- 學位論文
多重抗藥性基因的基因多型性和臟得樂引發甲狀腺功能異常在台灣心房顫動病人的研究
Polymorphism of multidrug resistance 1 (MDR1) gene and amiodarone induced thyroid dysfunction in Taiwan atrial fibrillation patients– a single medical center study
摘要
臟得樂(amiodarone)經常會引起甲狀腺功能異常。但是臟得樂引起甲狀腺功能異常的原因是否與臟得樂的服用期間與累積劑量有關這個問題目前仍有爭議。P-醣蛋白(p-glycoprotein，p-gp)是多重抗藥性基因(multiple drug resistance 1，MDR1)基因的產物並且與甲狀腺荷爾蒙的分佈有關。然而，MDR1基因的多型性與臟得樂引起甲狀腺功能異常的相關性尚未確立。本研究探討在台灣心房顫動(atrial fibrillation，Af)病人族群中MDR1基因的多型性與臟得樂引起甲狀腺功能異常的相關性。 我們共收納了130個因心房顫動長期使用低劑量臟得樂治療的病人。這些病人之前無甲狀腺疾病病史，並且在服藥之前已抽血檢驗血中游離甲狀腺素(free T4，fT4)及甲狀腺刺激素（thyroid stimulating hormone，TSH）值均在正常範圍內。收案期間為西元2010年9月1日至2012年8月31日。病患收集的資料包括年齡、性別、病史及生化檢查數值、臟得樂使用劑量及服用期間。採用聚合酶鏈反應-限制性片段長度多型性(PCR-RFLP)的方法，根據MDR1基因的多型性將病人分成Wild type, Heterozygous, homozygous三組。每六個月抽血檢驗血中游離甲狀腺素及甲狀腺刺激素值。來分析MDR1基因的多型性與臟得樂引起甲狀腺功能異常的相關性。 根據多變項回歸分析的結果顯示：女性[HR= 2.338 (95% CI: 1.328 - 4.117), p value= 0.003]，C1236T的TT基因型(genotype) [HR= 5.474 (95% CI:1.165 – 25.720), p value= 0.031]，G2677T的GT基因型[HR= 3.985 (95% CI:1.528 –10.392), p value= 0.005]與臟得樂引起甲狀腺刺激素(TSH)值異常有關。但是無法證明C1236T、G2677T、C3435T這三種MDR1基因的多型性與臟得樂引起游離甲狀腺素(free T4)值異常有相關性。 對於C1236T的單核酸基因多型性而言，具有TT基因型的患者較易因臟得樂而引起甲狀腺刺激素(TSH)值異常。對於G2677T的單核酸基因多型性而言，具有GT基因型的患者較易因臟得樂而引起甲狀腺刺激素(TSH)值異常。而對於C3435T的單核酸基因多型性而言，三種不同的基因型患者與因臟得樂而引起甲狀腺刺激素(TSH)值異常沒有統計學上有意義的相關性。我們的研究也發現，根據多變項回歸分析的結果顯示：女性，C1236T的TT基因型，G2677T的GT基因型與臟得樂引起甲狀腺刺激素(TSH)值異常有關。但是C1236T、G2677T、C3435T這三種MDR1基因的多型性與臟得樂引起游離甲狀腺素(free T4)值異常無關。
並列摘要
Amiodarone is frequently associated with thyroid dysfunction. There is conflicting evidence whether amiodarone-associated thyroid dysfunction is associated with exposure time and higher (cumulative) dosages. P-glycoprotein is the product of multidrug resistance (MDR1) gene and it may have a role in the distribution of thyroid hormone. The purpose of our study is to investigate the relationship of MDR1 gene polymorphism and amiodarone-associated thyroid dysfunction in Taiwan atrial fibrillation patients. We included 130 consecutive patients with low dose amiodarone therapy for atrial fibrillation. All of them were free from thyroid disease before. MDR1 polymorphism of C1236T, G2677T, and C3435T was checked when they were enrolled, and thyroid function tests were performed every 6 months. After multivariate analysis, female sex [HR= 2.338 (95% CI: 1.328 - 4.117), p value= 0.003], exon 12 C1236T homozygous genotype (TT) [HR= 5.474 (95% CI: 1.165 – 25.720), p value= 0.031], and exon 21 G2677T heterozygous genotype (GT) [HR= 3.985 (95% CI: 1.528 –10.392), p value= 0.005] were predictors for amiodarone- associated TSH level abnormality. There were statistically significant differences between C1236T (p value= 0.033), G2677T (p value= 0.041) genotype frequencies of both normal TSH level group and abnormal TSH level group, but C3435T genotype frequency of the two groups was not significant difference. Only C1236T genotype frequency is statistically significant differences between high TSH level group and low TSH level group. We also found female sex, exon 12 C1236T homozygous genotype (TT), and exon 21 G2677T heterozygous genotype (GT) were predictors for amiodarone-associated TSH level abnormality.