Discovery of a Polymorphic Biomarker More Accurately Associated with Reduced Chemotherapeutic Metabolism in a Diverse Cohort

Overview

UGT1A1 is an enzyme involved in metabolizing Irinotecan, a DNA topoisomerase class I inhibitor chemotherapeutic drug. Polymorphisms within the UGT1A1 gene promoter reduce UGT1A1 mRNA expression, rendering individuals susceptible to heightened drug toxicity. Irinotecan toxicity makes it crucial to identify the polymorphisms responsible for reduced mRNA expression and then use the polymorphism as a biomarker for personalized therapy. Previous research studied only Caucasian individuals and determined that a p olymorphism within the UGT1A1 gene promoter's TATA box was responsible for reduced mRNA expression. Although this polymorphism has been used to guide Irinotecan prescriptions, it is loosely associated with reduced mRNA expression in other populations. Comp aring mortality rates between Caucasians and African Americans prescribed Irinotecan based on the presence of the TATA box polymorphism, reveals higher mortality rates among African Americans. Therefore, this research expands its scope to encompass both Af rican-American and Caucasian populations. This study investigates a nearby single nucleotide polymorphism (SNP), rs887829, located within 300 base pairs of and in linkage disequilibrium with the TATA box. Liver samples were collected from both groups, with subsequent extraction of gDNA and total RNA. The UGT1A1 gene promoter region was amplified, and fragment analysis was conducted to genotype UGT1A1 gene promoter TATA repeats. The rs887829 polymorphism was genotyped using Illumina SNP Array, and UGT1A1 mRN A expression was quantified using real-time PCR. A linear regression model was used, which determined that the rs887829 SNP is a more accurate biomarker for reduced UGT1A1 mRNA expression, which better serves all ethnic groups.