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

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Dagli-Hernandez, Carolina ; Borges, Jessica Bassani ; Rodrigues Marcal, Elisangela da Silva ; Costa de Freitas, Renata Caroline ; Mori, Augusto Akira ; Goncalves, Rodrigo Marques ; Faludi, Andre Arpad ; de Oliveira, Victor Fernandes ; Ferreira, Glaucio Monteiro ; Bastos, Gisele Medeiros ; Zhou, Yitian ; Lauschke, Volker M. ; Cerda, Alvaro ; Hirata, Mario Hiroyuki ; Crespo Hirata, Rosario Dominguez

• Document type: Journal article
• Source: PHARMACEUTICS; v. 14, n. 5, p. 20-pg., 2022-05-01.

Abstract

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. (AU)

• FAPESP's process: 19/19009-4 - In silico functionality prediction analysis of pharmacogenes and development of a pharmacogenetic score for Brazilian familial hypercholesterolemia patients
• Grantee: Carolina Dagli Hernandez
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 16/25637-0 - Pharmacogenomic and pharmacoepigenomic analysis in individuals with familial hypercholesterolemia
• Grantee: Carolina Dagli Hernandez
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)