Tuberous Sclerosis Associated with MDR1 Gene Expression and Intractable Epilepsy
Date Issued
2004
Date
2004
Author(s)
Wang, Ling-Yi
DOI
en-US
Abstract
摘要
背景：癲癇是結節性硬化症（TSC）主要的神經學併發症之一，約影響85∼96％的患者，且多數是屬於難治型癲癇症。多重抗藥性基因（MDR1）所轉譯出的P-glycoprotein，係一個將藥品打出細胞外的轉運子，且MDR1被認為與癲癇控制成效有關。本研究欲探討在TSC併有癲癇的患者，MDR1的基因多型性如何影響其癲癇控制的成效。
方法：收集67個無血緣關係之指標病例與其父母的血液檢體，並萃取其DNA。利用denaturing high-performance liquid chromatography(DHPLC)進行結節性硬化症的基因診斷，並由神經科醫師評估其臨床表徵與癲癇控制的情形。藉Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) 來偵測MDR1的6個單點核酸多型性(single nucleotide polymorphism, SNP)：A61G, G1199A, C1236T, G2677T/A, C3435T。以卡方檢定來偵測三個最具多型性的SNPs(C1236T,G2677T, C3435T)和癲癇治療成效的關連,並利用TDT (transmission disequilibrium test)來偵測MDR1基因型和難治型癲癇是否有連鎖情形。以貝氏分析估計3435CC相對於3435TT 對難治型癲癇的posterior危險對比值。
結果：最後有52個併發癲癇的TSC病人納入分析（24位對藥品反應很好，28位為難治型癲癇患者）。我們嘗試了顯性，隱性，加成和倍數4種遺傳模式來評估何種模式較可有效地解釋這3個SNP影響癲癇控制成效的行為。在此3個SNP中，G2677T呈現邊界顯著，其他兩個SNPs無呈現統計顯著。G2677T中，對難治型癲癇的各危險對比值：GG相對於GT&TT、GG>相對於TT、G相對於T分別為7.10（95％信賴區間：0.77∼65.8, p=0.084），2.0（95％ 信賴區間：0.65∼6.17, p=0.225）和 2.13 （95％信賴區間：0.93∼4.83, p=0.069）。在加成模式中，Cochran-Armitage trend test 觀察到隨著G對偶基因數目的增加，危險性也增加（p >0.067)。由各SNP三種基因型的兩兩相比，G2677T呈現邊界顯著，其他兩個SNPs無呈現統計顯著。G2677T中，對難治型癲癇的各危險對比值，GG相對於TT、GT相對於TT、GG相對於GT分別為 8.75（95%信賴區間：0.86∼88.7, p =0.069）, 5.91 (95%信賴區間：0.60∼58.5,p=0.175)和1.48（95％信賴區間：0.45∼4.83，p=0.515）。C3435T經貝氏分析後，對難治型癲癇，CC相對於TT的posterior危險對比值為2.65( 95% 信賴區間：1.33∼4.82)。
結論：在本研究的基因型研究中，皆未達統計上之顯著，樣本數太小可能為其原因之一。由G2677T呈現的邊界顯著及C3435T經貝氏分析之結果來看，在本研究族群中，G2677T和C3435T 有趨勢可能成為難治型癲癇之易感受基因之一，但仍需要更大的樣本數來證實目前的研究結果。
關鍵字：結節性硬化症，難治型癲癇，多重抗藥性基因(MDR1)，P-glycoprotein
Abstract
Background: Epilepsy is one of the major neurological complication of tuberous sclerosis complex (TSC), affecting 85~96% of patients, and many of them are refractory to medical treatment. Multidrug resistance gene (MDR1),which encodes P-glycoprotein, an drug efflux transporter, is extensively investigated for its impact on various drugs and treatment efficacy. MDR1 is considered to be associated with efficacy of seizure control. In the present study, we will investigate how the polymorphisms of MDR1 affect the seizure control efficacy in TSC patients with epilepsy.
Methods: The blood samples of 67 TSC probands along with their parents were collected and had DNA extracted. TSC genetic diagnosis was performed by denaturing high-performance liquid chromatography (DHPLC). Clinical manifestation along with efficacy of seizure control were evaluated by the neurologist. MDR1 polymorphism were identified with PCR-RFLP for A61G, G1199A, C1236T, G2677T/A, C3435T. Chi square test were used to detect the association among three most polymorphic SNPs (C1236T, G2677T, C3435T) and drug-resistant epilepsy. Transmission disequilibrium test (TDT) was applied to detect the linkage between MDR1 polymorphisms and drug-resistant epilepsy. Bayesian method was used to estimate the posterior odds ratio (OR) for drug-resistant epilepsy of 3435CC/3435TT.
Results: 52 TSC patients with epilepsy (24 drug-responsive, 28 drug-resistant) were analyzed by the dominant, recessive, multiplicative and additive models, We would evaluate which model can explain the behavior of how these 3 SNPs affect the efficacy of seizure control efficiently. Among the three SNPs, G2677T showed a borderline significance, while the other two were not statistically significant. For G2677T, ORs for drug-resistant epilepsy of GG & GT/ TT, GG /GT& TT, G/T were 7.10 (95% CI:0.77 ~65.8, p=0.084), 2.0 (95%CI:0.65 ~ 6.17, p=0.225) and 2.13 (95% CI: 0.93 ~4.83, p=0.069), respectively. In the additive model with Cochran-Armitage trend test, the trend of risk increased with amount of G allele was observed (p > 0.067). After two-two comparisons between three genotypes in each SNP. G2677T revealed a borderline significance, while the other two were not statistically significant. For G2677T, ORs for drug-resistant epilepsy of GG/TT, GT/TT and GG/GT were 8.75 (95% CI: 0.86 ~ 88.7, p= 0.069), 5.91 (95 % CI: 0.60 ~ 58.5, p=0.175), and 1.48 (95% CI: 0.45 ~ 4.83, p=0.515), respectively. After Bayesian analysis, the posterior OR for drug-resistant epilepsy of 3435CC/3435TT was 2.65 (95% CI: 1.33~4.82).
Conclusions: The results in our study failed to achieve statistical significance, small sample size may be one of the reasons. From the borderline significance in G2677T and the result of Bayesian analysis in C3435T, it revealed a trend that C3435T and G2677T might be one of the susceptible genes for drug-resistant epilepsy in TSC. Larger sample size is needed to confirm the present results.
Keywords: Tuberous sclerosis complex (TSC), Drug-resistant epilepsy, MDR1, P-glycoprotein
Subjects
P-glycoprotein
結節性硬化症
多重抗藥性基因(MDR1)
難治型癲癇
Drug-resistant epilepsy
Tuberous sclerosis complex (TSC)
MDR1
Type
text
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