In a significant discovery for the medical community, Asst. Medical Prof. Charles Farber has shown genetic variation in the gene Bicc1, which regulates bone mass. The discovery opens doors for future work in preventative diagnosis and treatment of osteoporosis — a bone disease which is estimated to affect 9.9 million Americans.
“Genetic variation both in mice and humans in the Bicc1 gene is associated with difference in bone mass,” Farber said. “Bone mass is a trait that is one of the strongest predictors of osteoporotic fracture.”
Osteoporosis causes a decrease in bone mass, which results in weaker bones more prone to breakage. Osteoporosis causes two million fractures, 2.5 million office visits, 432,000 hospital visits and 180,000 nursing home admissions annually. These numbers will only increase as the population ages, and researchers predict the cost of care for those with osteoporosis will rise to to $25.3 billion by 2025.
Among the healthy, human skeletons constantly remodel themselves, utilizing osteoclasts and osteoblast — both cell types — to respectively resorb or create bone material. As humans develop throughout childhood, the balance between building up and breaking down bone favors the creation of new bone. As humans age, however, the balance shifts toward the deterioration of bone, resulting in decreasing bone mass.
This tendency makes osteoporosis most common among the elderly. The hormonal changes in menopause make postmenopausal women especially vulnerable.
Despite the massive social and economic implications of the disease, its genetic mechanisms have eluded researchers thus far. As with many genetic studies, Farber began his approach using mice. His group crossed two inbred strains of mice — one possessing high bone mass and the other possessing low bone mass. The group then targeted regions of the mouse’s chromosomes associated with the difference between the two parental strains, intending to identify the genetic variation controlling the trait.
“Through that approach, we identified a region on chromosome 10, and then — after a considerable amount of work — we were able to whittle that down to the causal gene, being Bicc1,” Farber said.
The shared evolutionary ancestry of mice and humans offers a powerful route for genetic studies. Farber’s group analyzed an online database containing bone mineral density and genetic information of 32,000 individuals genotyped for 2.5 million single nucleotide polymorphisms (SNPs), or variants at a single DNA base position.
“What we did was to look specifically at those genetic differences that were located within the human Bicc1 gene, and then look to see if they were associated with bone mineral density across those 32,000 individuals,” Farber said. “That’s how we were able to show that both variation in the mouse and human Bicc1 genes were associated with bone mass.”
The SNPs in question occur in introns — non-coding portions of a gene which are spliced or removed, prior to translation of a gene into a protein — present in the middle of the Bicc1 gene. These SNPs result in non-coding variation, altering expression of the Bicc1 gene — and consequently influencing bone density in individuals.
“It’s that difference in expression that’s associated with fairly subtle changes in bone mass in the general population,” Farber said.
With few exceptions, every cell in the human body largely possesses identical genetic information. Differences in cell type and function result from differential patterns of gene expression.
“What we would like to do is figure out what specific cell type Bicc1 is active in,” Farber said. “We’re [now] generating some mouse models [for this].”
Now, Farber’s group will move its analysis of Bicc1 toward its effect on humans. Because numerous genes often collectively determine an individual’s phenotype, however, human genetic analysis typically proves difficult.
“We think there are probably hundreds if not thousands of genetics variants controlling different genes in different ways that [...] determine an individual’s bone mass and thus risk of osteoporotic fracture,” Farber said.
Even if Bicc1 is not the sole predictor of osteoporosis risk, its identification makes it an important addition to a growing catalogue.
“If we can identify enough of these predictors that have subtle effects, we can actually start to explain a more significant fraction of the variation in a trait like bone mineral density — and then that would have the potential to have predictive power,” Farber said.
Understanding the genetic root of a disease is the first step toward the development of targeted therapies.
“We’re very much interested in kind of teasing apart the genetics of osteoporosis with the ultimate goal that the genes we identify... can not only be predictors of disease, but they could also pinpoint therapeutic targets that we could intervene on and improve bone mass in individuals,” Farber said.
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