetic protein 2) is known to be involved in bone development.
Sequencing the BMP2 gene in 188 patients and 94 controls to look for variants that might confer predisposition to osteoporosis flagged several possible haplotypes (which were subsequently shown to be associated with osteoporosis in the larger cohort). These at-risk haplotypes, or versions of the BMP2 gene, were shown to approximately triple the likelihood of developing the disease. Furthermore, an independent replication study with two groups of postmenopausal Danish women--one group with low BMD and one with osteoporotic fractures--found comparable results, with a higher incidence of the BMP2 variants associated with osteoporosis in Iceland in the affected Danish women compared to the controls.
Taken together, these results make a strong case for genetic variations of BMP2 as risk factors for osteoporosis. The researchers hope their work will inspire others to replicate their results, to confirm and elucidate the role of this gene in osteoporosis. Understanding the mechanisms and signaling pathways of BMP2's effects could not only identify drug targets for osteoporosis therapies, but also, through the application of these findings to the development of DNA-based diagnostics, make it possible to catch those at high risk before they take that fateful fall.
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