Many people think of osteoarthritis as a kind of wear-and-tear disease, but theres clearly a genetic component at work here as well.

The researchers were studying a gene called GDF5 that Kingsleys laboratory first linked to skeletal growth in the early 1990s. GDF5 is involved in bone growth and joint formation, and mutations in the coding portion of the gene have been shown to cause malformations in leg-bone structure in mice. In humans, GDF5 mutations are associated with shorter stature and joint problems; in particular, two nucleotide changes immediately upstream of the gene have been strongly associated with a 1.2- to 1.8-fold increase in the risk of osteoarthritis.

In the new study, the researchers were interested in learning more about how the DNA sequences surrounding GDF5 might affect the genes expression. Often, these noncoding sequences contain key regulatory regions known as promoters and enhancers. Capellini, Chen and Cao were able to identify a previously unknown enhancer region they termed GROW1, which is several thousand nucleotides downstream of GDF5.

When the researchers analyzed the sequence of GROW1 in the 1,000 Genomes Project database, which collects and compares sequences from many human populations around the globe, they identified a single nucleotide change that is highly prevalent in Europeans and Asians but that rarely occurs in Africans. When they introduced this nucleotide change into laboratory mice, they found that it decreased the activity of GDF5 in the growth plates of the long bones of fetal mice.

Further research showed that this nucleotide change has been repeatedly favored during human evolution. Modern humans migrated from Africa between 50,000 and 100,000 years ago. But they werent the first to leave the continent. Neanderthals and Denisovans moved north into Europe and Asia about 600,000 years ago. Interestingly, the researchers found that the same GROW1 variant was found in the DNA of both ancient and modern humans in Europe and Asia.

However, theres a dark side to this stocky, hardy body type: The GDF5 variant that reduces bone length comes hand-in-hand with the two upstream nucleotide changes known to confer an increased risk for osteoarthritis.

Its clear that the genetic machinery around a gene can have a dramatic impact on how it works, said Capellini. The variant that decreases height is lowering the activity ofGDF5in the growth plates of the bone. Interestingly, the region that harbors this variant is closely linked to other mutations that affect GDF5 activity in the joints, increasing the risk of osteoarthritis in the knee and hip.

The potential medical impact of the finding is very interesting because so many people are affected, said Kingsley. This is an incredibly prevalent, and ancient, variant. Many people think of osteoarthritis as a kind of wear-and-tear disease, but theres clearly a genetic component at work here as well. Now weve shown that positive evolutionary selection has given rise to one of the most common height variants and arthritis risk factors known in human populations.

A researcher from the University of Waterloo in Ontario, Canada, also contributed to the study.

The research was supported by the National Sciences and Engineering Research Council of Canada, the Arthritis Foundation, the National Institutes of Health (grant AR42236), the Howard Hughes Medical Institute, the Milton Fund of Harvard, the China Scholarship Council and the Jason S. Bailey Fund of Harvard.

Stanfords Department of Developmental Biology also supported the work.

Originally posted here:
In northern humans, evolution favored shorter bones but with a painful trade-off - Stanford Medical Center Report