Genetic Variant ABCC1 rs45511401 Is Associated with Increased Response to Statins in Patients with Familial Hypercholesterolemia.

Autor: Dagli-Hernandez C; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.; Department of Physiology and Pharmacology, Karolinska Institutet, 171177 Stockholm, Sweden., Borges JB; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.; Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology, Sao Paulo 04012-909, Brazil., Marçal EDSR; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.; Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology, Sao Paulo 04012-909, Brazil., de Freitas RCC; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil., Mori AA; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil., Gonçalves RM; Medical Clinic Division, Institute Dante Pazzanese of Cardiology, Sao Paulo 04012-909, Brazil., Faludi AA; Medical Clinic Division, Institute Dante Pazzanese of Cardiology, Sao Paulo 04012-909, Brazil., de Oliveira VF; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil., Ferreira GM; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil., Bastos GM; Laboratory of Molecular Research in Cardiology, Institute Dante Pazzanese of Cardiology, Sao Paulo 04012-909, Brazil.; Department of Teaching and Research, Real e Benemerita Associação Portuguesa de Beneficiencia, Sao Paulo 01323-001, Brazil., Zhou Y; Department of Physiology and Pharmacology, Karolinska Institutet, 171177 Stockholm, Sweden., Lauschke VM; Department of Physiology and Pharmacology, Karolinska Institutet, 171177 Stockholm, Sweden.; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany.; University of Tuebingen, Geschwister-Scholl-Platz, 72074 Tübingen, Germany., Cerda A; Center of Excellence in Translational Medicine, CEMT-BIOREN & Department of Basic Sciences, Universidad de La Frontera, Av. Alemania 0458, Temuco 4810296, Chile., Hirata MH; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil., Hirata RDC; Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.
Jazyk: angličtina
Zdroj: Pharmaceutics [Pharmaceutics] 2022 Apr 27; Vol. 14 (5). Date of Electronic Publication: 2022 Apr 27.
DOI: 10.3390/pharmaceutics14050944
Abstrakt: Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid change using molecular docking showed that ABCC1 rs45511401 possibly impairs statin efflux. Deleterious variants in PK genes were not associated with an increased risk of SRAE. In conclusion, the deleterious variant ABCC1 rs45511401 enhanced LDL-c response in Brazilian FH patients. As such, this variant might be a promising candidate for the individualization of statin therapy.
Databáze: MEDLINE
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