UGT1A1: the gene behind Gilbert syndrome and drug-related jaundice
Most people who carry a reduced-activity UGT1A1 genotype find out about it as an incidental result: a slightly high bilirubin on a routine blood test, and a doctor who says the word Gilbert and moves on. The same genotype has a much more concrete consequence for a small number of medicines.
Also known as: UDP glucuronosyltransferase family 1 member A1, bilirubin UDP-glucuronosyltransferase.
What UGT1A1 does
The enzyme attaches a sugar group to bilirubin, the yellow pigment left over when red cells are recycled. That step is what makes bilirubin water-soluble so the liver can dispose of it. Less enzyme activity means bilirubin clears more slowly and its level in blood runs higher. In everyday life that shows up as a mildly raised bilirubin that rises further during fasting, illness or stress, and yellows the whites of the eyes in some people. The same slowdown applies to drugs that leave the body by the same route.
The metabolizer groups
UGT1A1 is graded by diplotype into normal, intermediate and poor metabolizer, with Indeterminate where the pair cannot be graded. Nearly all of the common variation comes from a repeat in the promoter, the stretch that controls how much enzyme gets made: the usual sequence carries six repeats, and the *28 allele carries seven, which reduces production. Two copies of *28 is the classic Gilbert syndrome genotype and the poor metabolizer result here.
Medications where it matters
atazanavir (Reyataz)
Atazanavir is an HIV protease inhibitor that blocks UGT1A1 directly. In someone whose enzyme output is already low, that combination pushes bilirubin high enough to produce visible jaundice, and jaundice is the usual reason people stop taking it. The published guidance is unusual in that it is written as a conversation to have with the patient before starting, since the effect is cosmetic rather than dangerous but is a common reason for abandoning an otherwise working regimen.
| If your result is | Published CPIC guidance |
|---|---|
| Intermediate Metabolizer | Per CPIC (A): "There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result. Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient's genotype makes this unlikely (less than about a 1 in 20 chance of stopping atazanavir because of jaundice)." |
| Normal Metabolizer | Per CPIC (A): "There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result. Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient's genotype makes this unlikely (less than about a 1 in 20 chance of stopping atazanavir because of jaundice)." |
| Poor Metabolizer | Per CPIC (A): "Consider an alternative agent particularly where jaundice would be of concern to the patient. If atazanavir is to be prescribed, there is a high likelihood of developing jaundice that will result in atazanavir discontinuation (at least 20% and as high as 60%)." |
Is this in your raw DNA file?
UGT1A1 is not part of the standard chip or variant-file report. It is a Deep Read gene, read from aligned reads in a BAM or CRAM file, and the reason is the *28 allele itself. It is a change in the length of a repeated sequence rather than a single letter substitution, which is the kind of variant genotyping arrays are worst at and short-read data handles only with care. Some consumer files carry a marker in linkage with *28, which is a proxy rather than the variant. Aimosti reports what the reads support and returns Indeterminate where the repeat length is not resolved.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
Does this mean I have Gilbert syndrome?
A poor metabolizer result is the genotype most often behind it, but Gilbert syndrome is a clinical picture rather than a genotype: mildly raised unconjugated bilirubin with otherwise normal liver tests. Plenty of people carry the genotype without ever having a bilirubin measured. A blood test is what confirms it.
Is Gilbert syndrome something to worry about?
It is described as a relatively mild condition and it does not damage the liver. The reasons to know about it are practical: it explains an odd blood result without further investigation, and it changes how a few specific drugs behave.
What about irinotecan? I have read that UGT1A1 matters there.
It does, and the FDA label for irinotecan mentions UGT1A1 status. Aimosti's Deep Read currently restates the CPIC atazanavir guidance for this gene, which is what the table above shows. Irinotecan dosing is a decision for an oncology service working from a clinical test.
Is UGT1A1 in my 23andMe or AncestryDNA raw data?
Not in a form that settles the question. The variant that matters is a change in repeat length in the promoter, which arrays do not measure directly. Aimosti reads this gene from aligned reads and reports Indeterminate when the repeat is not resolved.