Vasavda Nisha, Menzel Stephan, Kondaveeti Sheila, Maytham Emma, Awogbade Moji, Bannister Sybil, Cunningham Juliette, Eichholz Andrew, Daniel Yvonne, Okpala Iheanyi, Fulford Tony, Thein Swee Lay
King's College London School of Medicine, Division of Gene and Cell Based Therapy, London, UK.
Br J Haematol. 2007 Jul;138(2):263-70. doi: 10.1111/j.1365-2141.2007.06643.x.
Serum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)-glucuronosyltransferase (UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase (HMOX1), a rate-limiting enzyme upstream of UGT1A in the haem catabolic pathway, and alpha-thalassaemia could explain some of the inconsistent effects. The UGT1A1 TA and HMOX1 GT promoter polymorphisms and alpha globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/beta(0), 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects (P < 0.0001 and P < 0.01, respectively). While HMOX1 genotype had no effect, co-inheritance of alpha-thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD.
镰状细胞病（SCD）患者的血清胆红素水平及胆结石易感性受肝脏尿苷二磷酸（UDP）-葡糖醛酸基转移酶（UGT1A1）基因的遗传变异影响，但这种关联并不一致。本研究调查了血红素加氧酶（HMOX1，血红素分解代谢途径中UGT1A上游的限速酶）编码基因的变异以及α地中海贫血是否能解释部分不一致的影响。在263例SCD患者（199例HbSS、5例HbS/β⁰、59例HbSC）中测定了UGT1A1 [TA]n和HMOX1 [GT]n启动子多态性以及α珠蛋白基因型。胆结石的检测基于肝脏/胆管树的超声检查。回归分析表明，血清胆红素水平和胆结石发生率在所有受试者中均与UGT1A1 [TA]重复序列的数量密切相关（分别为P < 0.0001和P < 0.01）。虽然HMOX1基因型无影响，但α地中海贫血的共同遗传可降低所有SCD患者的血清胆红素水平，且与UGT1A1 [TA]重复序列的数量无关。在SCD中，每增加一个[TA]重复序列，平均血清胆红素水平升高21%，胆石症风险增加87%。
