Comparative Mouse Genomics Centers Consortium (CMGCC): Mouse Models to Improve Understanding of the Biological Significance of Human Polymorphisms

Background: Statin-related skeletal muscle disorders range from benign myalgias – such as nonspecific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration – to true myositis with >10-fold elevation of serum CK, to rhabdomyolysis and myoglobinuria. The genetic basis of statin-related muscle disorders is largely unknown. Because mutations in the COQ2 gene are associated with severe inherited myopathy, we hypothesized that common, mild genetic variation in COQ2 would be associated with inter-individual variation in statin intolerance. We studied 133 subjects who developed myopathy on statin monotherapy and 158 matched controls who tolerated statins without incident or complaint. Results: COQ2 genotypes, based on two single nucleotide polymorphisms (SNP1 and SNP2) and a 2-SNP haplotype, all showed significant associations with statin intolerance. Specifically, the odds ratios (with 95% confidence intervals) for increased risk of statin intolerance among homozygotes for the rare alleles were 2.42 (0.99 to 5.89), 2.33 (1.13 to 4.81) and 2.58 (1.26 to 5.28) for SNP1 and SNP2 genotypes, and the 2-SNP haplotype, respectively. Conclusion: These preliminary pharmacogenetic results, if confirmed, are consistent with the idea that statin intolerance which is manifested primarily through muscle symptoms is associated with genomic variation in COQ2 and thus perhaps with the CoQ10 pathway. Background Large clinical trials over the past two decades have unequivocally established the benefit of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) inhibitors – or "statins" – in the primary and secondary prevention of coronary heart disease (CHD) [1]. Reduction of plasma low-density lipoprotein (LDL) cholesterol with statins has revolutionized clinical cardiology; this family of drugs is generally well-tolerated, easy to administer, and has very good patient acceptance. However, the potential for adverse effects exists. From clinical trials, the statin discontinuation rate due to adverse events ranges between 1 and 5% [1]. Frequently reported adverse effects include gastrointestinal complaints, rashes, dizziness, pruritus and headache [2]. Statin-related skeletal muscle disorders range from benign myalgias – such as non-specific muscle aches or joint pains without elevated serum creatinine kinase (CK) concentration – to true myositis with >10-fold elevation of serum CK [3]. The incidence of muscle aches and pains with statin monotherapy ranges from 1 to 7%, Published: 21 March 2007 Lipids in Health and Disease 2007, 6:7 doi:10.1186/1476-511X-6-7 Received: 5 February 2007 Accepted: 21 March 2007 This article is available from: http://www.lipidworld.com/content/6/1/7 © 2007 Oh et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.