台灣地區中草藥腎病變與CYP1A1/2、MDR1基因多型性之病例對照研究

Abstract

中草藥腎病變（Chinese herbs nephropathy，CHN）是一種快速進展至腎間質纖維化，因而導致進入末期腎衰竭（end-stage renal disease，ESRD）的疾病，致病原因除了馬兜鈴酸的細胞毒性之外，在此族群中是否也因基因耐受性不同而導致疾病，目前仍是未定論。 本研究經由2000至2007年間回溯性與前瞻性研究方式。在台大醫院篩選出可能為中草藥腎病變的病人共69名，以及曾使用中草藥一個月以上之健康對照組82名，紀錄他們的病史與用藥史。並使用SNPstream與PCR-RFLP方法分析CYP1A1、CYP1A2、NQO1、NAT2、NAT1、GSTM1、GSTT1、GSTP1、CYP2C19與MDR1基因共19個SNP。 結果顯示單一核苷酸多型性如CYP1A2 -3860 GA型、MDR1 2677 GT型與3435 CT型顯著增加疾病風險，校正後勝算比（odds ratio，OR）分別為2.71（CI95% 1.03 – 7.13）、3.94（CI95% 1.19 – 13.05）與3.65（CI95% 1.34 – 9.97）。而在雙體型（haplotype combinations）分析上，CYP1A1*2A/2B與MDR1 2677/3435的GC/TT型均達顯著水準，OR分別為7.76（CI95% 1.32 – 45.45）與4.82（CI95% 1.39 – 16.73）。另外結合MDR1 C3435T與CYP1A1單體型（haplotype）發現，同時攜帶MDR1 exon 26 3435位置的CT或TT型與CYP1A1的突變型（*2A或*2B），會大幅增加OR為13.33（CI95% 1.39 – 128.23，p = 0.03）。顯示兩個基因對於疾病可能有協同效應（synergistic effect）。 本研究顯示CYP1A1/2與MDR1的突變可能會影響中草藥腎病變的致病，並且可能有協同效應。因此未來可能需要更多的研究樣本以決定篩檢CYP1A1/2與MDR1是否可以有助於預測中草藥腎病變的風險。

Chinese herbs nephropathy (CHN) is characterized by progressive renal interstitial fibrosis followed by end-stage renal disease. It is known to be caused by the cellular toxicity of aristolochic acid. However, the association between genetic polymorphisms and complex diseases such as CHN has not been confirmed. Sixty-nine patients with a probability of CHN were found by a retrospective and a prospective study at National Taiwan University Hospital during 2000-2007. Eighty-two individuals with herbal-use for more than one month and normal renal function were recruited as controls. The 19 single nucleotide polymorphisms in CYP1A1, CYP1A2, NQO1, NAT2, NAT1, GSTM1, GSTT1, GSTP1, CYP2C19, and MDR1 were determined by SNPstream® and PCR-RFLP method. Our study showed that the CYP1A2 -3860 GA type, MDR1 2677 GT type, and 3435 CT type were significantly correlated with the risk of CHN with adjusted odds ratios (OR) of 2.71 (CI95% 1.03 - 7.13) , 3.94 (CI95% 1.19 - 13.05), and 3.65(CI95% 1.34 - 9.97), respectively. The analysis of haplotype combinations revealed an adjusted OR 7.76 (CI95% 1.32 - 45.45), and 4.82 (CI95% 1.39 - 16.73) for CYP1A1*2A/2B, and MDR1 2677/3435 GC/TT type in CHN. In addition, simultaneous mutation of MDR1 C3435T and CYP1A1 had an adjusted OR of 13.33 (CI95% 1.39 - 128.23). Our result showed that single nucleotide polymorphisms of CYP1A1/2 and MDR1 might be associated with CHN, and they might have synergy effect. Further study in more patients may be required to determine if CYP1A1/2 and MDR1 mutation screening is helpful in predicting risk of CHN.