Does the UGT1A1 rs887829 CT genotype indicate intermediate glucuronidation capacity?

UGT1A1 is a key glucuronidation enzyme, including for bilirubin and the irinotecan metabolite SN-38. For rs887829, the available human expression and pharmacokinetic evidence supports a graded effect of T-allele carriage, while emphasizing that this SNP is chiefly a marker of linked regulatory haplotypes.

Expression and functional evidence

• In human liver, rs887829 T carriage is strongly associated with lower UGT1A1 mRNA expression (regression β approximately −0.325; P = 2.16 × 10⁻⁸), explaining about 12% of transcript-expression variance. Similar direction and magnitude were reported in African-American and European-American donor subsets.
• CT is generally classified as an intermediate UGT1A1 metabolizer phenotype, with CC expected to have higher and TT lower activity.
• SN-38 pharmacokinetics support this ordering: CT was associated with approximately 34% lower SN-38 clearance than CC, compared with an approximately 60% reduction for TT. Reported median clearance was 81.3 L/h for CC versus 27.5 L/h for TT.

Mechanistic interpretation

• rs887829 T is in strong—often near-perfect—linkage disequilibrium with transcription-reducing UGT1A1 promoter TA-repeat haplotypes, particularly TA7 (*28) and TA8 (*37); C more often tracks with TA5/TA6 alleles.
• Reporter assays did not show an independent C-versus-T promoter-activity difference. Thus, reduced expression is best attributed to the linked regulatory haplotype rather than assumed to be caused directly by rs887829 itself.
• Linkage structure varies by ancestry, and other UGT1A1 variants, including *6, may modify the phenotype.

Bottom line

• The claim is supported: rs887829 T reliably marks lower hepatic UGT1A1 expression, and CT reasonably indicates intermediate population-level glucuronidation capacity between CC and TT. It is not, however, a fixed individual measure of enzyme activity; clinically meaningful interpretation depends on ancestry and the full UGT1A1 haplotype/diplotype.