ABCC2 rs2273697, rs717620, rs3740066 polymorphisms and antiseizure medication resistance: a systematic review and meta-analysis

Genetic variations in the ABCC2 gene have been proposed to influence resistance to antiseizure medications, but published findings to date are inconsistent. We aimed to systematically review and meta-analyze the association of three ABCC2 polymorphisms, rs2273697 (c.1249G >A, p.Val417Ile), rs717620 (c.-24C>T, 5′ UTR), and rs3740066 (c.3972C>T, p.Lys1324=), with antiseizure medication (ASM) resistance and to evaluate the statistical power, effect sizes, and required sample sizes. Searches covered PubMed, Scopus, the Cochrane Library, and NCBI dbSNP publication records (from inception to May 2026). The review followed PRISMA guidelines, and study quality was assessed using the Newcastle–Ottawa Scale (NOS). Statistical power and effect sizes (Cohen’s w) were estimated using G*Power 3.1, and random-effects meta-analyses were performed for all polymorphisms. Twenty studies (2627 ASM-resistant and 2639 ASM-responsive patients) met the inclusion criteria. Rs717620 was significantly associated with ASM resistance under the allelic (OR 1.25, 95% CI 1.06–1.48), dominant (OR = 1.25, 95% CI 1.01–1.54), recessive (OR 1.63, 95% CI 1.13–2.37), and homozygous (OR 1.79, 95% CI 1.17–2.74) genetic models, with low-to-moderate heterogeneity and no evidence of small-study bias. The pooled estimates for rs2273697 and rs3740066 were null across the genetic models. Most included studies were underpowered. Estimated median sample-size increases of 348%, 322%, and 289% were required for rs2273697, rs3740066, and rs717620 studies, respectively, to achieve 80% statistical power. The rs717620 (c.-24C>T, 5′ UTR) polymorphism showed the most consistent association with antiseizure medication resistance across genetic models. Given the limited statistical power of many existing studies, future research should focus on large consortium-based cohorts to improve statistical power and incorporate haplotype analysis.