Structural and functional implications of ABCC1 variants on clinical statin response

ATP-binding cassette (ABC) proteins are membrane transporters responsible for metabolites and active substances removal from cells. Their genes' variations have been associated with protein function and expression defects. Familial Hypercholesterolemia (FH) patients hosting those alterations might compromise the efficacy of high-dose statin treatment, a primary therapeutic strategy. ABCC1 is a member of the ABC-transporter superfamily, potentially relevant to pharmacological therapy responses and toxicity risks in hypercholesterolemic patients. Here, we evaluated specific non-synonymous (SNV) missense variants in the ABCC1 gene from a FH patient cohort, assessing potential impacts on protein structure, molecular dynamics and interactions with rosuvastatin, atorvastatin, pravastatin, pitavastatin, and lovastatin. Molecular docking, complemented by motion, visual and binding affinity analysis using the PLANNET model, suggested that these mutations had minimal impact on drug interactions. These findings prompted further analysis of two other efflux pumps, ABCG2 and P-gp, and their statin interactions. Interestingly, diminished binding affinities hinted at a compensatory mechanism wherein other transporters might mitigate potential ABCC1 mutation effects, ensuring effective drug efflux. Clinical profiles from the patient cohort did not show a correlation between these variants and clinical outcomes, potentially pointing to the role of alternate drug transporters in statin interaction.