<i>ABCG2</i>
            Gene Polymorphisms as Risk Factors for Atorvastatin Adverse Reactions: A Case–Control Study

Skvrce, Nikica Mirošević; Šarinić, Viola Macolić; Šimić, Iveta; Ganoci, Lana; Katanec, Diana Muačević; Božina, Nada

doi:10.2217/pgs.15.47

Cited by 31 publications

(15 citation statements)

References 59 publications

(78 reference statements)

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“…Single nucleotide polymorphism of ABCG2 421C>A (p.Q141K) results in its reduced activity – mRNA expression is maintained, but protein expression and function is reduced by 50–70% due to enhanced susceptibility to proteasomal degradation . Variant allele carriage is associated with a higher systemic exposure to several statins and sulfasalazine and with an increased incidence of adverse effects of statins and gefitinib . The present data suggest that it enhances the effect of valproate on exposure to lamotrigine.…”

Section: Discussionmentioning

confidence: 99%

Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Domjanović

Lovrić

Trkulja

et al. 2018

Brit J Clinical Pharma

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Section: Discussionmentioning

confidence: 99%

Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Domjanović

Lovrić

Trkulja

et al. 2018

Brit J Clinical Pharma

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“…The 421AA genotype has been associated with a 2.4-fold increased exposure to RVT,~2-fold increased exposures to ATV, FVT, and SVT, but no increased exposures to PIT or PVT [108]. Interestingly, carrying rs2231142 421A has been associated with an increased risk of myotoxicity with ATV [120], and in renal transplant recipients receiving FVT [105]. Both of these studies were small case control candidate gene studies and have not been confirmed in GWAS, although SRM GWAS analyses have included relatively few FVT cases to date [86,110,111,115].…”

Section: Abcb1 and Abcg2 Efflux Transportersmentioning

confidence: 99%

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Turner

Pirmohamed

2019

JCM

132

126

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Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.

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“…The mutated ABCG2 rs2231142 SNP has been previously associated with alterations in the pharmacokinetics of statins, with higher AUC being reported for atorvastatin and fluvastatin concentrations in 421A homozygotes vs 421C homozygotes . A case‐control study also showed that patients with the ABCG2 421CA or AA genotypes were 2.9 times more likely to develop adverse drug reactions—depending on the atorvastatin dose—than the ABCG2 421C homozygotes . Unfortunately, only one of our subjects carried this genotype.…”

Section: Resultsmentioning

confidence: 68%

Transporter genesABCG2rs2231142 andABCB1rs1128503 polymorphisms and atorvastatin response in Chilean subjects

2017

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SummaryWhat is known and objective: Statins are first-line therapy for reducing high cholesterol levels. However, response to these drugs shows high interindividual variability.We aimed to investigate the influence of two single nucleotide polymorphisms (SNP) (ABCB1 rs1128503 and ABCG2 rs2231142) in the ABC transporter genes on response to short-term low-dose atorvastatin in Chilean hypercholesterolaemic patients. Methods:We studied 127 Chilean hypercholesterolaemic patients treated with 10 mg/d atorvastatin for 4 weeks. The lipid profile was determined before and after drug administration. Genotyping of the rs1128503 and rs2231142 variants was performed using TaqMan ® Drug Metabolism Genotyping Assays. Results and discussion:Genotype distribution for all polymorphisms investigated was consistent with the Hardy-Weinberg equilibrium. Atorvastatin reduced TC, LDL-C and TG concentrations (P<.05), whereas HDL-C levels were found to be increased (P<.05).Minor allele frequencies for rs1128503 and rs2231142 variants were 0.453 and 0.075, respectively. In this study, patients prescribed with short-term low-dose atorvastatin and carrying ABCB1 (rs1128503) or ABCG2 (rs2231142) SNPs did not show differences in LDL-C response (P>.05).What is new and conclusion: The ABCB1 SNP was not associated with response to atorvastatin in Chilean subjects. The few ABCG2 421A homozygotes did not allow meaningful inferences to be made for this polymorphism. K E Y W O R D Spharmacogenetics, polymorphism, statin | WHAT IS KNOWN AND OBJECTIVEAtorvastatin is the treatment of choice in patients with hypercholesterolaemia in Chile. It is safe and effective in reducing the risk of cardiovascular diseases.

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ABCG2 Gene Polymorphisms as Risk Factors for Atorvastatin Adverse Reactions: A Case–Control Study

Abstract: Our study demonstrated an association between atorvastatin-induced ADRs and genetic variants in the ABCG2 gene.

Cited by 31 publications

References 59 publications

Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Transporter genesABCG2rs2231142 andABCB1rs1128503 polymorphisms and atorvastatin response in Chilean subjects

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