Dubé Marie-Pierre, Zetler Rosa, Barhdadi Amina, Brown Andrew M K, Mongrain Ian, Normand Valérie, Laplante Nathalie, Asselin Géraldine, Zada Yassamin Feroz, Provost Sylvie, Bergeron Jean, Kouz Simon, Dufour Robert, Diaz Ariel, de Denus Simon, Turgeon Jacques, Rhéaume Eric, Phillips Michael S, Tardif Jean-Claude
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.).
Circ Cardiovasc Genet. 2014 Dec;7(6):880-6. doi: 10.1161/CIRCGENETICS.113.000395. Epub 2014 Sep 11.
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.
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).
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.
他汀类药物（HMG-CoA还原酶抑制剂）是治疗和预防心血管疾病时处方最多的一类降脂药物。肌酸激酶（CK）是一种常用的生物标志物，有助于诊断他汀类药物引起的肌毒性，但CK浓度的正常范围较宽，这限制了其作为诊断生物标志物的应用。
我们对3412名服用他汀类药物的患者进行了血清CK水平的全基因组关联研究。患者在加拿大魁北克招募，并在Illumina Human610-Quad以及一个富集脂质稳态、高血压和药物代谢基因的iSelect芯片上进行基因分型。我们发现血清CK水平与肌肉型CK（CKM）基因（rs11559024：P=3.69×10⁻¹⁶；R²=0.02）以及白细胞免疫球蛋白样受体B5（LILRB5）基因（rs2361797：P=1.96×10⁻¹⁰；R²=0.01）之间存在强烈的关联信号。这两个基因中的遗传变异与服用他汀类药物患者的CK水平独立相关。结果在来自蒙特利尔心脏研究所生物样本库的5330名服用他汀类药物的参与者中成功复制，CKM基因（rs11559024：P=4.32×10⁻¹⁶；R²=0.02）和LILRB5基因（rs12975366 P=4.45×10⁻¹⁰；R²=0.01），在未服用他汀类药物的参与者中也得到复制（分别为P=4.08×10⁻⁷，R²=0.01；P=3.17×10⁻⁹，R²=0.02）。
这是第一项在服用他汀类药物人群中报告CK变异潜在遗传决定因素的全基因组研究。我们发现CKM和LILRB5基因变异具有统计学意义的关联。
