基因多型性對癲癇症藥物治療反應之影響

Abstract

背景介紹: 三成的癲癇病人即使給予適當的藥物治療仍有發作情形，成為難治型癲癇。同一類型的癲癇病人對藥物反應不盡相同，因此個體間基因型的差異可能在癲癇藥物治療上扮演重要角色。GABAA 受體是抗癲癇藥物治療重要的標的分子之一。其由五個次單元所組成，兩個α次單元、兩個β次單元及一個其它型次單元，其中α次單元是當中多樣性最高(α1-α6)且和GABA結合的次單元，有許多文獻指出不同α次單元所組成的GABAA受體對GABA及許多抗癲癇藥有不同的反應，因此α次單元上的基因多型性極有可能影響癲癇病人對藥物治療的反應。 目標:探討GABAA受體α次單元基因多型性對癲癇症藥物治療的影響。 研究方法: 我們收納了758位癲癇病人及194位正常受試者，針對α次單元六種亞型相對應的基因GABRA1-GABRA6，利用選取標籤單核苷酸多型性的方法，對這六個基因區域進行相關性分析。並額外分析了在SCN1A、SCN2A、ABCB1、ABCC2基因上報導過會影響癲癇治療的單核苷酸多型性。 結果:我們在GABRA1-GABRA6成功鑑定了132個標籤單核苷酸多型性，研究結果發現GABRA4 intron7 上rs17599416這個曾被報導過和自閉症相關的位點會影響使用phenobarbital病人對藥物的反應，反應不好的病人傾向帶有對偶基因型A (odds ratio 2.8261，95% confidence interval: 1.1968- 6.6736，未校正p-value=0.01792)，GABRA2基因下游的rs511310在使用phenobarbital的病人中傾向帶有對偶基因型G (odds ratio 6.413，95% confidence interval: 2.203-18.67，未校正p-value=0.000363)。另在羅吉斯迴歸中發現GABRA3 intron1上的rs4828696在不同藥物使用分組條件中對藥物反應有不同程度的影響。 討論與結論: 這是一篇完整探討GABAA受體α次單元基因和癲癇治療相關性的研究，我們發現了幾個標籤單核苷酸多型性所代表的基因區域可能影響癲癇藥物治療的效果，更多獨立樣本的研究可以進一步驗證我們的發現，定序標籤單核苷酸多型性附近可能影響基因功能的序列，並針對可能影響基因功能的單核苷酸多型性做進一步功能研究是未來可以探討的方向。

Background: Approximately 30% of patients continue to have seizures despite optimized drug treatment. The responses to AEDs may differ in patients even with the same type of epilepsy. It is possible that genetic polymorphisms may, to certain degree, cause the response variability of the epilepsy pharmacotherapy. The ionotropic receptors of gamma-aminobutyric acid (GABAA) are among the most important target sites for AEDs. The most common subunit composition of GABAA receptors is two α, two β, and one other subunits. The α subunit family is the most diverse, with six different subtypes (α1–α6). GABA binding occurs at α subunits. Many lines of evidence indicate different GABAA receptors composed of different α subunits have different response to GABA and other AEDs. Aims: Here we hypothesize that genetic polymorphisms in α subunits may, to certain degree, explain variable responses in different epilepsy patients. Methods: 758 epilepsy patients, all with comprehensive clinical data, and 194 controls were enrolled in this study. We genotyped tagging SNPs at the 6 α subunits genes, GABRA1-GABRA6,and other SNPs in SCN1A,SCN2A,ABCB1,ABCC2 ,which have previously associated with epilepsy treatment outcome. Results: We demonstrated the association between phenobarbital response and a SNP (rs17599416) in the intron7 of GABRA4, a gene previously shown to be associated with autism. Patients with the “A allele” were more likely to be drug resistant (odds ratio 2.8261, 95% confidence interval: 1.1968 to 6.6736, nominal p-value=0.01792). rs511310 in the downstream region of GABRA2 also showed an effect on phenobarbital response. Patients with the “G allele” were more likely to be drug resistant (odds ratio 6.413, 95% confidence interval: 2.203-18.67，nominal p-value=0.000363). Using the logistic regression model, rs4828696 in intron1 of GABRA3 was associated with the drug response on different level in patients with different drug usage. Discussion and conclusion: This report, to our knowledge, is the first association study to have comprehensive coverage of all 6 α subunits of GABAA receptor genes and reasonably good sample size. Further replication using an independent sample collection will be essential to confirm our findings. Functional assays will help to illustrate how those associated genes influence the pharmacotherapy responses of AEDs.