A collaborative study by Gualberto Ruano, M.D., Ph.D. of Genomas Inc. and Paul Thompson, M.D., of Hartford Hospital and collaborators at University of California San Francisco and Yale have demonstrated a strong association between serum creatine kinase (CK) activity during statin treatment and variability in genes related to vascular function.
The study, published in the December issue of Pharmacogenomics suggests that vascular smooth muscle function may contribute to the muscle side effects of statins.
Statins are effective at reducing coronary disease risk and are currently the most prescribed drugs in the USA. The main side effects are a variety of skeletal muscle complaints ranging from mild myalgia to frank rhabdomyolysis.
Muscle breakdown leads to elevated levels of CK in the blood. Hence, serum CK levels can be used as a clinical indicator of the extent of muscle damage.
To search for physiologic factors possibly influencing statin muscle injury, the team examined the relationship between genes affecting vascular function and serum CK activity in 102 patients on statin therapy from Hartford Hospital in Connecticut, USA.
Physiogenomic analysis of 10 vascular genes and a cross section of serum CK levels in these patients suggested that genetic variants in certain genes are significantly associated with CK activity in patients on statin therapy.
The endothelium regulates vascular tone through the release of vasoactive substances, such as angiotensin II and nitric oxide.
Angiotensin II stimulates a variety of pro-atherogenic responses, such as expression of adhesion molecules, platelet aggregation, thrombosis and cell migration.
The scientists included its receptor, AGTR1 in the survey, and found it to demonstrate significant genetic association to serum CK activity.
Nitric oxide, an important vasodilator, is generated by endothelial nitric oxide synthase (NOS3). NOS3 was the second ranking gene in the survey, and also significantly associated with serum CK activity.
Gualberto Ruano, M.D., Ph.D., President, Genomas and Director of Genetics Research, Hartford Hospital, stated, "The link between statins and vascular smooth muscle is the first published application of Genomas’ physiogenomics technology."
"The findings represent a powerful demonstration of new mechanistic insight that can pave the way for individualized management of cardiovascular disease with DNA arrays."
Paul D. Thompson, M.D., Director of Preventive Cardiology, Hartford Hospital, and Professor of Medicine, University of Connecticut, commented, "These results are intriguing and suggest that statins may affect skeletal muscle by a totally unexplored pathway."
"We will be undertaking the required clinical validation in other cohorts as the next step in this research."