The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

Abstract

Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (elnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC0-∞ (lnGM = 0.43; 95% CI = 0.35‒0.50; p < 0.00001) and Cmax (lnGM = 0.42; 95% CI = 0.33‒0.51; p < 0.00001) than non-carriers, while there was no significant difference in Tmax and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.

Pharmacogenetics of cardiovascular drugs

“…ABCG2 is also a transporter protein, and its genetic variation ( ABCG2∗A , rs2231142, c.421C>A) is associated with higher plasma levels of rosuvastatin (Fig. 3) [31]. CPIC guidelines recommend prescribing lower rosuvastatin doses (<20 mg) in patients with poor ABCG2 function and if higher doses are needed, it's recommended to consider combination or alternative therapy [29 ▪ ].…”

Influencia de la farmacogenética en la diversidad de respuesta a las estatinas asociada a las reacciones adversas

“…Un metaanálisis que incluyó 423 pacientes demostró que los portadores del alelo A en ABCG2 421C>A tenían una concentración aumentada de rosuvastatina. Debido a que la frecuencia del alelo A en población asiática es elevada (0.29) la FDA recomienda reducir la dosis en estos pacientes [ 46 ].…”

“…En la Tabla 4 se describen las recomendaciones terapéuticas sobre el ajuste de dosis para las diversas estatinas en base al fenotipo, predicho previamente por el análisis del genotipo. Los datos se basan en la guía del CPIC [ 9 ] y los metaanálisis [ 45 , 46 , 48 ]. Es aconsejable realizar el análisis del genotipo antes de iniciar el tratamiento y así poder considerar las recomendaciones pertinentes respecto al tipo y dosis de estatina.…”

Impacts of ABCG2 loss of function variant (p. Gln141Lys, c.421 C > A, rs2231142) on lipid levels and statin efficiency: a systematic review and meta-analysis

“…For instance, a clinical trial [ 14 ] revealed that the rs2231142 variant significantly improved the pharmacokinetics of fluvastatin and simvastatin. In contrast, a systematic review with meta-analysis [ 15 ] showed that the rs2231142 variant significantly increased the pharmacokinetics of rosuvastatin. In addition, a systematic review without meta-analysis [ 16 ] reported that the impact of rs2231142 on statin pharmacokinetics was stronger in rosuvastatin than in fluvastatin and simvastatin.…”