Marie-Pierre Dubé1, Rosa Zetler2, Amina Barhdadi2, Andrew M K Brown2, Ian Mongrain2, Valérie Normand2, Nathalie Laplante2, Géraldine Asselin2, Yassamin Feroz Zada2, Sylvie Provost2, Jean Bergeron2, Simon Kouz2, Robert Dufour2, Ariel Diaz2, Simon de Denus2, Jacques Turgeon2, Eric Rhéaume2, Michael S Phillips2, Jean-Claude Tardif1. 1. From the Montreal Heart Institute, Montreal, Quebec, Canada (M.-P.D., R.Z., A.B., A.M.K.B., I.M., V.N., N.L., G.A., Y.F.Z., S.P., S.d.D., E.R., M.S.P., J.-C.T.); Université de Montréal, Montreal, Quebec, Canada (M.-P.D., R.Z., A.B., R.D., S.d.D., J.T., E.R., M.S.P., J.-C.T.); Beaulieu-Saucier Pharmacogenomics Centre, Montreal, Quebec, Canada (M.-P.D., R.Z., A.B., I.M., A.M.K.B. V.N., G.A., Y.F.Z., S.P., S.d.D., M.S.P., J.-C.T.); Centre Hospitalier du CHU de Québec, Quebec city, Quebec, Canada (J.B.); Centre Hospitalier Régional de Lanaudière, Saint-Charles-Borromée, Quebec, Canada (S.K.); Institut de recherches cliniques de Montréal, Montreal, Quebec, Canada (R.D.); Centre de Santé et de Services Sociaux de Trois-Rivieères, Centre Hospitalier Affilié Universitaire Régional, Trois-Rivières, Quebec, Canada (A.D.); and Centre de recherche du CHUM, Montreal, Quebec, Canada (J.T.). jean-claude.tardif@icm-mhi.org marie-pierre.dube@umontreal.ca. 2. From the Montreal Heart Institute, Montreal, Quebec, Canada (M.-P.D., R.Z., A.B., A.M.K.B., I.M., V.N., N.L., G.A., Y.F.Z., S.P., S.d.D., E.R., M.S.P., J.-C.T.); Université de Montréal, Montreal, Quebec, Canada (M.-P.D., R.Z., A.B., R.D., S.d.D., J.T., E.R., M.S.P., J.-C.T.); Beaulieu-Saucier Pharmacogenomics Centre, Montreal, Quebec, Canada (M.-P.D., R.Z., A.B., I.M., A.M.K.B. V.N., G.A., Y.F.Z., S.P., S.d.D., M.S.P., J.-C.T.); Centre Hospitalier du CHU de Québec, Quebec city, Quebec, Canada (J.B.); Centre Hospitalier Régional de Lanaudière, Saint-Charles-Borromée, Quebec, Canada (S.K.); Institut de recherches cliniques de Montréal, Montreal, Quebec, Canada (R.D.); Centre de Santé et de Services Sociaux de Trois-Rivieères, Centre Hospitalier Affilié Universitaire Régional, Trois-Rivières, Quebec, Canada (A.D.); and Centre de recherche du CHUM, Montreal, Quebec, Canada (J.T.).
Abstract
BACKGROUND: Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs for the treatment and prevention of cardiovascular disease. Creatine kinase (CK) is a commonly used biomarker to assist in the diagnosis of statin-induced myotoxicity but the normal range of CK concentrations is wide, which limits its use as a diagnostic biomarker. METHODS AND RESULTS: We conducted a genome-wide association study of serum CK levels in 3412 statin users. Patients were recruited in Quebec, Canada, and genotyped on Illumina Human610-Quad and an iSelect panel enriched for lipid homeostasis, hypertension, and drug metabolism genes. We found a strong association signal between serum levels of CK and the muscle CK (CKM) gene (rs11559024: P=3.69×10(-16); R(2)=0.02) and with the leukocyte immunoglobulin-like receptor subfamily B member 5 (LILRB5) gene (rs2361797: P=1.96×10(-10); R(2)=0.01). Genetic variants in those 2 genes were independently associated with CK levels in statin users. Results were successfully replicated in 5330 participants from the Montreal Heart Institute Biobank in statin users for CKM (rs11559024: P=4.32×10(-16); R(2)=0.02) and LILRB5 (rs12975366 P=4.45×10(-10); R(2)=0.01) and statin nonusers (P=4.08×10(-7), R(2)=0.01; P=3.17×10(-9), R(2)=0.02, respectively). CONCLUSIONS: This is the first genome-wide study to report on the underlying genetic determinants of CK variation in a population of statin users. We found statistically significant association for variants in the CKM and LILRB5 genes.
BACKGROUND: Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs for the treatment and prevention of cardiovascular disease. Creatine kinase (CK) is a commonly used biomarker to assist in the diagnosis of statin-induced myotoxicity but the normal range of CK concentrations is wide, which limits its use as a diagnostic biomarker. METHODS AND RESULTS: We conducted a genome-wide association study of serum CK levels in 3412 statin users. Patients were recruited in Quebec, Canada, and genotyped on Illumina Human610-Quad and an iSelect panel enriched for lipid homeostasis, hypertension, and drug metabolism genes. We found a strong association signal between serum levels of CK and the muscle CK (CKM) gene (rs11559024: P=3.69×10(-16); R(2)=0.02) and with the leukocyte immunoglobulin-like receptor subfamily B member 5 (LILRB5) gene (rs2361797: P=1.96×10(-10); R(2)=0.01). Genetic variants in those 2 genes were independently associated with CK levels in statin users. Results were successfully replicated in 5330 participants from the Montreal Heart Institute Biobank in statin users for CKM (rs11559024: P=4.32×10(-16); R(2)=0.02) and LILRB5 (rs12975366 P=4.45×10(-10); R(2)=0.01) and statin nonusers (P=4.08×10(-7), R(2)=0.01; P=3.17×10(-9), R(2)=0.02, respectively). CONCLUSIONS: This is the first genome-wide study to report on the underlying genetic determinants of CK variation in a population of statin users. We found statistically significant association for variants in the CKM and LILRB5 genes.
Authors: Liam R Brunham; Steven Baker; Andrew Mammen; G B John Mancini; Robert S Rosenson Journal: Cardiovasc Res Date: 2018-07-01 Impact factor: 10.787
Authors: William A Murphy; Nan Lin; Amy Damask; Gregory G Schwartz; P Gabriel Steg; Michael Szarek; Poulabi Banerjee; Sergio Fazio; Garen Manvelian; Robert Pordy; Alan R Shuldiner; Charles Paulding Journal: Circ Genom Precis Med Date: 2022-05-11
Authors: Moneeza K Siddiqui; Cyrielle Maroteau; Abirami Veluchamy; Aleksi Tornio; Roger Tavendale; Fiona Carr; Ngu-Uma Abelega; Dan Carr; Katyrzyna Bloch; Par Hallberg; Qun-Ying Yue; Ewan R Pearson; Helen M Colhoun; Andrew D Morris; Eleanor Dow; Jacob George; Munir Pirmohamed; Paul M Ridker; Alex S F Doney; Ana Alfirevic; Mia Wadelius; Anke-Hilse Maitland-van der Zee; Daniel I Chasman; Colin N A Palmer Journal: Eur Heart J Date: 2017-12-21 Impact factor: 35.855