UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer*1

Abstract

This study identified several UGT1A1 haplotypes significantly associated with the reduced AUC ratio (*28 and *6) and with the increased total bilirubin level (*28, *60, and *IB) and suggested that the novel haplotype *IB might be functionally important. These findings will be useful for further pharmacogenetic studies on adverse reactions to irinotecan.

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations

“…14,15 A significant correlation between SN-38 and bilirubin glucuronidation has been found, high serum T-Bil concentration seemed to be a reasonably good predictor of lower irinotecan clean rate. [16][17][18] In the present study, the (TA)7 allele was significantly associated with higher T-Bil concentrations, in line with previous reports. 15,19 However, different to Koreans, no association between 211A allele and bilirubin level was found.…”

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

“…[16][17][18] The same common UGT1A1 variants associated with mild elevations of serum bilirubin are associated with diminished in vitro glucuronidation of the active irinotecan metabolite, SN-38, [19][20][21][22] and prolonged exposure and increased toxicity in patients receiving this agent. [23][24][25] As shown by Sai et al, 25 re-sequencing of the UGT1A1 gene in 85 Japanese patients treated with irinotecan confirmed that the haplotypes containing lower expression variants were associated with both a low SN-38G/SN-38 AUC ratio and elevated pretreatment bilirubin concentration. Importantly, however, additional haplotypes appeared to have distinct modifying effects on the SN-38 AUC ratio and total bilirubin level phenotypes, suggesting that more complete genetic variation data for UGT1A may better predict bilirubin and irinotecan metabolism phenotypes.…”

“…UGT1A1*6 has predictive value for irinotecan toxicity in the Japanese patient population; 25 however, owing to its low frequency in European-Americans and African-Americans, genotyping this variant is unwarranted in non-Asian populations. Not only do population differences in the frequency of DME alleles affect sensitivity and specificity parameters of a genotype as a clinical assay, but also the interpretation of the growing body of genotype/phenotype association studies.…”

“…Arrows highlight variants previously shown to be associated with human-health phenotypes in either multiple human subject studies or in individual association studies involving more than 100 human subjects; these include the UGT1A8*2 allele, 70,71 the three non-synonymous coding SNPs in UGT1A7 (*2,*3,*10), 69,72,73,81,82 two nsSNPs in UGT1A6 (*2,*3), 67,68,70 rs887829 -the SNP revealing the strongest association with tranilast-induced hyperbilirubinemia, 28 and the UGT1A1*6 allele. 10,24,25,[50][51][52][53][54][55][56][57][83][84][85][86][87] Figure 4 Two-point LD maps for variants of UGT1A1, UGT1A6, and UGT1A9 mapped by population. The patterns of pairwise LD, summarized by |D 0 |, include 60 variants in African-Americans (left), 52 in European-Americans (center), and 49 in Asians (right).…”

“…28 Although it is reasonable to assume that the association between hyperbilirubinemia and these pharmacologic agents is based on genetic variation at UGT1A1, for other metabolic/ toxicologic phenotypes of UGT1A, the overlapping tissue distributions and substrate affinities of enzymes encoded by this locus may complicate interpretation of single genotype or single exon-haplotype association studies. As suggested by the results of Sai et al, 25 detailed knowledge of the interindividual genetic variability across this region, especially if focused on the segments most likely to affect expression and activity of these enzymes, could yield a better understanding of the pathopharmacology of new drugs.…”