{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T20:17:09Z","timestamp":1767212229196,"version":"3.45.0"},"reference-count":31,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Statin exposure has been associated with a broad spectrum of muscle toxicity, ranging from asymptomatic creatine kinase (CK) elevation to immune-mediated necrotizing myopathy (IMNM) with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. The mechanisms underlying these adverse effects are not fully understood, and genetic predisposition may play a role. This observational study evaluated the association of HLA-DRB1*11 and SLCO1B1 rs4149056 variants with statin-induced muscle toxicity. A total of 62 statin-exposed patients treated at a single tertiary center were included and classified as follows: IMNM with anti-HMGCR antibodies (n = 11), non-immune myotoxicity (n = 20), and statin-exposed controls without myopathy (n = 31). The mean age was 66 \u00b1 7.5 years, and 62% were women. The frequency of the HLA-DRB1*11 allele was significantly higher in patients with anti-HMGCR IMNM compared to those with non-immune myotoxicity (81.0% vs. 25.0%; OR = 13.5, 95% CI 1.73\u201315.3; p &lt; 0.01) and controls (81.0% vs. 17.2%; OR = 21.6, 95% CI 2.87\u201323.7; p &lt; 0.01). No significant difference was found between the non-immune myotoxicity and control groups. Likewise, the SLCO1B1 rs4149056 variant showed no association with either IMNM or non-immune muscle toxicity. These findings confirm a strong association between the HLA-DRB1*11 allele and anti-HMGCR IMNM. This genetic marker may help to better distinguish immune-mediated from non-immune forms of statin-related myopathy.<\/jats:p>","DOI":"10.3390\/ijms262211144","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:33:04Z","timestamp":1763469184000},"page":"11144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Biomarkers for Statin-Induced Myopathy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8565-2985","authenticated-orcid":false,"given":"Diana","family":"Prieto-Pe\u00f1a","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"},{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan David","family":"Urriago-Gil","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2245-4639","authenticated-orcid":false,"given":"Gonzalo","family":"Ocejo-Vinyals","sequence":"additional","affiliation":[{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"},{"name":"Department of Immunology, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Garc\u00eda-Ibarbia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"},{"name":"Medicine Department, University of Cantabria, 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4734-2900","authenticated-orcid":false,"given":"Zaida","family":"Salmon-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"},{"name":"Department of Internal Medicine, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Martin-Mill\u00e1n","sequence":"additional","affiliation":[{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"},{"name":"Department of Internal Medicine, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"},{"name":"Medicine Department, University of Cantabria, 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Corrales-Selaya","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"},{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3534-8467","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Pulito-Cueto","sequence":"additional","affiliation":[{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0548-2689","authenticated-orcid":false,"given":"Raquel","family":"L\u00f3pez-Mej\u00edas","sequence":"additional","affiliation":[{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-2285","authenticated-orcid":false,"given":"Ricardo","family":"Blanco","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"},{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"},{"name":"Medicine Department, University of Cantabria, 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6585-8847","authenticated-orcid":false,"given":"Jose Luis","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Immunopathology Research Group, IDIVAL Health Research Institute of Cantabria, 39008 Santander, Spain"},{"name":"Department of Internal Medicine, Hospital Universitario Marqu\u00e9s De Valdecilla, IDIVAL, 39008 Santander, Spain"},{"name":"Medicine Department, University of Cantabria, 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/clpt.2014.121","article-title":"Phenotype standardization for statin-induced myotoxicity","volume":"96","author":"Alfirevic","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.14797\/mdcj-15-1-23","article-title":"Statins: Then and Now","volume":"15","author":"Toth","year":"2019","journal-title":"Methodist. Debakey Cardiovasc. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1161\/CIRCRESAHA.118.312782","article-title":"Statin Toxicity","volume":"124","author":"Ward","year":"2019","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Turner, R.M., and Pirmohamed, M. (2019). Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010022"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103286","DOI":"10.1016\/j.jaut.2024.103286","article-title":"Immune-mediated necrotizing myopathy: A comprehensive review of the pathogenesis, clinical features, and treatments","volume":"148","author":"Li","year":"2024","journal-title":"J. Autoimmun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"SEARCH Collaborative Group (2009). SLCO1B1 variants and statin-induced myopathy. N. Engl. J. Med., 360, 304.","DOI":"10.1056\/NEJMc081975"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1002\/acr.21671","article-title":"Increased Frequency of DRB1*11:01 in Anti-HMG-CoA Reductase-Associated Autoimmune Myopathy","volume":"64","author":"Mammen","year":"2012","journal-title":"Arthritis Care Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ejim.2022.04.017","article-title":"Epidemiological and genetic features of anti- 3-hydroxy-3-methylglutaryl-CoA reductase necrotizing myopathy: Single-center experience and literature review","volume":"101","author":"Genre","year":"2022","journal-title":"Eur. J. