Physiogenomics study suggests vascular smooth muscle statin link

Main Category: Cardiovascular / Cardiology
Article Date: 27 Nov 2005 - 0:00 PDT

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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 has 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 Pharmacogenomics1 suggests that vascular smooth muscle function may contribute to the muscle side effects of statins.

Statins are highly 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.

Physiogenomics - a medical application of sensitivity analysis - utilizes as input the variability of genes, measured by single nucleotide polymorphisms (SNPs) and determines how the SNP frequency among individuals relates to the variability in physiological characteristics the output. Using this approach, genetic associations to a phenotype are used to suggest possible physiological mechanisms underlying it.

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 highly 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 the most significant genetic association to serum CK activity. Nitric oxide, the most important vasodilator, is generated by endothelial nitric oxide synthase (NOS3). NOS3 was the second ranking gene in the survey, and also very significantly associated with serum CK activity.

Gualberto Ruaño, 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."

Until now, most of the muscular effects of statins had been ascribed to skeletal muscle, as suggested by clinical manifestations of myalgia, and by histopathology of muscle biopsies. However, these study results relate CK activity during statin therapy to genes affecting vascular smooth muscle and raise the possibility that statins may affect smooth muscle via alterations in vascular function.

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References
1. Physiogenomic analysis links serum creatine kinase activities during statin therapy to vascular smooth muscle homeostasis, Ruano G, Thompson PD, Holford TR, Wu AHB, et. al, Pharmacogenomics (2005), Vol. 6, No. 8 (December)

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Genomas Inc. is a biomedical company advancing personalized health with revolutionary diagnostic PHYSIOTYPE™ systems to treat metabolic conditions induced by drugs and by obesity in cardiovascular and psychiatric medicine. PHYSIOTYPE systems provide physicians with the unprecedented capability to prescribe personalized drug treatments avoiding side effects and to recommend highly effective preventive exercise and diet programs for each patient. Genomas is located in Hartford, CT on the campus of Hartford Hospital with which it has established a research and development partnership in personalized medicine. For more information please access http://www.genomas.net

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