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

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).

Impact of liraglutide versus atorvastatin on cardiovascular changes in rat model of adenine induced chronic renal failure

“…The evaluated data in this study declared a significant difference between all groups in collagen fibres. These results are in agreements with Deshmukh et al (2012) who reported similar results. Also, Liu et al (2013) reported that liraglutide significantly enhance cardiac structure and decreased the parameters of LV posterior wall and its end-diastolic diameter.…”

The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians

“…Previous studies have shown that the response to atorvastatin is affected by other genes. A genome-wide association study shows associations of LDL-c response to atorvastatin with polymorphisms in LPA and APOE genes (Deshmukh et al 2012). The CYP7A1 and CYP3A4 gene polymorphisms in Chinese Hans and Chileans (Rosales et al 2012;Jiang et al 2012), and the CYP3AP1*3 allele in Chinese women were also correlated to response to atorvastatin.…”

Erratum: Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

“…8 There is some debate as to whether statins are as effective at primary prevention of CVD events in women as they are in men, [9][10][11] so further investigation of potential sex differences in statin response is warranted. A number of pharmacogenetic studies have sought to identify singlenucleotide polymorphisms (SNPs) that influence LDL-C statin response using candidate-gene and genome-wide association approaches, but the findings to date account for less than 10% of the variation in statin-induced LDL-C lowering variability, [12][13][14][15][16][17][18][19][20] with variants near the apolipoprotein E (APOE) and lipoprotein, Lp(a) (LPA) genes showing some of the strongest and most replicated signals. 17,18,20 Genetic association studies of TG statin response have been even less fruitful, with two published genome-wide association studies revealing no genome-wide significant hits 15,16 and only a modest number of significant associations reported with genetic variation in candidate genes, such as lipoprotein lipase (LPL), 21 cholesteryl ester transfer protein, plasma (CETP), ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) 22 and APOE.…”