Common sequence variants in pharmacodynamic and pharmacokinetic pathway-related genes conferring LDL cholesterol response to statins

Abstract

Aims: This study assessed the association between pharmacokinetic- and pharmacodynamic-related genes and individual responses to low-density lipoprotein cholesterol (LDL-C) change by statins in a Chinese population. Materials & methods: A total of 386 patients with primary hypercholesterolemia were treated with statins for 9 months. The 62 haplotype-tagging SNPs of ten candidate genes were genotyped. Treating LDL-C reduction as an outcome variable, we performed multiple linear regression models in various modes of inheritance to test the effects of SNP and haplotype variants. Results: After correction for the multiple tests, only rs12916 in HMGCR and rs9902941 in SREBF1 remained significant. For rs12916 in the HMGCR gene, individuals with CC genotype showed a reduction of 56.9 mg/dl for LDL-C, with the reduction increasing to 60.1 and 62.5 mg/dl among individuals carrying CT and TT, respectively (p-value for additive model = 0.006). For the HMGCR gene, subjects carrying the CCGTCCA haplotype had a significant increase of LDL-C (adjusted mean -7.2 ± 2.3 mg/dl; p-value for global test = 0.002). For the ABCG8 gene, subjects carrying the ATTATCGAC haplotype had a significant reduction of LDL-C (adjusted mean -13.0 ± 4.6 mg/dl; p-value for global test = 0.005). Conclusion: Our results indicated a strong association of sequence variants of HMGCR, SREBF1 and ABCG8 genes with the reduction of LDL-C after statin treatment in a Chinese population. Future studies on the genes of drug-metabolism enzymes and transporters are warranted.