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


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).


CONCLUSIONS
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.
Chien
Kuo-Liong
KL
Institute of Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan. klchien@ntu.edu.tw
Wang
Kuei-Chen
KC
Chen
Yen-Ching
YC
Chao
Chia-Lung
CL
Hsu
Hsiu-Ching
HC
Chen
Ming-Fong
MF
Chen
Wei J
WJ
D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D008078:Cholesterol, LDL / Q000097:blood*; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D013624:Taiwan
C416946:ABCG8 protein, human; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D006903:Hydroxymethylglutaryl CoA Reductases