砷、DNA甲基轉移酶基因多形性及腎細胞癌

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Title:	砷、DNA甲基轉移酶基因多形性及腎細胞癌 Arsenic, Polymorphisms of DNA methyltransferases and Renal Cell Carcinoma
Authors:	謝毅勳 Hsieh, Yi-Hsun
Contributors:	薛玉梅
Keywords:	砷;砷甲基化能力;DNA甲基轉移酶;基因多形性;腎細胞癌 Arsenic;Arsenic methlytion capacity;DNA methyltransferases;polymorphisms;Renal cell carcinoma.
Date:	2015-07-13
Issue Date:	2020-08-28 14:16:08 (UTC+8)
Abstract:	背景砷已證實為人類致癌物質，過去無論在砷暴露或非砷暴露地區皆發現隨著尿液總砷增加會增加腎細胞癌的危險性。而砷甲基化代謝對於砷暴露來說是重要的去毒機轉，砷代謝能力較差可能與癌症有關且砷目前的致癌機轉尚不明確。近年發現與DNA甲基化相關酵素DNA甲基轉移酶(DNA methyltransferases, DNMTs)基因多形性與癌症的危險性有關，有鑑於目前DNA甲基轉移酶與腎細胞癌的相關研究鮮少，且砷甲基化代謝能力亦有可能影響DNA的甲基化，故本研究將探討尿液總砷、砷代謝能力及DNA甲基轉移酶 (DNMT1、DNMT3A及DNMT3B)基因多形性與腎細胞癌之間的相關性。方法本研究是以醫院為基礎的病例對照研究，在2007年3月至2014年10月於臺大醫院、萬芳醫院及臺北醫學大學附設醫院進行受試者招募，並以性別及年齡(± 5歲)進行1:1或1:2的匹配，共招募410位腎細胞癌病例及774位的健康對照。受試者在簽屬同意書後進行問卷訪視，並採集血液及尿液樣本。血液樣本萃取DNA，以聚合酶連鎖反應增幅DNA片段，及利用限制片段長度多形性分析DNA甲基轉移酶基因多形性。尿液樣本則利用高效能液相層析儀串聯氫化器及原子吸收光譜儀分析三價無機砷、五價無機砷、單甲基砷酸及雙甲基砷酸等砷物種濃度。結果在多變項校正模式分析下，發現尿液總砷越高，增加腎細胞癌的危險對比值，其危險對比值與95%信賴區間為1.02 (1.01-1.03)，而雙甲基砷酸百分比越高亦會增加腎細胞癌的危險對比值，單甲基砷酸百分比越高則會降低腎細胞癌的危險對比值。本研究所探討的5個DNA甲基轉移酶基因位點與腎細胞癌並無相關，但在DNMT3A rs1550117及rs34048824單倍體分析下，發現G-C單倍體比起G-T單倍體有顯著降低腎細胞癌的危險對比值，其危險對比值及95%信賴區間為0.77 (0.59-1.00)，在基因與基因的交互作用下，若DNMT1 rs2228611為A/A+G/G基因型且DNMT1 8101626為G/G基因型較DNMT1 rs2228611為A/G基因型且DNMT1 8101626為G/G基因型有顯著降低腎細胞癌的危險對比值。 DNMT1 rs2228611及DNMT3A rs34048824基因多形性發現與砷代謝能力指標有相關，且DNMT3A單倍體分析中也發現G-C單倍體比起G-T單倍體有較高的單甲基砷酸百分比，但在DNA甲基轉移酶、尿液總砷與砷代謝能力的聯合效應分析並無發現對於腎細胞癌有交互作用。結論尿液總砷、砷代謝能力與DNA甲基轉移酶基因多形性分別與腎細胞癌皆有相關，且DNA甲基轉移酶基因多形性會影響砷的代謝能力。但本篇並未發現DNA甲基轉移酶基因多形性、尿液總砷及砷代謝能力對於腎細胞癌之間有交互作用，未來可進行砷代謝能力及DNA甲基轉移酶基因多形性之間對腎細胞癌的可能機轉。 Background Arsenic is already defined as a human carcinogen. Several studies have proposed that high urinary arsenic level significantly increased the risk of renal cell carcinoma (RCC) whether the area was arsenic exposure or not. Arsenic methylation capacity is the most important detoxification pathway for arsenic exposure and that was associated with the risk of cancer. In addition, carcinogenic mechanism of arsenic is unclear; however, recent studies showed that DNA methyltransferases (DNMT) of DNA methylation were associated with the risk of cancer. There were few studies explored the relationship between DNMTs polymorphism, arsenic exposure and arsenic methylation capacity and RCC. Our propose is to investigate the relationship between the level of urinary total arsenic, arsenic methylation capacity, DNMT polymorphism (DNMT1, DNMT3A and DNMT3B) and renal cell carcinoma. Method This is a hospital-base case control study. 410 patients who have been diagnosed RCC and 774 healthy controls matched by sex and age (+5) 1:1 or1:2 on RCC cases were recruited from Taiwan National University hospital, Taipei Medical University hospital and Wan-fang hospital from March 2007 to October 2014.. All participants were interviewed by a structure questionnaire and collected their blood and urine befoe they provided their written informed concent. DNA was extracted by blood and used the PCR-RFLP method to analyze the genotype. Arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in urine sample were analyzed by high-performance liquid chromatography linked with hydride generator and atomic absorption spectrometry. Results We found high level of total arsenic in urine were associated with increased odds ratio (OR) of RCC and OR and 95% confidence interval was 1.02 (1.01-1.03) in the multivariate logistic regression model. The higher the presentage of dimethylarsinic acid (DMAV%) was the higher odds ratio of RCC and the higher presentage of methylarsonous acid (MMAV%) was the lower OR of RCC. There were no accociation between 5 SNPs of DNMTs polymorphisms and RCC, but the participants with G-C haplotype of DNMT3A rs34048824 and rs1550117 had desceased the OR of RCC than those with G-T haplotype, the OR and 95%CI was 0.77 (0.59-1.00). Participants with DNMT1 rs2228611A/A+G/G genotype and DNMT1 rs8101626 G/G genotype had a significantly lower OR of RCC than those with DNMT1 rs2228611 A/G genotype and DNMT1 rs8101626 G/G genotype. Finally, the polymorphisms of DNMT1 rs2228611 and DNMT3A rs34048824 were associated with the arsenic methylation capacity respectively.Participants with G-C haplotype of DNMT3A rs34048824 and rs1550117 had higher MMAV% than those with G-T haplotype of DNMT3A rs34048824 and rs1550117, but the interaction of total arsenic in urine, arsenic methylation capacity and DNMTs polymorphism on the risk of RCC were insignificant. Conculsion Total arsenic in urine, arsenic methylation capacity and polymorphisms of DNMTs were associated with the OR of RCC respectively. Polymorphisms of DNMTs also affected the arsenic methylation capacity. There were no significant interactions between total arsenic in urine, arsenic methylation capacity, and polymorphisms of DNMTs on the risk of RCC. The mechanism of arsenic methylation capacity and polymorphisms of DNMTs on the risk of RCC needs further investigation.
Description:	碩士指導教授:薛玉梅委員:黃昭淵委員:吳美滿
Data Type:	thesis
Appears in Collections:	[School of Public Health] Dissertations/Theses

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