| 1. |
- Chasman, D. I., et al.
(författare)
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Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial
- 2012
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Ingår i: Circulation-Cardiovascular Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 1942-325X .- 1942-3268. ; 5:2, s. 257-264
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Tidskriftsartikel (refereegranskat)abstract
- Background-In statin trials, each 20 mg/dL reduction in cholesterol results in a 10-15% reduction of annual incidence rates for vascular events. However, interindividual variation in low-density lipoprotein cholesterol (LDL-C) response to statins is wide and may partially be determined on a genetic basis. Methods and Results-A genome-wide association study of LDL-C response was performed among a total of 6989 men and women of European ancestry who were randomly allocated to either rosuvastatin 20 mg daily or placebo. Single nucleotide polymorphisms (SNPs) for genome-wide association (P<5x10(-8)) with LDL-C reduction on rosuvastatin were identified at ABCG2, LPA, and APOE, and a further association at PCSK9 was genome-wide significant for baseline LDL-C and locus-wide significant for LDL-C reduction. Median LDL-C reductions on rosuvastatin were 40, 48, 51, 55, 60, and 64 mg/dL, respectively, among those inheriting increasing numbers of LDL-lowering alleles for SNPs at these 4 loci (P trend=6.2x10(-20)), such that each allele approximately doubled the odds of percent LDL-C reduction greater than the trial median (odds ratio, 1.9; 95% confidence interval, 1.8-2.1; P=5.0x10(-41)). An intriguing additional association with sub-genome-wide significance (P<1x10(-6)) was identified for statin related LDL-C reduction at IDOL, which mediates posttranscriptional regulation of the LDL receptor in response to intracellular cholesterol levels. In candidate analysis, SNPs in SLCO1B1 and LDLR were confirmed as associated with LDL-C lowering, and a significant interaction was observed between SNPs in PCSK9 and LDLR. Conclusions-Inherited polymorphisms that predominantly relate to statin pharmacokinetics and endocytosis of LDL particles by the LDL receptor are common in the general population and influence individual patient response to statin therapy. (Circ Cardiovasc Genet. 2012;5:257-264.)
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| 2. |
- Chu, A. Y., et al.
(författare)
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Differential Genetic Effects on Statin-Induced Changes Across Low-Density Lipoprotein-Related Measures
- 2015
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Ingår i: Circulation: Cardiovascular Genetics. - 1942-325X .- 1942-3268. ; 8:5, s. 688-695
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Tidskriftsartikel (refereegranskat)abstract
- Background-Statin therapy influences not only low-density lipoprotein (LDL) cholesterol levels but also LDL-related biomarkers, including non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total number of LDL particles, and mean LDL particle size. Recent studies have identified many genetic loci influencing circulating lipid levels and statin-induced LDL cholesterol reduction. However, it is unknown how these genetic variants influence statin-induced changes in LDL subfractions and non-HDL-C. Methods and Results-One hundred sixty candidate single-nucleotide polymorphisms for effects on circulating lipid levels or statin-induced LDL-cholesterol lowering were tested for association with response of LDL subfractions and non-HDL-C to rosuvastatin or placebo for 1 year among 7046 participants from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Of the 51 single-nucleotide polymorphisms associated with statin response for ≥1 of the LDL subfractions or non-HDL-C, 20 single-nucleotide polymorphisms could be clustered according to effects predominantly on LDL particle size, predominantly on LDL particle number, and on apolipoprotein B but not on LDL cholesterol or non-HDL-C. Conclusions-These differential associations point to pathways of LDL response to statin therapy and possibly to mechanisms of statin-dependent cardiovascular disease risk reduction. © 2015 American Heart Association, Inc.
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| 3. |
- Chu, A. Y., et al.
