PII-086 - RACIAL DIFFERENCES IN THE ASSOCIATION BETWEEN UGT1A1*28 AND GENE EXPRESSION OF UGT1A1 AND SEARCHING FOR NOVEL REGULATORY VARIANTS OF UGT1A1.

A. Montalvo¹, J. Ferber², J. Collins², D. Wang²; ¹University of Florida College of Pharmacy, FL, United States, ²University of Florida College of Pharmacy.

Background: UDP-glucuronosyltransferase 1A1 (UGT1A1) is a phase II drug metabolizing enzyme responsible for the detoxification of endogenous and exogenous substrates. A promoter TA repeat polymorphism UGT1A1*28 has been associated with decreased activity of UGT1A1, leading to the accumulation of irinotecan active metabolite (SN-38) and severe toxicity. UGT1A1*28 is used as a biomarker for irinotecan dose adjustment to prevent toxicity. However, UGT1A1*28 does not fully account for variability in UGT1A1 activity, in particular, in persons with non-European ancestry. The objective of this study was to test the association between UGT1A1*28 and UGT1A1 expression in liver samples from European American (EA) and African American (AA) donors and search for potential additional polymorphisms that regulate UGT1A1 expression.

Methods: Human liver samples (EA n=107; AA n=100) were genotyped for UGT1A1*28, and a high LD SNP rs887829 (*80) ~300 bp upstream of UGT1A1*28. UGT1A1 gene expression was quantified using SYBR green quantitative real-time PCR. Linear regression models were used to test for associations with UGT1A1 gene expression, after adjusting for age, race, sex, and several transcription factors known to affect UGT1A1 expression in the liver.

Results: In the entire liver sample cohort (EA + AA) each variant allele of UGT1A1*28 was associated with a 44% reduction in UGT1A1 gene expression (P=4.56x10-6). However, when EA and AA were analyzed separately, the association between UGT1A1*28 and gene expression of UGT1A1 was diminished in AA (P=0.413) but remained the same for EA (P=1.06x10-6). The upstream SNP rs887829 was a better predictor for UGT1A1 expression in the whole cohort (P=3.3 x 10-7) and particularly in AA (P=0.07), compared to *28. As rs887829 is in high LD with many variants located in putative liver enhancers, it’s possible that it is acting as a marker SNP. Ongoing experiments to validate the functions of *28 and rs887829 and to identify any novel variants regulating the expression of UGT1A1 in both EA and AA are in progress.

Conclusion: Our results support the existence of regulatory variants other than UGT1A1*28 that control the expression of UGT1A1. The discovery and characterization of such variants will lead to better UGT1A1 biomarkers that are applicable across racial groups.