台灣健康人及肝癌病患對多種藥物抗藥性基因多型性變異之探討

台灣健康人及肝癌病患對多種藥物抗藥性基因多型性變異之探討

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在驅動區上游 -41 及 -145 位置之同合子突變型變異頻率皆為 0.00 ，與日本學者之研 究報告相同。而台灣健康人與肝癌病患 MDR1 基因多型性變異並無明顯的差異，但是 發現了台灣肝細胞癌病患 C3435T 與 C1236T 、 G2677T/A 同合子突變型變異的變異連 鎖性為 0.95 、 0.91 ，明顯的高於台灣健康人的 0.73 、 0.70 。另外，健康人及肝細胞 癌病患同合子突變型 C3435T 變異頻率分別為 0.15 及 0.12 ，顯著小於已發表研究報告 中之法國、沙烏地阿拉伯、中國和英國人的變異頻率 (0.20-0.28) 以及西南亞洲人之變 異頻率 (0.47) 及美國白人之變異頻率 (0.62) 。根據我們研究結果顯示，台灣人 MDR1 基因多型性變異的分佈與其他人種確實有所差異。此外我們也發現了 C1236T 無變異加 上病毒感染形成肝細胞癌的危險值是對照組的 29.42 倍，而有變異加上病毒感染下卻又 比對照組高出 68.74 倍之多，顯示之間具有強烈的關聯性。

Polymorphisms of multidrug resistance gene of healthy population and hepatocellular carcinoma patients in Taiwan

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P-glycoprotein is a ubiquitous transmembrane protein and exists in many tissues. The activity of this protei n affects the responsiveness of many drugs and toxic substances, such as digoxin, chemotherapeutic drugs, some suppressants for human acquired immunodeficiency virus and rhodamine. P-glycoprotein is a 170-k Da membrane protein, containing 1280 amino acids and it is produced by the multiple drug resistance (MD R1 or ABCB1) gene. The MDR1 gene is located on chromosome 7q21 and consists of 28 exons. To date, 2 8 single nucleotide polymorphisms (SNPs) in the promoter and exons of the MDR1 gene have been reporte d, and it has been demonstrated that the C3435T, C1236T, G2677T/A, A-41G and C-145G variations are a ssociated with the development of diseases. Current studies for MDR1 gene are concentrated on Caucasian and African, while those on Chinese are very rare.

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The goal of this study is try to pile up some more data and to establish a complete MDR1 gene data base fo

r Chinese. The 227 healthy adults and 169 hepatocellular carcinoma patients from local residents of Taiwa

n were registered as the study subjects. The methods of polymerase chain reaction, restriction fragment len

gth polymorphism and DNA sequencing were utilized to investigate MDR1 polymorphisms. The results in

dicate that both frequencies of homozygous variation at -41 and -145 were 0.00, concordant with the result

s from the study from Japanese. There is no difference between healthy adults and hepatocellular carcinom

a patients in the allele frequencies of MDR1 polymorphisms. However, in hepatocellular carcinoma patient

s, the degree of linkage disequilibrium between C3435T and C1236T and between C3435T and G2677T ho

mozygous variations are higher than that in the healthy control group, (0.95 and 0.91 vs. 0.73 and 0.70, res

pectively). The frequency of homozygous variation at nucleotide 3435 in the healthy adults and the hepato

cellular carcinoma patients is 0.15 and 0.12, respectively, which is lower than that reported for French, Sau

di Arabia, China and British populations (with a range between 0.20 to 0.28), as well as lower than that in

Southwestern Asians (0.47) and in American Caucasians (0.62). From these experimental results, we can c

onclude that MDR1 polymorphism distribution is different among ethnic groups. In addition, we found that

the C1236T variation in the MDR1 gene is an additive risk factor for hepatocellular carcinoma in viral hep

atitis B or C infected patients.