Innocenti Federico, Grimsley Carrie, Das Soma, Ramírez Jacqueline, Cheng Cheng, Kuttab-Boulos Hala, Ratain Mark J, Di Rienzo Anna
Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, Cancer Research Center, The University of Chicago, Chicago, IL 60637, USA.
Pharmacogenetics. 2002 Dec;12(9):725-33. doi: 10.1097/00008571-200212000-00006.
Genetic variation in UDP-glucuronosyltransferase 1A1 (UGT1A1)expression has several important clinical implications. UGT1A1 basal transcription is affected by a polymorphic (TA)n repeat, and another important regulatory element is the phenobarbital-responsive enhancer module (PBREM) which might contain variants affecting inducible gene expression. We assessed the extent of linkage disequilibrium between the (TA)n polymorphism and variants in the PBREM and UGT1A1 promoter. We also investigated the relationship between PBREM-(TA)n haplotypes and the glucuronidation rate of the UGT1A1 substrate SN-38. DNAs from 83 human livers were genotyped for the (TA)n polymorphism and microsomes from the same livers were phenotyped for SN-38 glucuronidation. The (TA)n polymorphism was genotyped in 24 additional African-Americans included in the Human Variation Panel (Coriell Institute). A 606-bp region spanning the PBREM was sequenced in 81 liver and a subset of 22 Human Variation Panel DNAs and six variants were found. The -3279G T and -3156G A variants are common (0.39 and 0.30, respectively). -3279G T is more common in Caucasians than African-Americans (P = 0.001). In Caucasians, linkage disequilibrium was highly significant between sites -3279, -3156, and the (TA)n polymorphism (P < 0.0001). In contrast, in African-Americans, only marginal levels of significance were observed between (TA)n and -3279 (P = 0.02) and between -3279 and -3156 (P = 0.04). Ten promoter haplotypes were identified. Haplotype I is the most common (0.39), from which haplotype II (0.15) differs at position -3279. SN-38G formation rates were correlated with (TA)n genotypes. This study showed that (i) common promoter variants are in linkage disequilibrium and (ii) the haplotype structure of promoter is probably different between Caucasians and African-Americans.
尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT1A1）表达中的基因变异具有若干重要的临床意义。UGT1A1基础转录受多态性（TA）n重复序列影响，另一个重要的调控元件是苯巴比妥反应增强子模块（PBREM），其可能包含影响诱导型基因表达的变异。我们评估了（TA）n多态性与PBREM及UGT1A1启动子变异之间的连锁不平衡程度。我们还研究了PBREM - （TA）n单倍型与UGT1A1底物SN - 38的葡萄糖醛酸化率之间的关系。对83例人类肝脏的DNA进行（TA）n多态性基因分型，并对来自同一肝脏的微粒体进行SN - 38葡萄糖醛酸化表型分析。另外对人类变异库（科里尔研究所）中纳入的24例非裔美国人进行了（TA）n多态性基因分型。对81例肝脏以及22例人类变异库DNA的一个子集进行了跨越PBREM的606 bp区域测序，发现了6个变异。 - 3279G>T和 - 3156G>A变异较为常见（频率分别为0.39和0.30）。 - 3279G>T在白种人中比在非裔美国人中更常见（P = 0.001）。在白种人中， - 3279、 - 3156位点与（TA）n多态性之间的连锁不平衡高度显著（P < 0.0001）。相比之下，在非裔美国人中，仅观察到（TA）n与 - 3279之间（P = 0.02）以及 - 3279与 - 3156之间（P = 0.04）有边缘显著水平。鉴定出了10种启动子单倍型。单倍型I最为常见（0.39），单倍型II（0.15）在 - 3279位点与之不同。SN - 38G形成率与（TA）n基因型相关。本研究表明：（i）常见的启动子变异处于连锁不平衡状态；（ii）白种人和非裔美国人启动子的单倍型结构可能不同。