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41572-021-00321-x","article-title":"Idiopathic inflammatory myopathies","volume":"7","author":"Lundberg","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1002\/art.30156","article-title":"Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy","volume":"63","author":"Mammen","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/343425a0","article-title":"Regulation of the mevalonate pathway","volume":"343","author":"Goldstein","year":"1990","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s10557-019-06904-x","article-title":"State of the art comprehensive review of individual statins, their differences, pharmacology, and clinical implications","volume":"33","author":"Azemawah","year":"2019","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1161\/CIRCULATIONAHA.112.136101","article-title":"Effect of statins on skeletal muscle function","volume":"127","author":"Parker","year":"2013","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/MD.0000000000000028","article-title":"Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: Inconstant exposure to statin","volume":"93","author":"Allenbach","year":"2014","journal-title":"Medicine"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ge, Y., Lu, X., Peng, Q., Shu, X., and Wang, G. (2015). Clinical characteristics of anti-3-hydroxy-3-methylglutaryl coenzyme a reductase antibodies in Chinese patients with idiopathic inflammatory myopathies. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141616"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41584-020-00515-9","article-title":"Immune-mediated necrotizing myopathy: Clinical features and pathogenesis","volume":"16","author":"Allenbach","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.semarthrit.2019.03.005","article-title":"Novel susceptibility alleles in HLA region for myositis and myositis specific autoantibodies in Korean patients","volume":"49","author":"Kang","year":"2019","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/mus.24541","article-title":"Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase in patients with immune-mediated myositis and necrotizing myopathy","volume":"52","author":"Limaye","year":"2015","journal-title":"Muscle Nerve"},{"key":"ref_19","first-page":"24","article-title":"Utilidad del gen SLCO1B1 como marcador de inter\u00e9s en la farmacogen\u00f3mica de las estatinas","volume":"26","author":"Robledo","year":"2019","journal-title":"Rev. Colomb. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1007\/s00296-021-05063-3","article-title":"The prevalence and clinical characteristics of anti-HMGCR (anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) antibodies in idiopathic inflammatory myopathy: An analysis from the MyoCite registry","volume":"42","author":"Gupta","year":"2022","journal-title":"Rheumatol. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3233\/JND-170282","article-title":"Anti-HMGCR myopathy","volume":"5","author":"Mohassel","year":"2018","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e200285","DOI":"10.1212\/NXI.0000000000200285","article-title":"Absence of pathogenic mutations and strong association with HLA-DRB1*11:01 in statin-na\u00efve early-onset anti-HMGCR necrotizing myopathy","volume":"11","author":"Malfatti","year":"2024","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103468","DOI":"10.1016\/j.autrev.2023.103468","article-title":"Anti-HMGCR immune-mediated necrotising myopathy: Addressing the remaining issues","volume":"22","author":"Khoo","year":"2023","journal-title":"Autoimmun. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1212\/WNL.0000000000003160","article-title":"HLA-DRB1 alleles in immune-mediated necrotizing myopathy","volume":"87","author":"Ohnuki","year":"2016","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.endonu.2016.01.001","article-title":"Statin-related myotoxicity","volume":"63","author":"Fernandes","year":"2016","journal-title":"Endocrinol. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.drudis.2016.09.001","article-title":"Statin-associated myopathy and the quest for biomarkers: Can we effectively predict statin-associated muscle symptoms?","volume":"22","author":"Muntean","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1093\/eurheartj\/ehv043","article-title":"Statin-associated muscle symptoms: Impact on statin therapy\u2014European Atherosclerosis Society consensus panel statement on assessment, aetiology and management","volume":"36","author":"Stroes","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"SEARCH Collaborative Group (2008). SLCO1B1 variants and statin-induced myopathy\u2014A genomewide study. N. Engl. J. Med., 359, 789\u2013799.","DOI":"10.1056\/NEJMoa0801936"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Stewart, A. (2013). SLCO1B1 polymorphisms and statin-induced myopathy. PLoS Curr., 5.","DOI":"10.1371\/currents.eogt.d21e7f0c58463571bb0d9d3a19b82203"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/cvr\/cvy119","article-title":"Role of genetics in the prediction of statin-associated muscle symptoms and optimization of statin use and adherence","volume":"114","author":"Brunham","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sridharan, K., and Sivaramakrishnan, G. (Curr. Rev. Clin. Exp. Pharmacol., 2025). Genetic Determinants of Statin-induced Myopathy: A Network Meta-analysis of Observational Studies, Curr. Rev. Clin. Exp. Pharmacol., in press.","DOI":"10.2174\/0127724328356429250315163111"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:39:26Z","timestamp":1763469566000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,18]]},"references-count":31,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211144"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211144","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,18]]}}}