We carried out a genome-wide association study (GWAS) of
LDL-c response to
statin using data from participants in the Collaborative
Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed
atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of
LDL-c response to
atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 × 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the
APOE region (rs445925; P = 2.22 × 10(-16) and rs4420638; P = 1.01 × 10(-11)) that are proxies for the ε2 and ε4 variants, respectively, in
APOE. The novel association with the LPA SNP was replicated in the PROspective Study of
Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that
atorvastatin therapy did not alter
lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent
LDL-c response levels. However,
statin therapy had a similar effect in reducing
cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of
LDL-c and the clinical estimation of
LDL-c response. Therefore, an apparently lower
LDL-c response to
statin therapy may indicate a need for measurement of Lp(a). However,
statin therapy seems beneficial even in those with high Lp(a).