rs887829 — UGT1A1 UGT1A1*80

UGT1A1*80 — The Bilirubin Gene Variant That Also Affects Drug Safety

Bilirubin is best known as the yellow pigment of jaundice — a signal that something is wrong with the liver. But in small amounts, unconjugated bilirubin is a normal and potent endogenous antioxidant, and the enzyme responsible for clearing it from the blood, UGT1A1 (UDP-glucuronosyltransferase 1A1)¹¹ UGT1A1 (UDP-glucuronosyltransferase 1A1)
a Phase II liver enzyme that conjugates bilirubin with glucuronic acid for biliary excretion, varies substantially across people. The variant rs887829 — designated UGT1A1*80 — sits in the promoter region of UGT1A1, approximately 211 base pairs upstream of the TATA box TA-repeat sequence. It is in near-complete linkage disequilibrium (r² ≈ 0.99) with UGT1A1*28²² UGT1A1*28
the (TA)7TAA insertion in the TATA box that directly reduces UGT1A1 transcription by ~70%, meaning rs887829 reliably tags the *28 haplotype in most populations and serves as a practical proxy in clinical pharmacogenomics testing.

The Mechanism

The T allele at rs887829 marks the *28 haplotype, which carries seven TA repeats in the promoter TATA box rather than the usual six. The extra repeat reduces UGT1A1 binding efficiency for transcriptional machinery, lowering enzyme production and slowing bilirubin conjugation in the liver. Heterozygous CT carriers have intermediate UGT1A1 activity; TT homozygotes typically have bilirubin levels roughly 65% higher than CC homozygotes and fall within the Gilbert syndrome phenotype spectrum — mildly elevated unconjugated (indirect) bilirubin, especially during fasting or illness.

This same enzyme handles the glucuronidation of multiple drugs. Atazanavir, an HIV protease inhibitor, directly inhibits UGT1A1, compounding the effect in TT carriers and causing pronounced jaundice. Irinotecan, a chemotherapy drug, is converted to its active metabolite SN-38, which is subsequently inactivated by UGT1A1 glucuronidation — TT carriers accumulate SN-38, increasing risk of severe neutropenia and diarrhea.

The Evidence

Bilirubin and cardiovascular risk — observational vs. causal:

The Framingham Heart Study (n=1,780, 24-year follow-up)³³ Framingham Heart Study (n=1,780, 24-year follow-up)
Lin et al., Circulation 2006 reported that *28 TT homozygotes had hazard ratios of 0.36 for CVD and 0.30 for coronary heart disease compared with carriers of the *1 allele — an apparently striking ~65% protection. Multiple smaller studies reinforced this picture.

However, a landmark UK Biobank analysis (n=463,060 genotyped for rs887829)⁴⁴ UK Biobank analysis (n=463,060 genotyped for rs887829)
Gill et al., BMJ Medicine 2023 using Mendelian randomization found that while observational bilirubin-cardiovascular associations are real and consistent, the genetic instrument showed no causal effect of bilirubin on cardiovascular disease outcomes. The authors concluded that bilirubin likely acts as a biomarker of underlying health rather than as an active cardiovascular protective molecule, and that it represents a poor target for therapeutic intervention. Only 3% of rs887829 TT homozygotes in the UK Biobank had a recorded clinical diagnosis of Gilbert syndrome, illustrating how undercoded the condition is.

Endothelial function:

A controlled study of 108 Gilbert syndrome patients vs matched controls⁵⁵ 108 Gilbert syndrome patients vs matched controls
Vítek et al., Metabolism 2012 found improved flow-mediated vasodilation (7.2% vs 5.9%) and lower oxidative stress markers in those with hyperbilirubinemia, confirming a biological signal — but whether this is cause or correlation cannot be established from the data alone.

Drug safety — the actionable findings:

For atazanavir, CPIC guidelines based on rs887829 genotype show positive predictive values for bilirubin-related drug discontinuation within 96 weeks of 60% in Europeans, 29% in Hispanics, and 20% in Black patients — strongly supporting pre-treatment genotyping. For irinotecan, decreased UGT1A1 activity in TT carriers leads to SN-38 accumulation with increased risk of grade 3-4 neutropenia and diarrhea; dose adjustment or closer monitoring is clinically justified.

Practical Actions

The clearest actionable implications of rs887829 are pharmacogenomic. Anyone considering atazanavir as HIV treatment or irinotecan-based chemotherapy should have their UGT1A1 genotype factored into treatment decisions. For TT homozygotes starting atazanavir, clinicians should advise on the high probability of visible jaundice and consider alternative antiretrovirals unless the patient accepts this risk. For irinotecan, starting at a reduced dose (typically one step down) and monitoring closely for myelosuppression is the evidence-based approach for TT carriers.

The cardiovascular story is biologically interesting but not currently actionable: the Mendelian randomization evidence does not support targeting bilirubin levels for cardiovascular risk modification.

Interactions

rs887829 is in near-complete LD (r² ≈ 0.99) with the UGT1A1*28 TA-repeat variant (rs8175347/rs3064744) — these variants track together in most populations. The related rs4148323 (*6, Gly71Arg) is a second independent UGT1A1 loss-of-function allele common in East Asian populations; compound heterozygotes carrying both *28 and *6 (common in East Asian populations) have substantially greater UGT1A1 impairment than either allele alone and face amplified drug toxicity risk with irinotecan. The interaction between rs887829 (as a *28 tag) and rs4148323 (*6) is a candidate compound action for East Asian patients on irinotecan-based chemotherapy.