Impact of CYP3A5 rs776746 and CYP3A7 rs2257401 polymorphism on steroid metabolism and dose optimization in pediatric nephrotic syndrome

Abstract

A multicentric genetic study was conducted on 200 paediatric patients with nephrotic-range proteinuria, including 100 cases each of steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS). The study analysed two genetic variants: CYP3A5 (rs776746) and CYP3A7 (rs2257401). For CYP3A5 Variant rs776746 A > G is also known as 6986A > G CYP3A5*3 allele. Individuals with the A allele (6986A) carry the CYP3A5*1 (functional) allele. Individuals with the G allele (6986G) carry the CYP3A5*3 (non-functional) allele. overall genotype frequencies were 20.5 % AA, 30 % GG, and 49.5 % AG. In the SSNS group, the distribution was 13 % AA, 36 % GG, and 51 % AG (A allele: 0.38, G allele: 0.62), while the SRNS group showed 28 % AA, 24 % GG, and 48 % AG (A allele: 0.52, G allele: 0.48). For CYP3A7 rs2257401, genotype frequencies were 15 % GG, 21 % CC, and 64 % GC. In SSNS, 14 % were GG, 24 % CC, and 62 % GC; in SRNS, 16 % GG, 18 % CC, and 66 % GC. G and C allele frequencies were equal (0.5) in both groups for CYP3A7. The findings suggest that CYP3A5 rs776746, particularly the GG genotype, may be associated with reduced steroid response, potentially requiring alternative treatment approaches in SRNS patients. The rs776746 polymorphism involves an A > G substitution, where the AA genotype (CYP3A5 3/3) indicates non-functional enzyme expression. Genotypic comparison showed higher AA frequency in SRNS patients. The AA genotype was associated with lower steroid metabolism, necessitating dose reduction. In contrast, CYP3A7 rs2257401 showed no significant correlation. This suggests that CYP3A5 genotyping could aid dose optimization in steroid-resistant cases.