UGT1A1
UGT1A1 makes the only enzyme that clears bilirubin — the yellow pigment from recycled red blood cells. A common variant lowers its activity, causing Gilbert syndrome: mild, harmless rises in bilirubin that often show up unexpectedly on a routine blood test. The same variant also slows the breakdown of a few drugs, most importantly the chemotherapy agent irinotecan, where it changes the safe dose.
The bilirubin clearance enzyme.
When old red blood cells are recycled, their hemoglobin breaks down into bilirubin — which is fat-soluble and toxic if it accumulates. UGT1A1 attaches a sugar group (glucuronidation) to bilirubin, making it water-soluble so the liver can excrete it in bile. It is essentially the body's only enzyme for this job, which is why its activity sets your baseline bilirubin level.
When UGT1A1 activity is reduced, unconjugated bilirubin rises — usually mildly and harmlessly. Levels often climb further during fasting, illness, dehydration, or physical stress, which is why people with Gilbert syndrome notice a faint yellow tinge to the eyes at those times. It is benign and needs no treatment; the main value of recognising it is to avoid an unnecessary workup for liver disease.
UGT1A1 also glucuronidates several drugs. The most clinically important is irinotecan: its active metabolite SN-38 is cleared by UGT1A1, so low activity means higher SN-38 exposure and more toxicity. The HIV drug atazanavir is another example, where reduced activity causes visible but benign jaundice.
A promoter repeat, not a coding change.
The headline UGT1A1 variant is unusual — it is a length change in the gene's promoter, not a single amino-acid swap:
For Gilbert syndrome and irinotecan dosing, the genotype categories used are normal, intermediate (one reduced allele), and poor metabolizer (*28/*28 or equivalent).
Mostly benign — except for one chemotherapy drug.
UGT1A1 genotype has clinical guidance from CPIC and DPWG and appears on FDA drug labels. The two faces of the gene:
- Gilbert syndrome: benign. The practical value of a UGT1A1 result is reassurance and avoiding repeat liver investigations when mildly raised bilirubin is the only abnormality.
- Irinotecan (colorectal and other cancers): the FDA label notes a higher risk of severe neutropenia with *28/*28, *6/*6 or *6/*28 and advises considering a reduced starting dose; DPWG recommends 70% of the standard starting dose for poor metabolizers and no reduction for intermediate metabolizers — one of the clearest oncology pharmacogenomic actions.
- Atazanavir (HIV): CPIC reports a high likelihood of jaundice (hyperbilirubinemia) leading to discontinuation in poor metabolizers (two decreased-function alleles) and suggests considering an alternative where jaundice would be a concern; for intermediate metabolizers the likelihood is low.
"Gilbert syndrome is the most common thing UGT1A1 will tell you about — and the least dangerous. The result that actually changes care is irinotecan dosing in cancer treatment."
Primary sources: CPIC — UGT1A1 gene page; Gammal et al., Clin Pharmacol Ther 2016 (CPIC atazanavir guideline); Hulshof et al., Eur J Hum Genet 2023 (DPWG irinotecan guideline); Camptosar (irinotecan) prescribing information, FDA/DailyMed; MedlinePlus — UGT1A1; PharmGKB UGT1A1.
What consumer arrays do — and don't — tell you about UGT1A1.
The classic *28 variant is a TA-repeat length change, which SNP arrays cannot measure directly — but a nearby tag SNP usually stands in for it:
- rs887829 — a SNP in strong linkage with *28 that consumer arrays commonly genotype. Its T allele usually travels with *28, but how closely depends on ancestry, so T/T is a hint about *28, not a reading of it or a diagnosis of Gilbert syndrome.
- rs4148323 (*6) — sometimes genotyped; the key reduced-function allele in East Asian ancestry.
That makes consumer data more informative here than for most pharmacogenes, but unexplained high bilirubin still needs a clinician's work-up: an rs887829 result is supporting context, not a diagnosis of Gilbert syndrome, and it does not rule out liver disease, and for anything involving irinotecan or other chemotherapy, dosing decisions belong to your oncology team using a clinical-grade test.