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Title: Statin-associated muscle toxicity : clinical and genomic perspectives
Author: Turner, R.
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Statins are lipid-lowering agents and amongst the most commonly prescribed medications worldwide. Although generally well-tolerated, statins cause a range of adverse myotoxicity phenotypes ranging from mild myalgia to rare life-threatening rhabdomyolysis. The aetiology of statin-associated myotoxicity (SAM) is incompletely understood but clinical risk factors that increase systemic statin exposure (e.g. older age, drug interactions) have been identified. A common nonsynonymous variant (rs4149056, V174A) in the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene that encodes the hepatocyte-specific sinusoidal influx transporter, organic anion-transporting polypeptide 1B1 (OATP1B1), is associated with increased statin exposure and simvastatin myopathy. The aims of this thesis were to: examine whether muscular complaints impact statin use, assess if suboptimal statin use affects cardiovascular events, and investigate statin pharmacogenomics using both the hepatic reductase null (HRN) mouse model and the Pharmacogenetics of Acute Coronary Syndrome (PhACS) study, which was a UK multicentre prospective observational study of non-ST elevation ACS patients (n=1,470). One month after hospitalisation, 15.5% (n=156) of PhACS participants discharged on high potency statin therapy (n=1,005) had switched statin, reduced their dose, discontinued, or were statin non-adherent. Suboptimal statin therapy was associated with increased risks of time to major adverse cardiovascular events (HR 2.10, 95% CI 1.25-3.53, p= 0.005) and all-cause mortality (HR 2.46, 95% CI 1.38-4.39, p=0.003), and self-reported SAM was a risk factor for suboptimal statin use (OR 4.28, 95% CI 1.30-14.08, p=0.017). Two novel liquid chromatography-mass spectrometry assays were developed to quantify statin analytes in murine dried blood spots or human plasma. An in vivo study revealed that HRN mice, which lack hepatic P450 oxidoreductase (Por) reducing cytochrome P450 (Cyp) activity, have increased blood levels of rosuvastatin, atorvastatin (ATV) and ATV metabolites relative to wild type mice. ATV and ATV metabolite levels were quantified in a pre-specified sub-cohort of PhACS patients on regular ATV 40mg or 80mg daily (n=590) at one month after index hospitalisation, and were associated with several clinical factors including novel interactions with furosemide, proton pump inhibitors and clopidogrel. Genome-wide association analyses identified that SLCO1B1 rs4149056 was suggestively associated with increased ATV (p=2.21x10-6) and 2-hydroxy (2- OH) ATV (p=1.09x10-6) levels. Importantly, the uridine 5'-diphosphoglucuronosyltransferase 1A (UGT1A) locus was associated with increased ratios of 2-OH ATV/ATV (lead SNP, rs887829, p=7.25x10-16) and 2-OH ATV lactone (L)/ATV L (rs887829 p=3.95x10-15). A novel locus near CYP3A7 was associated with increased hydroxylation. SLCO1B1 rs4149056 was associated with muscular complaints (p=0.016) and suboptimal ATV use (p=0.019). There was no association between POR variants and ATV levels. In conclusion, muscular complaints increase the risk of suboptimal statin use, which is associated with a poorer prognosis. SLCO1B1 rs4149056 increases the risk of high dose ATV-associated muscular complaints and suboptimal ATV use. Further work is required to understand mechanistically the novel drug-statin interactions and UGT1A and CYP3A7 loci associations identified in this thesis.
Supervisor: Pirmohamed, Munir ; Morris, Andrew ; Carr, Dan ; Kitteringham, Neil Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral