Genome-wide study of gene variants associated with differential cardiovascular event reduction by pravastatin therapy.
Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8 × 10(-7)). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.
Celera Inc, Alameda, California, United States of America. dov.shiffman@celera.com
Dov
D
Shiffman
Stella
S
Trompet
Judy Z
JZ
Louie
Charles M
CM
Rowland
Joseph J
JJ
Catanese
Olga A
OA
Iakoubova
Todd G
TG
Kirchgessner
Rudi G J
RG
Westendorp
Anton J M
AJ
de Craen
P Eline
PE
Slagboom
Brendan M
BM
Buckley
David J
DJ
Stott
Naveed
N
Sattar
James J
JJ
Devlin
Christopher J
CJ
Packard
Ian
I
Ford
Frank M
FM
Sacks
J Wouter
JW
Jukema
D000368:Aged; D003327:Coronary Disease / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use
D017035:Pravastatin