Association of ABCG2 421G>T (rs2231142) Polymorphism with rosuvastatin induced adverse effects in dyslipidemic patients: Implication for personalized medicine.

Abstract

Statins are considered as the first line drugs for the treatment of hyperlipidemia. Despite proven efficacy of rosuvastatin, inter-individual variations in plasma rosuvastatin levels have been documented in various studies which causes variable response to statin tolerance. This study aims to evaluate the possible association of ABCG2 421 G > T (rs2231142) polymorphism with inter-individual variations in plasma rosuvastatin levels which potentially increases the rosuvastatin related adverse effects. This quasi experimental study was carried out from June 2022 till December 2023 in two tertiary care hospitals of Pakistan. Hyperlipidemic patients with low density lipoprotein more than 130 mg/dl were enrolled through non-probability purposive sampling. All the enrolled patients were treated with rosuvastatin 10 mg once daily for 12 weeks. Fasting lipid profile, serum creatine phosphokinase, liver and renal function tests were measured at the start of study and after 12 weeks of intervention with rosuvastatin. Blood samples were also collected for genotyping and determination of plasma rosuvastatin levels. Frequency of ABCG2 421 G > T polymorphism for wild type GG, heterozygous mutant GT and homozygous mutant TT genotypes were 54.5, 36.2 and 9.3% respectively. Minor allele frequency was 0.27. Patients with TT and GT genotypes have significantly raised plasma levels of rosuvastatin with mean value of 30.23 ± 4.8 ng/mL and 22.35 ± 5.1 ng/mL respectively as compared to wild GG genotypes 13.95 ± 8.9 ng/mL (p=<0.001). Frequency of myopathy, hepatotoxicity and nephrotoxicity in study population was 5.3, 3.2 and 4.8% respectively. All the genetic models including co-dominant model GT (OR= 5.45, 95% CI: 3.09-9.62, p= < 0.0001), TT (OR= 88.51, 95% CI: 24.84-315.44), dominant model (OR= 8.45, 95% CI: 4.91-14.52, p= < 0.0001), recessive model (OR=37.29, 95%CI 11.06-125.78, p < 0.001), over-dominant model, (OR= 2.26, 95% CI: 1.42-3.60, p= < 0.0001) showed significant association with rosuvastatin adverse effects. It is inferred that patients having T variant allele is associated with higher plasma rosuvastatin concentration and increased the risk of development of adverse effects compared with G allele carriers. It is therefore suggested that genetic profiling may be done for dose tailoring to minimize the statin intolerance.