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A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering.

ABSTRACT: To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome.In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE.No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 × 10(-4)).The GRS was associated with statin response, but the small effect size (˜2% of the average low-density lipoprotein cholesterol reduction) limits applicability.

SUBMITTER: Leusink M

PROVIDER: S-EPMC5558527 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering.

Leusink Maarten M Maitland-van der Zee Anke H AH Ding Bo B Drenos Fotios F van Iperen Erik Pa EP Warren Helen R HR Caulfield Mark J MJ Cupples L Adrienne LA Cushman Mary M Hingorani Aroon D AD Hoogeveen Ron C RC Hovingh G Kees GK Kumari Meena M Lange Leslie A LA Munroe Patricia B PB Nyberg Fredrik F Schreiner Pamela J PJ Sivapalaratnam Suthesh S de Bakker Paul Iw PI de Boer Anthonius A Keating Brendan J BJ Asselbergs Folkert W FW Onland-Moret N Charlotte NC

Pharmacogenomics 20160405 6

<h4>Aim</h4>To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome.<h4>Patients & methods</h4>In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG ...[more]

PMID: 27045730

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Project description:ImportanceLow-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes.ObjectiveTo investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes.Design, setting, and participantsThe associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016.ExposuresLow-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR.Main outcomes and measuresOdds ratios (ORs) for type 2 diabetes and coronary artery disease.ResultsLow-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles.Conclusions and relevanceIn this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.

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A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering.

Publications

A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering.

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