Multiple strategies for examining genetic determinants of thrombosis are likely to explain clotting events mediated by a complex set of interactions that includes multiple genes and environmental factors, according to David Ginsburg, who delivered Wednesday’s Michael E. Nesheim Plenary Lecture.

This progress is important, he said, because none of the genes associated with blood clotting disorders and bleeding offer clinically meaningful accuracy in predicting thrombotic events by themselves.


David Ginsburg

This does not discount the importance of mutations, such as those involving factor V Leiden and the prothrombin gene mutation, which have been found to be highly significant risk factors for thromboembolism. Ginsburg, of the University of Michigan, Ann Arbor, U.S.A., pointed out that he is cautious about their clinical value if the goal is to identify tests that influence risk management.

“I would argue at this point that there really is no clear clinical indication for doing thrombophilia testing,” said Ginsburg, who is the James V. Neel Distinguished University Professor in the Departments of Internal Medicine, Human Genetics, and Pediatrics. He noted that several organizations, including the American Society of Hematology, have drawn the same conclusion.

Still, he added, “I am sure this is going to change,” noting “an explosion” of recent progress driven by a growing number of tools, such as genome-wide association studies (GWAS), genome sequencing in large groups of individuals, and mouse studies.

While describing progress in each of these areas, Ginsburg devoted considerable focus to the value of the mouse model. Although he cautioned that it cannot be assumed that genetic information from mice will translate to the clinic, the data are, at the very least, useful for understanding the principles of gene interactions and may help uncover mechanisms relevant to human disease.

In the mouse model, the technology for manipulating genes “is getting easier and easier, and, today, one can truly in a matter of months change any nucleotide in the mouse genome—introduce any mutation—that one would like to do. The power of this technology is truly astounding,” Ginsburg observed.

As an example, he recounted a series of studies conducted in his laboratory with mice engineered to have the factor V Leiden mutation. Complex and often painstaking studies to find other mutations that interact with the factor V Leiden mutation led to many successes, but failures were also instructive. In one case, isolation of an 8-pair deletion in the NBEAL2 gene appeared to be a potential breakthrough for identifying a mutation that blocks the pro-thrombotic activity of factor V Leiden. Instead, it turned out to be a mutation unrelated to the pro-thrombotic mouse model.

“When we traced the mutation back through the pedigree, we found that the mutation was present in a 129 mouse that we obtained from Jackson Labs,” Ginsburg reported. This, he said, was an “important cautionary tale,” emphasizing that spontaneous mutations can confound even the most careful studies.

“Every single mouse or human has on average 60 to 100 new mutations that were not present in either parent,” Ginsburg noted. Emphasizing the complexity of these studies, he noted that many of the associations in GWAS studies have not been confirmed in more detailed analyses. Indeed, he noted that “we can conclude with near certainty” that MTHFR mutations, which are sometimes included in laboratory screening for thrombotic risk, are not risk factors.

At last count, there were 3,412 genes associated with human diseases, including those responsible for bleeding and clotting, according to Ginsburg. Overall, about 50% to 60% of the risk of having a blood clot is attributable to inherited risk, Ginsburg added. Few diseases appear to be autosomal dominant disorders mediated by a single gene, which are called monogenic diseases. Rather, most are complex genetic diseases, a term referring to those “that involve many genes interacting in complex ways and with factors other than genes.”

This complexity was once overwhelming, but the series of rapid advances described by Ginsburg in streamlining genomic studies to provide complex data at relatively low cost is rapidly changing the landscape. Although the value of gene testing for considering clinical management, such as initiating anticoagulant therapy, has a limited role at present, Ginsburg foresees an evolution.

“I suspect that in the not too distant future, newborn screening is going to be performed by full genome sequencing so that we will have whole genome data on all our patients linked to medical records, and the potential for new discoveries is almost unimaginable,” Ginsburg said.


By Ted Bosworth |June 24, 2015