台灣地區成年人未結合型高膽紅素血症之基因變異型分析

Genetic interactions in Taiwanese adults with unconjugated hyperbilirubinemia

黃美真

指導教授 ： 華國媛 ； 李宏謨

臺北醫學大學/醫學院/醫學檢驗生物技術學研究所/碩士(2003年)

摘要

未結合型高膽紅素血症(unconjugated hyperbilirubinemia)形成的原因可能有：(1)紅血球破壞增加(2)未結合型膽紅素(unconjugated bilirubin)進入肝細胞受阻(3)肝細胞內的葡萄糖醛酸作用(glucuronidation)能力下降等因素，為了想探討相關基因變異對未結合型高膽紅素血症的影響，本篇研究收集了103名未結合型高膽紅素血症的台灣健康成年人及100名膽紅素(bilirubin)正常的對照組檢體，利用PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism)分析其glucose-6-phosphate dehydrogenase (G6PD)、organic anion transporter 2 (OATP2)及UDP-glucuronosyltransferase 1 A1 (UGT1A1)的基因變異情形；並以chi-square test、t-test、ANOVA及logistic regression等統計方式，分析不同基因變異對未結合型高膽紅素血症的影響；結果顯示在未結合型高膽紅素血症者帶有nt 388A高於control組(29.6% vs. 20.5%, p=0.035)，而nt 521C則無差異；在未結合型高膽紅素血症者的G6PD缺乏率及UGT1A1基因的變異比率，分別高達18.4 %及92.2%，若同時有G6PD活性缺乏及UGT1A1基因變異，會造成未結合型高膽紅素血症之OR (95% CI)比單獨出現G6PD活性缺乏或UGT1A1基因變異為高，各為168.8 (17.5-1630)、22.5 (3.1-163.2)及 17.3 (5.9-51.0)；在G6PD活性正常且UGT1A1為variation下，若同時帶有OATP2 nt 388 AA or AG可再增高造成未結合型高膽紅素血症的危險率；將造成台灣健康成人未結合型高膽紅素血症的多重危險因子共同以stepwise logistic regression分析，顯示homozygous UGT1A1 variation、compound heterozygous UGT1A1 variation、G6PD活性缺乏、Hb、heterozygous UGT1A1 variation及OATP-388 AA or AG之OR (95% CI)分別為，292.6 (30-2854)、58.2 (15.5-218.8)、32.0 (6.4-159.2)、5.7 (2.2-14.7)、3.8 (1.2-12.0)及2.8 (1.2-6.6)，其中homozygous UGT1A1 variation可能是造成台灣健康成人未結合型高膽紅素血症的最重要危險因子，包括有homozygous A(TA)7TAA佔77.4%及homozygous 211A變異佔22.6%；由本研究結果顯示，多重基因的交互作用下，對台灣健康成人的未結合型高膽紅素血症的確會有輕重不同程度的影響。

關鍵字

未結合型高膽紅素血症 ； G6PD ； OATP2 ； UGT1A1 ； genotype

並列摘要

Unconjugated hyperbilirubinemia is associated with (1) increased erythrocyte hemolysis, (2) decreased hepatic uptake of unconjugated bilirubin and (3) decreased conjugation of bilirubin. The aim of this study is to investigate whether the genetic interactions among the genes involved in the metabolism of bilirubin influence bilirubin levels in Taiwanese healthy adults with unconjugated hyperbilirubinemia. One hundred and three Taiwanese healthy adults with unconjugated hyperbilirubinemia and 100 random controls were recruited. All subjects were analyzed for G6PD, OATP2, UGT1A1 genotypes by PCR-RFLP (polymerase chain reaction — restriction fragment length polymorphism) method, and were compared using the chi-square test, t-test, ANOVA and logistic regression. The results showed that the allelic frequency of OATP2 nt 388A in the unconjugated hyperbilirubinemia subjects was higher than the frequency in the control subjects (29.6% vs. 20.5%, p=0.035), but there was no significant differences in nt 521 distributions between the two groups. The incidence of G6PD deficiency was 18.4% and the overall variation rate of UGT1A1 gene was 92.2% in unconjugated hyperbilirubinemia group. Subjects with the coinheritance of G6PD deficiency and UGT1A1 variations were higher risk to develop unconjugated hyperbilirubinemia than subjects with G6PD deficiency or UGT1A1 variations along, and the OR (95% CI) were 168.8 (17.5-1630), 22.5 (3.1-163.2) and 17.3 (5.9-51.0), respectively. OATP2 nt 388 AA or AG could increase the risk ratio of unconjugated hyperbilirubinemia in G6PD normal coexisted with UGT1A1 variations. All the suspicious risk factors of unconjugated hyperbilirubinemia in Taiwanese adults, such as homozygous UGT1A1 variation, compound heterozygous UGT1A1 variation, G6PD deficiency, Hb, heterozygous UGT1A1 variation and OATP2-388 AG or AA were compared using the logistic regression analyses, the OR (95%CI) were 292.6 (30-2854), 58.2 (15.5-218.8), 32.0 (6.4-159.2), 5.7 (2.2-14.7), 3.8 (1.2-12.0) and 2.8 (1.2-6.6), respectively. The results indicated that homozygous UGT1A1 variation including homozygous A(TA)7TAA (77.4%) and homozygous 211A (22.6%), was the most important risk factor for unconjugated hyperbilirubinemia. In conclusion, the results of my study suggest that genetic interactions among the genes associated with bilirubin metabolism are involved in the development of unconjugated hyperbilirubinemia in Taiwanese healthy adults.

參考文獻

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