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
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 (glucuro nidation) 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 glucos e-6-phosphate dehydrogenase (G6PD) 、 organic anion transporter 2 (OATP2) 及 UDP-glucuronosyltransf erase 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 G 6PD 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 A G 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 21 1A 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。
Genetic interactions in Taiwanese adults with unconjugated hyperbilirubinemia
Unconjugated hyperbilirubinemia is associated with (1) increased erythrocyte hemolysis, (2) decreased hep atic 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 influe nce bilirubin levels in Taiwanese healthy adults with unconjugated hyperbilirubinemia. One hundred and t hree Taiwanese healthy adults with unconjugated hyperbilirubinemia and 100 random controls were recruit ed. All subjects were analyzed for G6PD, OATP2, UGT1A1 genotypes by PCR-RFLP (polymerase chain r eaction — 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 i n 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 gro ups. 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 U GT1A1 variations were higher risk to develop unconjugated hyperbilirubinemia than subjects with G6PD d eficiency 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 hyper bilirubinemia in G6PD normal coexisted with UGT1A1 variations. All the suspicious risk factors of unconj ugated hyperbilirubinemia in Taiwanese adults, such as homozygous UGT1A1 variation, compound hetero zygous 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 indicate d that homozygous UGT1A1 variation including homozygous A(TA)7TAA (77.4%) and homozygous 211 A (22.6%), was the most important risk factor for unconjugated hyperbilirubinemia. In conclusion, the resu lts 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.