(författare)
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Genome-Wide Association Study Evaluating Lipoprotein-Associated Phospholipase A(2) Mass and Activity at Baseline and After Rosuvastatin Therapy
- 2012
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Ingår i: Circulation-Cardiovascular Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 1942-325X .- 1942-3268. ; 5:6, s. 676-685
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Tidskriftsartikel (refereegranskat)abstract
- Background-Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a proinflammatory enzyme bound to low-density lipoprotein cholesterol and other circulating lipoproteins. Two measures of Lp-PLA(2), mass and activity, are associated with increased cardiovascular risk. Data are sparse regarding genetic determinants of Lp-PLA(2) mass and activity, and no prior data are available addressing genetic determinants of statin-induced changes for this proinflammatory biomarker. Methods and Results-We performed a genome-wide association study of Lp-PLA(2) mass and activity at baseline and after 12 months of rosuvastatin therapy (20 mg/d) among 6851 participants of European ancestry from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and performed replication in a meta-analysis of 13 664 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Novel associations were identified and replicated at MS4A4E and TMEM49 for baseline Lp-PLA(2) activity with genome-wide significant joint P values (P=2.0x10(-11) and P=2.9x10(-9), respectively). In addition, genome-wide associations (P<5x10(-8)) were identified and replicated for baseline Lp-PLA(2) mass at CETP and for Lp-PLA(2) activity at the APOC1-APOE and PLA2G7 loci. Among 2673 statin-allocated participants, both Lp-PLA(2) mass and activity were reduced by >30% and low-density lipoprotein cholesterol by 50% after 12 months of statin therapy (P<0.001 for both). Variants in ABCG2 and LPA were associated with change in statin-induced Lp-PLA(2) activity at genome-wide significance but were substantially attenuated after adjustment for statin-induced changes in lipid levels. Conclusions-Genome-wide significant associations at MS4A4E and TMEM49 may reflect novel influences on circulating levels of Lp-PLA(2) activity. In addition, genome-wide significant associations with rosuvastatin-induced change in Lp-PLA(2) activity were observed in ABCG2 and LPA, likely because of their impact on statin-induced low-density lipoprotein cholesterol lowering. (Circ Cardiovasc Genet. 2012;5:676-685.)
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| 4. |
- Chu, A. Y., et al.
(författare)
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Pharmacogenetic Determinants of Statin-Induced Reductions in C-Reactive Protein
- 2012
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Ingår i: Circulation-Cardiovascular Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 1942-325X .- 1942-3268. ; 5:1, s. 58-65
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Tidskriftsartikel (refereegranskat)abstract
- Background-In randomized trials, statins reduce plasma levels of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C), and the magnitude of event reduction relates to on-treatment levels of both. However, whether different mechanisms underlie statin-induced CRP and LDL-C reduction is unknown. Methods and Results-We performed a study to evaluate potential genetic determinants of CRP response using genome-wide genetic data from a total of 6766 participants of European ancestry randomly allocated to 20 mg/d of rosuvastatin or placebo in the JUPITER trial. Among 3386 rosuvastatin-allocated individuals, both CRP and LDL-C levels were reduced by 50% after 12 months of therapy (P<0.001 for both) and essentially uncorrelated (r(2)<0.03). No variants in the 3 genes (ABCG2, LPA, and APOE) that previously showed genome-wide association with LDL-C reduction in this cohort and none of the candidate single-nucleotide polymorphisms associated with LDL-C reduction were associated with rosuvastatin-induced CRP change after multiple testing correction. Among candidate single-nucleotide polymorphisms selected from prior genetic analyses of baseline CRP, CRP reduction was associated with rs2794520 in CRP (mean, -3.5% [SE, 2.0%] change in CRP per minor allele; P=6.4 x 10(-4)) and with rs2847281 in PTPN2 (mean, 3.7% [SE, 1.9%] change in CRP per minor allele; P=7.4 x 10(-4)). These associations remained significant after multiple testing correction but were not significant in a formal test of interaction. Neither variant was associated with rosuvastatin-induced LDL-C reduction or with CRP reduction among 3380 placebo-allocated JUPITER participants. Conclusions-The genetic determinants of rosuvastatin-induced CRP reduction differ from, and are largely independent of, the major pharmacogenetic determinants of rosuvastatin-induced LDL-C reduction. This supports the hypothesis that differing pathways may mediate the anti-inflammatory and lipid-lowering properties of statin therapy. (Circ Cardiovasc Genet. 2012;5:58-65.)
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