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.

KEYWORDS::

• candidate genes
• cholesterol
• low-density lipoprotein
• statins

Acknowledgements

The authors express their thanks to the patients who participated in this study and Mr Che-Tsung Wu‘s technical support in laboratory work.

Financial & competing interests disclosure

The study was supported by the Department of Health, Taiwan (DOH 96D047). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The study was supported by the Department of Health, Taiwan (DOH 96D047). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.