Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts

Dagli-Hernandez, Carolina; Zhou, Yitian; Lauschke, Volker M.; Genvigir, Fabiana Dalla Vecchia; Hirata, Thiago Dominguez Crespo; Hirata, Mário Hiroyuki; Hirata, Rosário Dominguez Crespo

doi:10.1007/s43440-021-00319-y

Cited by 11 publications

(16 citation statements)

References 157 publications

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“…CYP3A5*3 , for example, has been shown to decrease total cholesterol, LDL-c, and HDL-c reduction after atorvastatin treatment in Brazilian hypercholesterolemic patients [ 18 ], but no differences were observed in another study with Chilean hypercholesterolemic patients [ 43 ]. Other variants, such as SLCO1B1*5 , have been shown to increase statin blood levels in previous studies, but did not show to impact statin response, which is in agreement with the results in our study [ 19 ].…”

Section: Discussionsupporting

confidence: 94%

“…MRP1 (encoded by ABCC1 ) is an ABC membrane transporter highly expressed in the thymus, skeletal muscle tissue, kidney, urinary bladder, and gastrointestinal tract. It promotes the efflux of drugs, including statins and their metabolites, from hepatocytes to the bloodstream [ 19 ]. MRP1 is a highly conserved protein [ 35 ], but several variants, deleterious or not, have been identified worldwide [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…In this study, no deleterious PK-related variants were significantly associated with increased risk of SRAE. We previously discussed the lack of association between SRAE and SLCO1B1*5 and *15 , a well-described variant, in the Brazilian population in a recent review [ 19 ]. This is probably due to low sample sizes, which impaired the statistical power of the analysis in previous studies with Brazilian patients [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Statin pharmacogenetics studies have been performed in Brazilian cohorts and have brought important contributions, as we discussed in a recent review [ 19 ]. However, most Brazilian studies focused on nonfamiliar forms of hypercholesterolemia, and some of the results were not in agreement with reports from the literature.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…In addition to pharmacokinetics genes of statin, the polymorphisms of pharmacodynamics genes such as CETP, ApoE, lipoprotein lipase (LPL), low-density lipoprotein receptor (LDLR), and LXR also influence susceptibility to dyslipidemia and statin response. [60][61][62] Moreover, LDLR and LXR genes polymorphisms were found to be associated with variations in blood pressure, 63 which is one of the risk factors for cardiovascular disease. Further studies are needed to investigate the impact of the genetic variations in the pharmacodynamic pathway on statin response in the Thai population.…”

mentioning

confidence: 99%

Association of Drug-Metabolizing Enzyme and Transporter Gene Polymorphisms and Lipid-Lowering Response to Statins in Thai Patients with Dyslipidemia

Vanwong¹,

Tipnoppanon²,

Nakorn³

et al. 2022

PGPM

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Statins are increasingly widely used in the primary and secondary prevention of cardiovascular disease. However, there is an inter-individual variation in statin response among patients. The study aims to determine the association between genetic variations in drug-metabolizing enzyme and transporter (DMET) genes and lipid-lowering response to a statin in Thai patients with hyperlipidemia. Patients and Methods: Seventy-nine patients who received statin at steady-state concentrations were recruited. Serum lipid profile was measured at baseline and repeated after 4-month on a statin regimen. The genotype profile of 1936 DMET markers was obtained using Affymetrix DMET Plus genotyping microarrays. Results: In this DMET microarray platform, five variants; SLCO1B3 (rs4149117, rs7311358, and rs2053098), QPRT (rs13331798), and SLC10A2 (rs188096) showed a suggestive association with LDL-cholesterol-lowering response. HDL-cholesterol-lowering responses were found to be related to CYP7A1 gene variant (rs12542233). Seven variants, SLCO1B3 (rs4149117, rs7311358, and rs2053098); SULT1E1 (rs3736599 and rs3822172); and ABCB11 (rs4148768 and rs3770603), were associated with the total cholesterol-lowering response. One variant of the ABCB4 gene (rs2109505) was significantly associated with triglyceride-lowering response. Conclusion:This pharmacogenomic study identifies new genetic variants of DMET genes that are associated with the lipid-lowering response to statins. Genetic polymorphisms in DMET genes may impact the pharmacokinetics and lipid-lowering response to statin. The validation studies confirmations are needed in future pharmacogenomic studies.

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Apport de la pharmacogénétique dans le domaine cardio-vasculaire, l’exemple des statines

Abbes

Boujaafar

Ajmi

et al. 2022

Actualités Pharmaceutiques

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Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts

Cited by 11 publications

References 157 publications

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

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

Association of Drug-Metabolizing Enzyme and Transporter Gene Polymorphisms and Lipid-Lowering Response to Statins in Thai Patients with Dyslipidemia

Apport de la pharmacogénétique dans le domaine cardio-vasculaire, l’exemple des statines

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