Author:
Matsui Katsuyuki,Maruo Yoshihiro,Sato Hiroshi,Takeuchi Yoshihiro
Abstract
Abstract
Background
Gilbert syndrome is caused by defects in bilirubin UDP-glucuronosyltransferase (UGT1A1). The most common variation believed to be involved is A(TA)7TAA. Although several polymorphisms have been found to link with A(TA)7TAA, the combined effect of regulatory polymorphisms in the development of Gilbert syndrome remains unclear.
Methods
In an analysis of 15 patients and 60 normal subjects, we detected 14 polymorphisms and nine haplotypes in the regulatory region. We classified the 4-kbp regulatory region of the patients into: the TATA box including A(TA)7TAA; a phenobarbital responsive enhancer module including c.-3275T>G; and a region including other ten linked polymorphisms. The effect on transcription of these polymorphisms was studied.
Results
All haplotypes with A(TA)7TAA had c.-3275T>G and additional polymorphisms. In an in-vitro expression study of the 4-kbp regulatory region, A(TA)7TAA alone did not significantly reduce transcription. In contrast, c.-3275T>G reduced transcription to 69% of that of wild type, and the linked polymorphisms reduced transcription to 88% of wild type. Transcription of the typical regulatory region of the patients was 56% of wild type. Co-expression of constitutive androstane receptor (CAR) increased the transcription of wild type by a factor of 4.3. Each polymorphism by itself did not reduce transcription to the level of the patients, however, even in the presence of CAR.
Conclusions
These results imply that co-operation of A(TA)7TAA, c.-3275T>G and the linked polymorphisms is necessary in causing Gilbert syndrome.
Publisher
Springer Science and Business Media LLC
Subject
Gastroenterology,General Medicine
Reference35 articles.
1. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, Chowdhury NR, Jansen PL: Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. J Biol Chem. 1994, 269: 17960-17964.
2. Owens D, Evans J: Population studies on Gilbert's syndrome. J Med Genet. 1975, 12: 152-156. 10.1136/jmg.12.2.152.
3. Carey RG, Balistreri WF: Inherited Deficient Conjugation of Bilirubin (Familial Nonhemolytic Unconjugated Hyperbilirubinemia). Nelson textbook of pediatrics. Edited by: Kliegman RM, Behrman RD, Jenson HB, Stanton BF. 2007, Philadelphia: Saunders, 1676-1677. 18
4. Pratt DS, Kaplan MM: Jaundice. Harrison's Principles of Internal Medicine. Edited by: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J. 2008, New York: McGraw-Hill, 261-266. 17
5. Sieg A, Arab L, Schlierf G, Stiehl A, Kommerell B: Prevalence of Gilbert's syndrome in Germany. Deutsch Med Wochenschr. 1987, 112: 1206-1208. 10.1055/s-2008-1068222.
Cited by
23 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献