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

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.

• Authors: Carolina Dagli-Hernandez, Jéssica Bassani Borges, Elisangela da Silva Rodrigues Marçal, Renata Caroline Costa de Freitas, Augusto Akira Mori, Rodrigo Marques Gonçalves, Andre Arpad Faludi, Victor Fernandes de Oliveira, Glaucio Monteiro Ferreira, Gisele Medeiros Bastos, Yitian Zhou, Volker M Lauschke, Alvaro Cerda, Mario Hiroyuki Hirata, Rosario Dominguez Crespo Hirata
• Journal: Pharmaceutics (Pharmaceutics) Vol. 14 Issue 5 (Apr 27 2022) ISSN: 1999-4923 [Print] Switzerland
• PMID: 35631530 (Publication Type: Journal Article)