Statin-induced muscle disorders are focus of $2.5 million in grants from NIH

Oct 2 2008

Approximately 200,000 of the 38 million people in the U.S. who take statins to treat high cholesterol may develop life-threatening muscle disease.

Currently there is no comprehensive way to identify those who may be at risk for this debilitating condition, but new research by University at Buffalo scientists may correct that situation.

Georgirene D. Vladutiu, Ph.D., professor of pediatrics, neurology, and pathology and anatomical sciences, heads a research group that has received three grants totaling $2.5 million to investigate the genetics behind these myopathies.

"The combined NIH-funded research projects will contribute to developing a better understanding of the risk factors associated with statin myopathy and its prevalence in the general population, will develop tools used in comprehensive genetic testing for muscle disease and contribute to the characterization of new genes associated with neurodegenerative disease and aging," stated Vladutiu.

The lead grant is a $2 million, five-year award to Vladutiu from the National Heart Lung and Blood Institute (NHLBI) to study the relationship between certain rare mutations, more common genetic variants and the development of myopathy triggered by statin therapy.

In addition, Paul J. Isackson, Ph.D., research associate professor of pediatrics in Vladutiu's laboratory, received $383,000 from the National Institute of Arthritis and Musculoskeletal and Skin Disorders to characterize the structure, function and expression of a novel gene associated with statin myopathy.

The third grant, for $110,000 from the NHLBI, funds a Phase I Small Business Technology Transfer (STTR) project that will explore the technological feasibility of commercializing customized genotype technology (chip development) for variants implicated in muscle disease.

Vladutiu expects the results of this project to lead to launching a business that will use the chip technology to screen for individuals at high risk of developing metabolic muscle disease if exposed to one or more triggers. These triggers include extreme exertion, extreme temperatures, anesthesia, viral infection, fasting, sleep deprivation and taking statins and other medications. Groups who could benefit from such screening include the armed services, patients undergoing anesthesia, those prescribed statins and people in strenuous professions such as firefighters, police and professional athletes. The chip also could identify individuals who carry risks for as-yet-unidentified muscle myopathies.

Vladutiu's five-year statin myopathy project has dual aims.

"The first aim is to determine the prevalence of mutations known to cause metabolic muscle diseases in patients taking statins who developed serious muscle symptoms triggered by environmental stressors, such as exercise, fasting, exposure to extreme temperatures (both hot and cold) or anesthesia," said Vladutiu.

"The second aim is to identify clinically relevant associations between statin myopathies and common genetic variations in the human genome known as single nucleotide polymorphisms or SNPs," he said.

For the first aim, the investigators will use a customized genotyping technology that will allow them to expand their genetic screening studies from seven common mutations causing three disorders, to more than 380 mutations causing at least 10 disorders.

The genome-wide association studies, scanning more than 1 million SNPs across the entire human genome, will be performed on DNA samples from individuals with severe statin myopathy. The results will be compared with those of age- and gender-matched individuals who have no muscle side effects from statin therapy.

"Identifying underlying hereditary risk factors will lead to cost-effective screening of individuals who take statins, reduced illness and deaths caused by taking statins, and lower health-care costs," said Vladutiu.

Project collaborators include investigators at Johns Hopkins University School of Medicine in Baltimore; McMaster University Health Sciences Center in Ontario, Canada; Cedars-Sinai Medical Center in Los Angeles; the Medical College of Wisconsin in Milwaukee; Henry Ford Hospital in Detroit; Scripps Mercy Hospital in La Jolla, and William Beaumont Hospital in Ann Arbor.

Isackson is working with a novel gene he has named narexin for its similarities to two molecules known as notch and agrin. "Both of these molecules play critical roles in skeletal muscle formation, maintenance of integrity and regenerative potential," he said.

"The predicted functions and specific expression of the narexin gene in the spinal cord suggests it will have novel diagnostic and therapeutic applications to neuromuscular disease and skeletal muscle degeneration during aging."

The STTR grant requires partnering between an academic research laboratory and a small business with common interests - in this case JK Autoimmunity, Inc., in Oklahoma City. Kenneth Kaufman, Ph.D., who heads the firm, is principal investigator. Vladutiu applied for the grant and serves as the local principal investigator.

"The goal of this project is to develop comprehensive genetic-based testing for metabolic muscle diseases triggered by environmental exposures that are increasingly prevalent in the U.S. and Canada," said Vladutiu.

"We have identified at least seven high-risk groups that will benefit from genetic risk assessment," she said. "The proposed technology also will be very useful for the diagnosis of muscle disease in individuals referred to our clinical laboratory."

The Robert Guthrie Biochemical Genetics Laboratory, which Vladutiu directs, receives more than 700 muscle biopsies annually from across the United States and Canada for diagnostic studies. The laboratory, located in the Buffalo General Hospital, performs more than 5,000 biochemical and molecular tests per year on various blood and tissue specimens to diagnose inborn errors of metabolism.

The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system that is its largest and most comprehensive campus. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.