The relationships between UGT1A candidate markers across the gene (n = 21) and toxicity were evaluated prospectively. The results demonstrate that several functional UGT1A variants, including UGT1A1*28, significantly influenced the risk of severe hematological toxicity. A 5-marker risk haplotype (HII; UGTs 1A9/1A7/1A1) was associated with severe neutropenia. The inclusion of a 3′-untranslated region (UTR) single nucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts. Among all of the tested UGT1A variations, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3–4. Haplotype analyses of these markers with the 3′-UTR SNP allowed the identification of a protective HI and two risk haplotypes HII and HIII characterized by 2 and 3 unfavorable alleles, respectively.
See article at J Pharmacol Exp Ther 2013, 345:95–101.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics