Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany.
Pharmacogenet Genomics. 2011 Oct;21(10):624-30. doi: 10.1097/FPC.0b013e3283498131.
Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters, in particular ABCB1. Recently, we found a significant association of ABCC2 -24C>T with nonresponse, primarily in the context of generalized epilepsy. Moreover, ABCC2 1249G>A was reported to alter transmembranal carbamazepine transport. Therefore, we aimed to confirm the association of ABCC2 variants with pharmacotherapy-resistance in Caucasians mainly affected by partial epilepsy.
A total of 208 patients (114 male; age: 11.3±5.9 years) were genotyped for three putatively functionally relevant polymorphisms of ABCC2 (-24C>T, 1249G>A, 3972C>T). Genotype and haplotype frequencies were compared between responders and nonresponders to first-line antiepileptic treatment.
Carriers of the ABCC2 1249G>A variant (417V>I) were more frequent among responders [odds ratio (OR)=2.68 (1.25-5.78); P=0.010]. This association remained significant after adjusting for age, sex and seizure type, [OR=2.88 (1.23-6.73); P=0.015]. The impact of 1249G>A was more pronounced among 64 patients receiving carbamazepine or oxcarbazepine (P=0.005), but nonsignificant in patients receiving other anticonvulsants. ABCC2 -24C>T and 3972C>T showed lack of association to therapy response. Haplotype analyses revealed that haplotype H2 containing solely the 1249A variant allele was more frequent in the responder group [OR=2.98 (1.38-6.44); P=0.004].
These data argue for a greater probability of antiepileptic drug response among carriers of the ABCC2 1249A variant that is associated with reduced carbamazepine transport. Although we could not confirm an impact of ABCC2 -24C>T, these results suggest that ABCC2 genotype may also modulate the response to anticonvulsants besides the extensively studied ABCB1 (P-glycoprotein).
已有研究表明，药物外排转运体的基因多态性，尤其是 ABCB1，可调节抗癫痫药物的治疗反应。最近，我们发现 ABCC2-24C>T 与无应答显著相关，主要是在全面性癫痫的情况下。此外，有报道称 ABCC21249G>A 会改变跨膜卡马西平的转运。因此，我们旨在主要针对部分性癫痫的白种人群，确认 ABCC2 变体与药物治疗抵抗的相关性。
对 208 名患者（114 名男性；年龄：11.3±5.9 岁）进行了 ABCC2 三个潜在功能相关多态性（-24C>T、1249G>A、3972C>T）的基因分型。比较了一线抗癫痫治疗的应答者和无应答者之间的基因型和单倍型频率。
ABCC21249G>A（417V>I）变异携带者在应答者中更为常见[比值比（OR）=2.68（1.25-5.78）；P=0.010]。在调整年龄、性别和发作类型后，该关联仍然显著[OR=2.88（1.23-6.73）；P=0.015]。在接受卡马西平或奥卡西平治疗的 64 名患者中，1249G>A 的影响更为明显（P=0.005），但在接受其他抗惊厥药物治疗的患者中无显著差异。ABCC2-24C>T 和 3972C>T 与治疗反应无关联。单体型分析显示，仅包含 1249A 变异等位基因的单体型 H2 在应答者组中更为常见[OR=2.98（1.38-6.44）；P=0.004]。
这些数据表明，ABCC2 1249A 变异携带者的抗癫痫药物反应概率更高，这与卡马西平转运减少有关。尽管我们不能证实 ABCC2-24C>T 的影响，但这些结果表明，ABCC2 基因型除了广泛研究的 ABCB1（P-糖蛋白）外，还可能调节抗惊厥药物的反应。
