{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:56:48Z","timestamp":1782316608324,"version":"3.54.5"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012095","name":"Scottish Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012095","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (\u00b11.04) mmol\/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (<jats:italic>ABCB1<\/jats:italic>; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (<jats:italic>LILRB5<\/jats:italic>; rs12975366), were associated with statin efficacy. In <jats:italic>ABCB1<\/jats:italic>, homozygous carriers of the C allele at rs1045642 had 0.06mmol\/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In <jats:italic>LILRB5<\/jats:italic> (rs12975366), carriers of the C allele had 0.04mmol\/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol\/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; <jats:italic>p<\/jats:italic>&amp;lt;0.001).<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the <jats:italic>ABCB1<\/jats:italic> variant has been shown to have an association with statin pharmacokinetics, no similar evidence for <jats:italic>LILRB5<\/jats:italic> has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.<\/jats:p>","DOI":"10.3389\/fgene.2021.713181","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T09:25:26Z","timestamp":1633080326000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records"],"prefix":"10.3389","volume":"12","author":[{"given":"Alaa\u2019 Lutfi","family":"Melhem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehul Kumar","family":"Chourasia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Bigossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrielle","family":"Maroteau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alasdair","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Pola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adem Y.","family":"Dawed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksi","family":"Tornio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin N. A.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moneeza K.","family":"Siddiqui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/clpt.2014.121","article-title":"Phenotype standardisation for statin-induced myotoxicity","volume":"96","author":"Alfirevic","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1056\/NEJMoa061894","article-title":"High-dose atorvastatin after stroke or transient ischemic attack","volume":"355","author":"Amarenco","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1472-6904-9-6","article-title":"Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomised placebo-controlled trial in 20,536 high-risk people","volume":"9","author":"Armitage","year":"2009","journal-title":"BMC Clin. Pharmacol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1016\/S0140-6736(10)60310-8","article-title":"Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial","volume":"376","author":"Armitage","year":"2010","journal-title":"Lancet"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1016\/S0140-6736(05)67394-1","article-title":"Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins","volume":"366","author":"Baigent","year":"2005","journal-title":"Lancet"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1097\/FJC.0000000000000808","article-title":"Predictors of statin intolerance in patients with a new diagnosis of atherosclerotic cardiovascular disease within a large integrated health care institution: the IMPRES study","volume":"75","author":"Bair","year":"2020","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.2217\/pgs.09.105","article-title":"Common genetic variation in the ABCB1 gene is associated with the cholesterol-lowering effect of simvastatin in males","volume":"10","author":"Becker","year":"2009","journal-title":"Pharmacogenomics"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/pds.1866","article-title":"Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy","volume":"19","author":"Becker","year":"2010","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1093\/cvr\/cvy119","article-title":"Role of genetics in the prediction of statin-associated muscle symptoms and optimisation of statin use and adherence","volume":"114","author":"Brunham","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/tpj.2010.92","article-title":"Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin","volume":"12","author":"Brunham","year":"2012","journal-title":"Pharmacogenomics J."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1038\/gim.2014.41","article-title":"Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review","volume":"16","author":"Canestaro","year":"2014","journal-title":"Genet. Med."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1111\/jep.13286","article-title":"Treatment patterns of lipid-lowering therapies and possible statin intolerance among statin users with clinical atherosclerotic cardiovascular disease (ASCVD) or diabetes mellitus (DM) in Taiwan","volume":"26","author":"Chen","year":"2020","journal-title":"J. Eval. Clin. Pract."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"796","DOI":"10.5551\/jat.26856","article-title":"Association between SLCO1B1 521 T > C and 388 A > G polymorphisms and statins effectiveness: a meta-analysis","volume":"22","author":"Dai","year":"2015","journal-title":"J. Atheroscler. Thromb."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/clpt.2010.255","article-title":"Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study","volume":"89","author":"Donnelly","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1161\/CIRCGENETICS.113.000395","article-title":"CKM and LILRB5 are associated with serum levels of creatine kinase","volume":"7","author":"Dub\u00e9","year":"2014","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.clpt.2005.08.003","article-title":"The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment","volume":"78","author":"Fiegenbaum","year":"2005","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e1082","DOI":"10.1161\/CIR.0000000000000625","article-title":"2018 AHA\/ACC\/AACVPR\/AAPA\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology\/American Heart Association task force on clinical practice guidelines","volume":"139","author":"Grundy","year":"2019","journal-title":"Circulation"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1093\/ije\/dyx140","article-title":"Cohort profile: genetics of diabetes audit and research in Tayside Scotland (GoDARTS)","volume":"47","author":"H\u00e9bert","year":"2018","journal-title":"Int. J. Epidemiol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"n135","DOI":"10.1136\/bmj.n135","article-title":"Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials","volume":"372","author":"Herrett","year":"2021","journal-title":"BMJ"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.jacl.2011.01.001","article-title":"The C3435T polymorphism in ABCB1 influences atorvastatin efficacy and muscle symptoms in a high-risk vascular cohort","volume":"5","author":"Hoenig","year":"2011","journal-title":"J. Clin. Lipidol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/j.jacc.2021.01.027","article-title":"Apolipoprotein B and non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients","volume":"77","author":"Johannesen","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1111\/jcpt.12369","article-title":"Genetic determinants of lipid-lowering response to atorvastatin therapy in an Indian population","volume":"41","author":"Kadam","year":"2016","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.amjcard.2004.01.014","article-title":"Polymorphisms in the multidrug resistance-1 (MDR1) gene influence the response to atorvastatin treatment in a gender-specific manner","volume":"93","author":"Kajinami","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.3389\/fgene.2020.575678","article-title":"Pharmacogenetics of statin-induced myotoxicity","volume":"11","author":"Kee","year":"2020","journal-title":"Front. Genet."