基因對於高脂血症藥物療效之影響

Effect of genes on drug therapy for hyperlipidemia

林旻萱(Min-Hsuan Lin)

指導教授 ： 黃慶三

中臺科技大學/健康科學院/醫學檢驗生物技術系碩士班/碩士(2011年)

摘要

由於心臟性疾病以及腦血管疾病為近年來台灣十大死因中排名第 2 及第 3 名，耗用了許多的醫療資源，因此，評估心臟血管疾病的治療成效，可以在醫療上提供良好的治療策略，有效的降低醫療的成本與時間。冠脂妥 （Rosuvastatin） 是治療高脂血症有效藥物之一。近期研究報告顯示，以同樣劑量治療患者，冠脂妥在血中的濃度亞洲人較白種人高，這可能是不同人種其代謝冠脂妥的基因有所差異的關係。目前已知與冠脂妥代謝有關的去毒蛋白有細胞色素 P450 （CYP） 2C9、尿苷雙磷酸葡萄糖醛酸基轉移酶 （UGT） 1A1、UGT1A3、有機陰離子轉移胜肽鏈 （OATP2）與抗乳癌蛋白 （BCRP）。本實驗主要的目的，要找出與 rosuvastatin 治療成效相關之去毒蛋白基因的變異。
本研究以每天服用 5 mg rosuvastatin 的病患為研究族群，患者治療前及使用藥物三個月後，測量其低密度脂蛋白膽固醇 （LDL-C）、高密度脂蛋白 （HDL-C）、三酸甘油酯 （TG） 及總膽固醇 （TC）。另一方面，利用 PCR-RFLP 及 Allele-Specific PCR Assay 方法分析影響 rosuvastatin 代謝的去毒蛋白基因變異之 nucleotide （nt），包含了 UGT1A1 基因之位點 nt -53 及 nt 211、UGT1A3 基因之位點 nt 31 及 nt 140 以及 OATP2 基因之位點 nt 388 及 nt 521，依據檢測結果分為幾種組合型；總和以上結果進行統計分析。
目前已分析 107 位受試者的 UGT1A1 基因之位點 nt -53 及 nt 211、UGT1A3 基因之位點 nt 31 及 nt 140 以及 OATP2 基因之位點 nt 388 及 nt 521 共六個基因的位點，將其變異情況各分成四個群組，並收集受試者之 LDL-C、TG、TC 及 HDL-C 臨床生化檢驗值，分為 UGT1A1、UGT1A3 與 OATP2 三個群組個別利用統計軟體進行統計分析。根據實驗結果發現，在服用 5 mg rosuvastatin 三個月後，與未同時出現變異的另外三組比較起來，OATP2 第四組 （nt 388 及 nt 521 都有變異） 能夠有效降低LDL-C 的有約 9 倍 （OR = 8.63，95% CI 1.37 - 54.48，point-wise p = 0.021） 的差異。
所以，可能當 OATP2 的 nt 521 及 nt 388 都變異時，血液中藥物較不易代謝，以至於服用藥物後的效果上升。但由於本試驗樣本數只有107人，且病人服用劑量為 rosuvastatin 最低劑量 （5 mg），所以若繼續增加樣本數或適當提高治療劑量，可能更可以看出病人在服用 rosuvastatin 後，去毒蛋白基因位點間的變異對於藥物療效的差異。

關鍵字

冠脂妥 ； 尿苷雙磷酸葡萄糖醛酸基轉移酶 ； 有機陰離子轉移胜肽鏈 ； 抗乳癌蛋白 ； 低密度脂蛋白膽固醇

並列摘要

Cardiovascular disease and stork are always the number 2 and 3 killers for Taiwanese population in recent years, and they really cost much from our medical resource. Thus, monitoring the impact of treatment on cardiovascular risks is essential to enable the implementation of appropriate strategies towards to effectively reduce the medical resource and time.
Rosuvastatin (RAV) is one of the powerful lipid-lowering statin. Recently, several studies show that after a same dosage, the serum level of RAV has been proved to be higher in Asian people than that in Caucasians. This may be attributable to genetic differences on RAV metabolism among ethnic groups. The metabolism of RAV is principally mediated by the cytochrome P450 (CYP) 2C9, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, organic anion transporter polypeptide 2 (OATP2) and breast cancer resistance protein (BCRP). The aim of this study is to find which single nucleotide polymorphism (SNP) of the detoxification protein influencing the therapeutic effectiveness of RAV in Taiwanese hyperlipidemic patients.
This study enrolled 107 hyperlipidemic patients who treated with 5 mg RAV daily. Before and 3 months after RAV treatment, lipid profile including total cholesterol (TC); low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) were determined. Single nucleotide polymorphism (SNPs) at nucleotides (nts) -53 and 211 of UGT1A1 gene, SNPs at nts 31 and 140 of UGT1A3 gene and SNPs at nts 388 and 521 of OATP2 gene were detected for those patients with the method of PCR-RFLP or Allele-Specific PCR Assay. The 107 study subjects were divided into 4 groups according to their variation status of UGT1A1, UGT1A3 and OATP2 genes, respectively. Then the 4 groups were divided into 2 subgroups according to therapeutic effectiveness: ≧ 40% and < 40% for LDL-C reduction; ≧ 15% and < 15% for TG reduction; ≧ 30% and < 30% for TC reduction and ≧ 6% and < 6% for HDL-C increasing, respectively. Odds ratio (OR) and its 95% confidence interval (CI) of each genetic group were calculated. The 95% CI of an OR above or below 1.00 was defined as statistically significant.
Individuals carrying variations at nucleotide 388 and 521 in the OATP2 gene have an approximately 9-fold chance of effective treatment for LDL-C than individuals with any other genotype pattern [OR = 8.63, 95% CI (1.37-54.48), point-wise p = 0.021]. It has been reported that variation at nt 388/nt 521 in OATP2 should be gene may cause decreased elimination rate of RAV and increase the plasma concentration of RAV. This is the reason that effective lipid reduction is observed in the subjects carrying such a genetic variation when they receive RAV treatment, as we found in this study. However, in our study, the dosage of RAV is low (5 mg) and the number size is too small (N = 107). Therefore, a more comprehensive investigation with larger number of study subjects is necessary in order to prove that variation of detoxification protein genes affect therapeutic effectiveness of RAV.

並列關鍵字

UDP-glucuronosyl-transferase 1A1 ； Rosuvastatin ； UGT1A3 ； organic anion transporter polypeptide 2 and brea ； low-density lipoprotein cholesterol

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