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
中文摘要
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。
英文摘要
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.
