Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach

Cela, Luis Ramudo; Santana-Martínez, Sara; García-Ramos, Maite; Bergamino, Mariano; García-Giustiniani, Diego; Vélez-Vieitez, Paula; Hernández, José L.; García-Ibarbia, Carmen; González‐Bustos, Pablo; Ruíz-Martín, Patricia; González-Lozano, Jaime; Santomé-Collazo, Luis; Grana-Fernandez, Andrea; Cabaleiro-Cerviño, Pablo; Ortiz, Martín; Monserrat, Lorenzo

doi:10.1038/s41397-022-00274-8

Cited by 1 publication

(1 citation statement)

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“…Polymorphisms in pharmacokinetics (PK)-related genes, such as drug transporters (SLCO1B1, ABCB1, ABCC2, and ABCG2) and cytochrome P450 enzyme system (CYP3A4, CYP3A5), as well as polymorphisms in pharmacodynamics (PD)-related genes (APOE, LDLR, PCSK9 and KIF6) were proven to affect the efficacy and safety of statins in FH and non-FH patients worldwide [7,[10][11][12]. Additionally, a recent study implemented a nextgeneration sequencing strategy combining genetic and pharmacogenetic studies of FH patients, most of whom (66.5%) were carriers of pharmacogenetic actionable variants and combinations of loss-of-function variants in SLCO1B1, CYP3A4/5 and CYP2C9 were the major contributors of response to statins [13]. The authors concluded that this implementation approach improves the pharmacotherapeutic process and management of FH patients.…”

Section: Introductionmentioning

confidence: 99%

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

Dagli-Hernandez,

Ferreira,

Freitas

et al. 2024

Pharmacogenetics and Genomics

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Objectives This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. Methods Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. Results A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. Conclusion Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.

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