Determinants of hsCRP levels in Chinese patients treated with rosuvastatin

Abstract

Instruction: Convincing evidence supports that inflammation plays a pivotal role in the formation and activation of atherosclerotic plaques in all phases of their development. CRP has been proven to be a strong and independent risk factor for various cardiovascular endpoints in prospective cohort studies. Rosuvastatin was shown to prevent vascular events in apparently healthy subjects with elevated hsCRP. We examined which genotypic and phenotypic factors might influence hsCRP levels in patients on rosuvastatin treatment. Methods: Concentrations of hsCRP were measured using a high-sensitive immunonephelometric method in Chinese patients with increased risk of cardiovascular disease (CVD) who had been treated with rosuvastatin 10 mg daily for at least 4 weeks. A total of 15 single nucleotide polymorphisms (SNPs) in 9 candidate genes/loci potentially related to the pharmacokinetics of rosuvastatin and metabolic or inflammatory regulation were genotyped, including CYP2C19, ABCG2, SLCO1B1 CRP, HNF1A, LEPR, APOE, APOE-APOC cluster, and ABCA1. Results: In 284 patients with hsCRP levels less than 10.0 mg/L, (including 145 with familial hypercholesterolaemia and 71 with diabetes) advanced age, female gender, high body mass index (BMI), high triglycerides but low HDL-cholesterol on-treatment levels were significantly associated with increased hsCRP levels, whereas the LDL-cholesterol on-treatment level was not related to hsCRP levels. Three SNPs (rs1169288, I27L in HNF1 (alpha); rs1205 3872G>A and rs2808630, 5237A>G in CRP) were found to be independently associated with hsCRP levels before and after adjustment for other clinical variables. The association between hsCRP concentrations and rs1205 in CRP was still significant after correction for multiple testing (P=1 null 10-6). Subjects carrying one or two copies of variant alleles in CRP or HNF1A had reduced CRP levels compared to those with wild-type alleles in a gene-dose dependent manner. In multiple regression analysis, these genotypic and phenotypic factors totally explained 34% of the variance in plasma hsCRP concentrations. Conclusions: Genetic variations within the CRP locus and another gene related to its regulatory pathway together with some conventional environmental factors were associated with hsCRP levels in Chinese patients who were receiving potent statin treatment.