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"10572","DOI":"10.1038\/ncomms10572","article-title":"Common and rare variants associating with serum levels of creatine kinase and lactate dehydrogenase","volume":"7","author":"Kristjansson","year":"2016","journal-title":"Nat. Commun."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"147","DOI":"10.3390\/jpm4020147","article-title":"Genetically guided statin therapy on statin perceptions, adherence, and cholesterol lowering: a pilot implementation study in primary care patients","volume":"4","author":"Li","year":"2014","journal-title":"J. Pers. Med."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1056\/NEJMoa0801936","article-title":"SLCO1B1 variants and statin-induced myopathy\u2013a genome-wide study","volume":"359","author":"Link","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e1000022","DOI":"10.1371\/journal.pmed.1000022","article-title":"STrengthening the REporting of Genetic Association Studies (STREGA)\u2014an extension of the STROBE statement","volume":"6","author":"Little","year":"2009","journal-title":"PLoS Med."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1093\/eurheartj\/ehz455","article-title":"2019 ESC\/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)","volume":"41","author":"Mach","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/sj.tpj.6500384","article-title":"Clinical implications of pharmacogenomics of statin treatment","volume":"6","author":"Mangravite","year":"2006","journal-title":"Pharmacogenomics J."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1161\/01.CIR.101.2.207","article-title":"Current perspectives on statins","volume":"101","author":"Maron","year":"2000","journal-title":"Circulation"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1002\/cpt.1927","article-title":"Exome sequencing reveals common and rare variants in F5 associated with ACE inhibitor and angiotensin receptor blocker-induced angioedema","volume":"108","author":"Maroteau","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e013351","DOI":"10.1136\/bmjopen-2016-013351","article-title":"Cohort profile: the Scottish research register SHARE. A register of people interested in research participation linked to NHS data sets","volume":"7","author":"McKinstry","year":"2017","journal-title":"BMJ Open"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/S0140-6736(12)60367-5","article-title":"The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials","volume":"380","author":"Mihaylova","year":"2012","journal-title":"Lancet"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e38","DOI":"10.1161\/ATV.0000000000000073","article-title":"Statin safety and associated adverse events: a scientific statement from the American Heart Association","volume":"39","author":"Newman","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1476-511X-6-7","article-title":"Genetic determinants of statin intolerance","volume":"6","author":"Oh","year":"2007","journal-title":"Lipids Health Dis."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e002043","DOI":"10.1161\/CIRCGEN.117.002043","article-title":"Characterization of statin low-density lipoprotein cholesterol dose-response using electronic health records in a large population-based cohort","volume":"11","author":"Oni-Orisan","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1080\/14740338.2019.1615053","article-title":"Muscle and statins: from toxicity to the nocebo effect","volume":"18","author":"Pedro-Botet","year":"2019","journal-title":"Expert Opin. Drug Saf."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.atherosclerosis.2010.02.026","article-title":"Genetic involvement in statins induced myopathy. Preliminary data from an observational case-control study","volume":"211","author":"Puccetti","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1056\/NEJMoa0807646","article-title":"Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein","volume":"359","author":"Ridker","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1111\/j.1472-8206.2004.00299.x","article-title":"Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update","volume":"19","author":"Schachter","year":"2005","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref43","year":"2011"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1080\/1744666X.2018.1440206","article-title":"Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations","volume":"14","author":"Selva-O\u2019Callaghan","year":"2018","journal-title":"Expert. Rev. Clin. Immunol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"3569","DOI":"10.1093\/eurheartj\/ehx467","article-title":"A common missense variant of LILRB5 is associated with statin intolerance and myalgia","volume":"38","author":"Siddiqui","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1515\/cclm.2011.804","article-title":"SLCO1B1 gene variability influences lipid-lowering efficacy on simvastatin therapy in southern Brazilians","volume":"50","author":"Sortica","year":"2012","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s12944-015-0114-2","article-title":"ABCB1 C3435T polymorphism and the lipid-lowering response in hypercholesterolemic patients on statins: a meta-analysis","volume":"14","author":"Su","year":"2015","journal-title":"Lipids Health Dis."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1007\/s13311-018-0670-z","article-title":"Statin-associated muscle disease: advances in diagnosis and management","volume":"15","author":"Taylor","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3390\/jcm9010022","article-title":"Statin-related myotoxicity: a comprehensive review of pharmacokinetic, pharmacogenomic and muscle components","volume":"9","author":"Turner","year":"2019","journal-title":"J. Clin. Med."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"247","DOI":"10.2165\/00129784-200404040-00005","article-title":"Genetic polymorphisms in cytochrome P450 enzymes: effect on efficacy and tolerability of HMG-CoA reductase inhibitors","volume":"4","author":"Vermes","year":"2004","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1161\/CIRCRESAHA.118.312782","article-title":"Statin toxicity","volume":"124","author":"Ward","year":"2019","journal-title":"Circ. Res."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1097\/01213011-200506000-00007","article-title":"Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage","volume":"15","author":"Wilke","year":"2005","journal-title":"Pharmacogenet. 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