Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Postmus, Iris; Trompet, Stella; Deshmukh, Harshal; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, I.; Zhou, Kaixin; Arsenault, Benoît J.; Donnelly, Andrew P.; Wiggins, Kerri L.; Avery, L. B.; Taylor, Kristin; Evans, Sharon S.; Smith, Albert V.; Keyser, Catherine E. de; Johnson, David C.; Stott, D. A.; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Nickerson, Deborah A.; Smith, Joshua D.; Boekholdt, S. Matthijs; Durrington, N.; Morris, Andrew D.

doi:10.1038/ncomms6068

Cited by 234 publications

(170 citation statements)

References 72 publications

(101 reference statements)

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“…Interestingly, a recent meta-analysis study found that genetic variances in the SORT1 locus are associated with the LDL-cholesterol response to statin therapy. 42 Our study demonstrates that regulation of the LDLR by the (P)RR is a post-transcriptional event culminating in lysosomal degradation of the LDLR. Grossly, 2 cellular scenarios may fit this pattern of regulation.…”

Section: Discussionmentioning

confidence: 96%

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Meima

Nelson

et al. 2016

Circulation Research

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T he (pro)renin receptor [(P)RR] has been implicated as a receptor for renin/prorenin (denoted as [pro]renin)-stimulated signaling, and plays a role in local renin-angiotensin system activation by nonproteolytically activating bound prorenin. 1 In experimental assays (pro)renin-(P)RR signaling results in extracellular signal-regulated kinase 1/2 (Erk1/2) activation, and as a consequence upregulation of profibrotic factors, such as transforming growth factor β, collagen, and fibronectin. [2][3][4][5][6] However, the physiological relevance of the (pro)renin-(P)RR interaction is questionable because the (pro)renin concentrations required are >1000× higher than observed under (patho) physiological conditions. 7,8 Recently, (pro)renin-independent functions for (P)RR have been reported, including a function as an accessory protein of the vacuolar H + -ATPase (V-ATPase). 9 V-ATPases are multisubunit complexes, and they are expressed virtually in all cells types. They play an important role in protein trafficking, receptor recycling, and lysosomal degradation by acidifying intracellular compartments.10,11 Depletion of the (P)RR results in decreased protein levels of V-ATPase subunits, impaired acidification of intracellular compartments, and defects in autophagy.12-14 V-ATPases are also found at the plasma membrane in certain cell types, such as intercalated cells of the collecting duct. Accordingly, we previously reported that the (P)RR is required for both prorenin-dependent and proreninindependent regulation of V-ATPase activity in collecting duct cells.15 The (P)RR has been also recently implicated in canonical Wnt and PCP signaling, [16][17][18] emphasizing the notion that our understanding of (P)RR function remains incomplete. In This Issue, see p 183Editorial, see p 187To address this, we used an unbiased proteomics approach to discover potential novel functions of the (P)RR. We mapped the (P)RR-interactome and identified sortilin 1 (SORT1) as Objective: To uncover renin-angiotensin system-independent functions of the (P)RR. Methods and Results: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins.This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (

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Section: Discussionmentioning

confidence: 96%

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Meima

Nelson

et al. 2016

Circulation Research

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“…A recent meta-analysis using individual subject data collected from 32,258 patients treated with atorvastatin 10-80 mg, rosuvastatin 5-40 mg, or simvastatin 10-80 mg showed that the standard deviation of LDL-C reduction for all statins and doses ranged from 13 to 18%, whereas the percentage of patients experiencing a suboptimal response (\30% reduction in LDL-C) ranged from 5 to 53% [15]. This somewhat unpredictable response to statins is thought to be due to a complex interplay between genetic and environmental factors [16,17] that translates into a large variability in the balance between cholesterol synthesis and absorption and, at least in part, a compensatory increase in intestinal cholesterol uptake [18,19]. Recently, the PRECISE-IVUS (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial found that sterols (lathosterol, campesterol, and sitosterol) and their ratio to cholesterol increased with atorvastatin monotherapy but decreased with the atorvastatin-ezetimibe combination.…”

Section: Variability In Individual Response To Statin Therapymentioning

confidence: 99%

Defining the Place of Ezetimibe/Atorvastatin in the Management of Hyperlipidemia

Ferreira

Silva

2016

Am J Cardiovasc Drugs

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Statin-ezetimibe combinations are a potentially advantageous therapeutic option for high-risk patients who need additional lowering of low-density lipoprotein cholesterol (LDL-C). These combinations may overcome some of the limitations of statin monotherapy by blocking both sources of cholesterol. Recently, a fixed-dose combination with atorvastatin, one of the most extensively studied statins, was approved and launched in several countries, including the USA. Depending on atorvastatin dose, this combination provides LDL-C reductions of 50-60%, triglyceride reductions of 30-40%, and highdensity lipoprotein cholesterol (HDL-C) increases of 5-9%. Studies comparing the lipid-lowering efficacy of the atorvastatin-ezetimibe combination with the alternatives of statin dose titration or switching to a more potent statin consistently showed that combination therapy provided greater LDL-C reduction, translating into a greater proportion of patients achieving lipid goals. Simvastatinezetimibe combinations have been shown to reduce the incidence of major atherosclerotic events in several clinical settings to a magnitude that seems similar to that observed with statins for the same degree of absolute LDL-C lowering. The atorvastatin-ezetimibe combination has also been shown to induce the regression of coronary atherosclerosis measured by intravascular ultrasound in a significantly greater proportion of patients than atorvastatin alone. Atorvastatin-ezetimibe combinations are generally well tolerated. Previous concerns of a possible increase in the incidence of cancer with ezetimibe were dismissed in large trials with long follow-up periods. In this paper, we examine the rationale for an atorvastatin-ezetimibe combination, review the evidence supporting it, and discuss its potential role in the management of dyslipidemia. Key PointsStatin-ezetimibe combinations are a realistic treatment option for patients who do not achieve low-density lipoprotein cholesterol (LDL-C) targets while receiving statin monotherapy and for patients prone to dose-dependent statin side effects.The IMPROVE-IT trial was the first to demonstrate a reduction in cardiovascular events with ezetimibe.Recently, combination therapy with atorvastatin plus ezetimibe was also associated with greater coronary plaque regression than atorvastatin alone.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Theusch¹,

Kim²,

Stevens³

et al. 2016

Pharmacogenomics J

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Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR = 15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho = 0.32, q = 0.11) was driven by men (interaction P = 0.0055). rs73161338 was associated with INSIG1 expression changes (P = 5.4 × 10 − 5 ) and TG response in two statin clinical trials (P = 0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P = 5.6 × 10 −6 ). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.

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Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Cited by 234 publications

References 72 publications

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Defining the Place of Ezetimibe/Atorvastatin in the Management of Hyperlipidemia

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

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