Abstract 2131: Genome-wide Association Analysis of Creatine Kinase and Statin Response
Purpose: To identify genetic determinants of variation in plasma levels of creatine kinase (CK), an enzyme measured as a marker of muscle damage, and CK response to statin treatment.
Methods: Plasma CK, lipids and C-reactive protein levels were measured at baseline and after 8 wk treatment with simvastatin 40 mg/day in 575 Caucasian subjects in the Cholesterol/Atherosclerosis Pharmacogenetics Study. Genotyping was performed in 298 subjects using Illumina 317K beadchips and in the remaining subjects using Illumina 610K beadchips. Further imputation to ~2.5 million SNPs was peformed using BIMBAM v0.95. After excluding SNPs with minor allele frequency <0.05 and/or with poor imputation quality, ~2.1 million SNPs were available for the final analysis. Under the additive model, a linear model analysis (SNPTEST 1.15) was performed with log transformed CK values and adjustment for age and gender.
Results: For baseline CK, four SNPs (rs10821766 at 10q21.2, rs10892252 at 11q23.3, rs10994386 at 10q21.2 and rs4625500 at 11q13.5) reached genome-wide significance level (p=8.5×10−8, 4.0×10−7, 5.1×10−7, and 5.3×10−7). After 8-week statin treatment, mean CK increased by 6.7 ± 78.8 U/L (16.6% of baseline). This was significantly associated with reductions of plasma LDLC (p=0.009), triglyceride (p=0.003) and CRP (p=0.02). No SNP associations with CK response to simvastatin reached genome-wide significance, although 16 SNPs exhibited associations at of p<10−6 significance. Notably, SNP rs4363657 in the SLCO1B1 gene, which has been associated with both altered statin transport and simvastatin-associated myopathy, was not significantly associated with CK either at baseline or in response to simvastatin.
Conclusions: Using GWAS, we have identified four SNPs associated with variation in CK level, but none that were predictive of CK change with statin treatment at the genome-wide level of significance. In addition, we have shown that statin-induced increases in CK are associated with lipid and inflammatory biomarkers of statin response.