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HOB1 gene may be major cause of hereditary obesity, and diabetes link

SALT LAKE CITY, UTAH, Oct. 29, 2002 -- Myriad Genetics announced that it has discovered a novel gene that causes human obesity.

Myriad scientists, led by Drs. Steven Stone and Donna Shattuck and University of Utah collaborators Drs. Steven Hunt and Ted Adams, have named the gene HOB1, for Human Obesity 1, in recognition of its direct causal tie to obesity in humans.

The HOB1 gene is being described as a breakthrough discovery of an important gene for a complex genetic disorder. In addition, HOB1 appears to provide an important molecular link between obesity and diabetes.

Its discovery could be a necessary first step towards the development of novel therapeutics to treat a condition that, in moderate to severe forms, affects nearly one third of Americans.

The HOB1 gene is the first obesity gene discovered that is significantly involved in human obesity. Previous obesity-related genes have only been found to be an important cause of genetic obesity in mice or other animal models.

"The HOB1 gene appears to be powerful evidence of the role of heredity in the cause of obesity," said Donna Shattuck, Ph.D., Vice President of Metabolic Disease Research for Myriad Genetics, Inc. "The association with diabetes is also intriguing and sheds light on the known clinical association between the two disorders. The potential exists to address both conditions with a therapeutic development program based on HOB1."

Polygenic diseases such as obesity were thought to be prohibitively complex and unyielding to discovery by molecular techniques. With this discovery, Myriad says it has demonstrated that, using its proprietary technologies coupled with multi-generational Utah family pedigrees and medical databases, complex diseases with multiple contributing factors can be untangled and the causative elements identified.

The HOB1 gene's role in diabetes was demonstrated through Myriad's protein interaction and drug target discovery technologies, which have developed a diabetes disease pathway involving a network of over 300 human proteins. Myriad scientists discovered that the HOB1 gene was directly involved in the diabetes pathway and that it interacted with a key protein in the pathway.

Myriad has also identified structural and biological characteristics which have predicted functions that make this gene readily amenable to assay development for small-molecule drug discovery.

In addition, the HOB1 gene appears to be a highly druggable target, in part because the mutation in the gene that contributes to serious obesity appears to result in a gain of function rather than a loss of function. In drug development, it is generally far easier to block a drug target than to replace its lost function.

The HOB1 gene is in pharmaceutical development at Myriad. High-throughput screening assays for small molecule drugs are being developed. These assays will be run against Myriad's proprietary library of over 200,000 small molecular weight compounds.

Myriad says that recently introduced prescription medications intended to help individuals manage their weight have demonstrated limited efficacy and less than ideal tolerability. Similarly, despite a tremendous medical need, the pharmaceutical industry has enjoyed only limited success developing therapeutics to manage diabetes. The most common therapeutics, sulfonylureas, are not widely effective and the most promising new drugs, thiazolidinediones, have demonstrated rare but potentially fatal side effects. There is an urgent need for more comprehensive understanding and more effective therapies for these metabolic disorders.

As a predictive medicine product, HOB1 may also offer an opportunity to identify the genetic basis of an individual's obesity and to define the associated risk of developing type 2 diabetes. Such information may provide the grounds for prevention and differential treatment of affected individuals.

Source: Myriad Genetics

Posted: October 2002