Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)

Harshal A Deshmukh, Helen M Colhoun, Toby Johnson, Paul M McKeigue, D John Betteridge, Paul N Durrington, John H Fuller, Shona Livingstone, Valentine Charlton-Menys, Andrew Neil, Neil Poulter, Peter Sever, Denis C Shields, Alice V Stanton, Aurobindo Chatterjee, Craig Hyde, Roberto A Calle, David A DeMicco, Stella Trompet, Iris Postmus, Ian Ford, J Wouter Jukema, Mark Caulfield, Graham A Hitman, Harshal A Deshmukh, Helen M Colhoun, Toby Johnson, Paul M McKeigue, D John Betteridge, Paul N Durrington, John H Fuller, Shona Livingstone, Valentine Charlton-Menys, Andrew Neil, Neil Poulter, Peter Sever, Denis C Shields, Alice V Stanton, Aurobindo Chatterjee, Craig Hyde, Roberto A Calle, David A DeMicco, Stella Trompet, Iris Postmus, Ian Ford, J Wouter Jukema, Mark Caulfield, Graham A Hitman

Abstract

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).

Trial registration: ClinicalTrials.gov NCT00327418.

Figures

Fig. 1.
Fig. 1.
Quantile-quantile plot of meta-analysis P-values for statin response. A plot of the quantiles of observed and expected distribution ofP-values against each other.
Fig. 2.
Fig. 2.
Manhattan plot of P-values from meta-analysis of all SNPs that passed stringent quality control. The Manhattan plots [also known as −log10 (P) association plots[ show the chromosomal position of SNPs exceeding the genome-wide significance threshold (P < 5 × 10−8) as indicated by the solid red line.
Fig. 3.
Fig. 3.
Regional association plot of LPA locus with statin response. Correlations between the target SNP (the SNP with the lowest P value, depicted in purple) and nearby SNPs within a 500 kb region. Ther2 values were based on the HapMap CEU population.
Fig. 7.
Fig. 7.
Regional association plot of LPA locus with Lp(a) levels in the CARDS dataset. Correlations between the target SNP (the SNP with the lowest Pvalue, depicted in purple) and nearby SNPs within a 500 kb region. Ther2 values were based on the HapMap CEU population.
Fig. 5.
Fig. 5.
Regional association plot of APOE locus with statin response. Correlations between the target SNP (the SNP with the lowest P value, depicted in purple) and nearby SNPs within a 500 kb region. Ther2 values were based on the HapMap CEU population.
Fig. 6.
Fig. 6.
Regional association plot of ALG10 locus with statin response before Lp(a) adjustments. Correlations between the target SNP (the SNP with the lowestP value, depicted in purple) and nearby SNPs within a 500 kb region. The r2 values were based on the HapMap CEU population.

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