Pharmacological effects of lipid-lowering drugs recapitulate with a larger amplitude the phenotypic effects of common variants within their target genes.
BACKGROUND
A major expectation underlying the search for novel susceptibility genes for common diseases using genome-wide association studies (GWAS) is that these discoveries will lead to new drug targets. This claim has not been verified yet. Here, we tested the hypothesis that common single nucleotide polymorphisms (SNPs) within drug target genes are associated with the corresponding phenotypes, using a population-based GWAS dataset and lipid-lowering drugs as a test case.


METHODS
We examined the association between 36 genotyped and 193 imputed SNPs within four lipid-lowering drug target genes (HMGCR, PPARA, HM74A/GPR109A and CETP) and four non-lipid drug target genes (ACE, AGTR1, P2RY12, and ATP4B) and lipid phenotypes, blood pressure, and coronary artery disease in 5635 adult participants of the Lausanne, Switzerland, CoLaus study, genotyped using the Affymetrix 500K SNP chip technology.


RESULTS
The phenotypes associated with SNPs within drug target genes recapitulated to a certain extent the pharmacological effects of the drug. The amplitude of the SNP effect was about 10 times smaller than the pharmacological effect of the corresponding drug. In particular, several CETP SNPs were associated with an elevation in HDL-cholesterol levels, yet a lower diastolic blood pressure, providing evidence that the blood pressure elevation induced by the CETP inhibitor torcetrapib is more likely compound specific than class specific.


CONCLUSIONS
Pharmacological modulation of lipid-lowering drug targets recapitulates, and markedly amplifies, the phenotypic effects of common SNPs within these target genes. This data provides indirect evidence that, with certain limitations, large-scale GWAS represent a new tool for the discovery and the development of innovative drugs.
Knouff
Christopher W
CW
Genetics Division, GlaxoSmithKline King of Prussia, Pennsylvania 19406, USA.
Lim
Noha
N
Song
Kijoung
K
Yuan
Xin
X
Walker
Max C
MC
Townsend
Ray
R
Waeber
Gerard
G
Matthews
Paul M
PM
Vollenweider
Peter
P
Waterworth
Dawn M
DM
Mooser
Vincent
V
D000328:Adult; D000368:Aged; D001786:Blood Glucose; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D001786:Blood Glucose; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids