Genetic Variations of UGT1A1 1A7 1A9 and 1A10

UGT1A1 is one of the abundantly expressed UGTs in the liver and is responsible for bilirubin glucuronidation in humans. Genetic defects cause hyperbilirubinemia, such as Gilbert's syndrome and Crigler-Najjar syndrome types I and II. Much information on the genetic variations of UGT1A1 has been accumulated with relevance to hyperbilirubinemia, and more than 60 variations have so far been reported (http://www.pharmacogenomics.pha.ulaval.ca/sgc/ugLalleles/site/pharmacogenomics). In this Chapter, the term "allele" represents a genetic variation at one site, and the term "haplotype" refers to a combination of genetic variations on a chromosome.

The most extensively investigated polymorphism is a variation of the number of TA repeats (A(TA)nTAA, n = 5-8) in the promoter region. The wild-type allele contains six [(TA)6] repeats that are located -53 to -42 from the translational start codon. UGT1A1*28 [(TA)7], a common variation in Gilbert's syndrome (25, 26), has an in vitro translational activity that is 63% of the wild-type allele (27). Minor TA variations include *36 (n = 5) and *37 (n = 8), which result in enhanced and reduced, respectively, transcriptional activity in vitro (Table 1).

The UGT1A1*60 allele (-3279T>G), located in the distal enhancer region [phenobarbital-responsive enhancer module (PBREM)], is another genetic variation that reportedly reduces transcriptional activity and has been associated with increased plasma bilirubin levels (28). UGT1A1*6 [211 G>A (G71R)] was originally found in Japanese patients with Crigler-Najjar type II and Gilbert's syndrome (29, 30) and results in reduced SN-38 glucuronidation activity (5,31). UGT1A1*27 [686C>A (P229Q)] is a rare nonsynonymous polymorphism with reduced or marginal in vitro glucuronidation of SN-38 that has also been detected in Asians with Gilbert's syndrome (5, 30, 31). 1A1*7 [1456T>G (Y486D)] is another rare nonsynonymous variation, in exon 5, detected in Asians with Crigler-Najjar type II (29) and shown to have reduced SN-38 glucoronidation activity (5,31).

Among the common functional 1A7 polymorphisms, 1A7*2 [387T>G, 391C>A (N129K, R131K)], 1A7*3 [387T>G, 391C>A, 622C>T (N129K, R131K, W208R)], and 1A7*4 [622C>T (W208R)] (32), 1A7*3 and 1A7*4 were shown to cause reduced SN-38 G formation in vitro (5). In contrast, a common variation in the 1A9 promoter region, 1A9*1b (originally named *22) [-118 (T)9>10)] enhances transcriptional activity in vitro (33). Some rare genetic variations, 1A9*3a [98T>C(M33T)] (34), 1A9*5 [766 G>A(D256N)] (35), and 1A10*6 [605C>T(T202I)] (originally named *3) (36), were also shown to result in reduced SN-38 G formation in vitro (Table 1).

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