Genome-wide analysis of creatine kinase levels in statin-users. M. P. Dubé1-3, R. Zetler1-3, Y. Feroz Zada1,3, V. Normand1,3, I. Mongrain1,3, N. Laplante1, A. Barhdadi1,3, G. Asselin1,3, S. Provost1,3, J. D. Rioux1,2, S. deDenus1-3, E. Kritikou1,2, J. Turgeon2,4, M. S. Phillips1-3, J. C. Tardif1-3 1) Montreal Heart Institute, Montreal, QC, Canada; 2) Université de Montréal, Montreal, QC, Canada; 3) Beaulieu Saucier Pharmacogenomics Centre, Montreal, QC, Canada; 4) Centre de recherche du CHUM Hôtel-Dieu, Montreal, QC, Canada.
Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid lowering drugs used in the treatment and prevention of cardiovascular disease. Despite their benefits, statins are associated with muscle-related adverse effects. Approximately 10% of statin-users report symptoms of myopathy including myalgia without abnormal creatine kinase (CK) elevation and myositis with CK elevation. In order to better understand the predisposing genetic factors to statin-induced myalgia, we conducted a case-control association study of 4600 statins-users, half present myalgia and half without. We found that patients with ongoing muscle pain presented with slightly higher plasma CK levels (P=9.9x10-5), despite the fact that the majority of CK values were within the normal clinical range. To follow on this observation, we did a genome-wide study of on-statin CK levels as secondary phenotype analysis. We included 3412 patients on statin at the time of recruitment into the case-control myalgia study. Recruitment proceeded from 9 clinical care centres throughout the province in Quebec, Canada. Genotyping was performed by using the Illumina Human610-Quad BeadChip and an iSelect panel enriched for genes of lipid homeostasis, statin pharmacokinetics and pharmacodynamics, and general drug metabolism. We found a strong association signal between plasma levels of CK and the muscle CK gene (CKM) (P=5.0x10-16) and with the LILRB5 gene (P=2.6x10-11) which is located 9Mb downstream of CKM. Genetic variants at those two genes were shown to be independently associated to CK levels in statin users. Results were successfully replicated in a cohort including 4000 statin users and 1500 non-users from the Montreal Heart Institute hospital cohort and genotyped with the ExomeChip (CKM: P=7.6x10-16; LILRB5: P=3.5x10-13). The genetic factors alone were shown to explain 1.5% and 2% of the variability in CK values in statin users and non-statin users respectively. A predictive model including genetic factors plus known clinical factors contributing to CK variability could explain over 10% of the variability in CK values. This is the first genome-wide study to report on the underlying genetic determinants of CK, a widely used biomarker of statin-induced myotoxicity.
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