rs4148323 — UGT1A1 *6 Gly71Arg

The Gly71Arg Variant — East Asia's Gilbert Syndrome Mutation

UGT1A1 (UDP-glucuronosyltransferase 1A1) is a Phase II detoxification enzyme responsible for glucuronidation¹¹ glucuronidation
the addition of a glucuronic acid molecule to make substances more water-soluble for excretion. Its primary job is metabolizing bilirubin, the yellow breakdown product of red blood cells, but it also processes many pharmaceutical drugs including the chemotherapy agent irinotecan, HIV protease inhibitors, and statins.

The rs4148323 variant (c.211G>A) causes a glycine-to-arginine substitution at position 71 of the protein (p.Gly71Arg). This amino acid change, designated UGT1A1*6²² UGT1A1*6
the star-allele nomenclature used in pharmacogenomics, reduces enzyme activity by approximately 50% in vitro³³ 50% in vitro
measured by bilirubin glucuronidation clearance assays.

The Mechanism

Glycine at position 71 sits near the enzyme's active site. Replacing this small, flexible amino acid with arginine (which is larger and positively charged) appears to reduce the enzyme's maximum reaction rate (Vmax)⁴⁴ reduce the enzyme's maximum reaction rate (Vmax)
the parameter that reflects how much substrate the enzyme can process when saturated without substantially affecting substrate binding affinity. The result: the enzyme works more slowly, causing substrates like bilirubin and certain drugs to accumulate in the bloodstream.

This variant is functionally similar to the more widely known UGT1A1*28 (a TA repeat polymorphism in the promoter), but *6 predominates in East Asian populations⁵⁵ East Asian populations
allele frequency ~16% in East Asians vs <1% in Europeans while *28 is more common in Europeans and Africans.

The Evidence

Gilbert Syndrome: Homozygosity for UGT1A1*6 (AA genotype) is the primary cause of Gilbert syndrome in East Asian populations. A study of 120 Chinese patients with Gilbert syndrome⁶⁶ A study of 120 Chinese patients with Gilbert syndrome
Wang et al. Gene, 2021 found that compound heterozygous *28/*6 (20.83%), homozygous *28 (20.00%), and heterozygous *6 (15.00%) were the most frequent genotypes. Gilbert syndrome causes mild unconjugated hyperbilirubinemia (elevated bilirubin), typically manifesting as yellowing of the eyes (scleral icterus) during fasting, illness, or stress. It is benign and requires no treatment.

Neonatal Hyperbilirubinemia: Meta-analysis of 32 studies with 6,520 participants⁷⁷ Meta-analysis of 32 studies with 6,520 participants
Wang et al. Med Sci Monit, 2015 confirmed that UGT1A1 Gly71Arg significantly increases the risk of neonatal jaundice in both Asian and Caucasian infants. The A allele confers an odds ratio of approximately 9.8 for homozygotes and 3.2 for heterozygotes. Breastfed infants with the AA genotype are at particularly high risk and may require phototherapy.

Irinotecan Toxicity: Irinotecan is a topoisomerase inhibitor used in colorectal and other cancers. The drug is converted to its active metabolite SN-38, which is then glucuronidated by UGT1A1 for elimination. Patients with reduced UGT1A1 activity accumulate toxic levels of SN-38, causing severe neutropenia⁸⁸ neutropenia
dangerously low white blood cell counts and diarrhea⁹⁹ diarrhea
from damage to rapidly dividing gut cells. A Korean study¹⁰¹⁰ A Korean study
Cho et al. Pharmacogenet Genomics, 2015 found that *6/*6 homozygotes had a 7.4-fold increased risk (95% CI 1.2–44.2) of grade 4 neutropenia. The Dutch Pharmacogenetics Working Group (DPWG)¹¹¹¹ Dutch Pharmacogenetics Working Group (DPWG)
clinical guideline with Level 1 evidence recommends a 70% starting dose of irinotecan for poor metabolizers (homozygous *6 or *28, or compound heterozygotes).

Combined Genetic Risk: The combination of UGT1A1*6 and variants in SLCO1B1 (which encodes a transporter that moves drugs into liver cells for metabolism) creates synergistic toxicity risk¹²¹² synergistic toxicity risk
additive effects beyond either variant alone. A case report documented life-threatening toxicities in a patient with both UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes, resulting from extensive accumulation of SN-38 due to low metabolic and transport capacity.

Atorvastatin Metabolism: A study of 1,079 Chinese patients with coronary artery disease¹³¹³ A study of 1,079 Chinese patients with coronary artery disease
Su et al. Front Pharmacol, 2021 followed for 5 years found that the rs4148323 A allele was associated with increased formation of 2-hydroxy atorvastatin (an active metabolite) and a 1.77-fold higher risk of death (HR 1.774, 95% CI 1.031–3.052, p=0.020). The mechanism is unclear but may involve altered drug metabolism kinetics or tissue distribution of atorvastatin metabolites.

Atazanavir and Other HIV Drugs: Atazanavir (an HIV protease inhibitor) inhibits UGT1A1, causing predictable unconjugated hyperbilirubinemia¹⁴¹⁴ unconjugated hyperbilirubinemia
elevated bilirubin without liver damage. Patients who are poor metabolizers (homozygous for *6 or *28) are most likely to experience jaundice from atazanavir. CPIC guidelines¹⁵¹⁵ CPIC guidelines
Level A recommendation suggest considering alternative antiretroviral therapy for known poor metabolizers.

Practical Actions

For Gilbert Syndrome (AA genotype): No treatment is needed. Bilirubin levels typically range from 20–80 μmol/L (vs normal <20 μmol/L). The mild elevation is cosmetic (yellowing of eyes) and may even be protective¹⁶¹⁶ may even be protective
higher bilirubin is an antioxidant and associated with lower cardiovascular risk, though this remains controversial. Avoid fasting and stay hydrated during illness to minimize bilirubin spikes.

For Irinotecan Chemotherapy: If you have cancer and are prescribed irinotecan, request UGT1A1 genotyping before starting treatment. If you're a known poor metabolizer (AA genotype, or compound heterozygote with *28), your oncologist should reduce the starting dose by 30% and monitor closely for neutropenia and diarrhea. Some centers use 70% of standard dose initially, with escalation if tolerated.

For Atazanavir: If prescribed atazanavir for HIV, expect mild jaundice (yellowing of eyes) if you carry the A allele. This is harmless but cosmetically noticeable. If jaundice is severe or bothersome, alternative protease inhibitors (like darunavir) that don't inhibit UGT1A1 are available.

For Statins: The clinical significance of the atorvastatin-mortality association from one Chinese study is uncertain and not replicated. However, if you're East Asian ancestry with the AA genotype and taking atorvastatin, ensure regular lipid and liver function monitoring. Other statins metabolized by different pathways (rosuvastatin, pravastatin) may be alternatives if concerns arise.

For Neonates: If you're pregnant and have the AA genotype (or family history of Gilbert syndrome or neonatal jaundice), inform your obstetrician. Plan for early and frequent bilirubin monitoring after birth, especially if breastfeeding. Most cases resolve with phototherapy; kernicterus (brain damage from severe jaundice) is extremely rare in developed countries with newborn screening.

Interactions

UGT1A1*28 Compound Heterozygosity: The combination of *6 and *28 (one copy of each) produces an additive reduction in enzyme activity similar to being homozygous for either variant alone. Chinese Gilbert syndrome patients¹⁷¹⁷ Chinese Gilbert syndrome patients
Wang et al. 2021 showed that compound *6/*28 heterozygotes (20.83% of cases) had elevated bilirubin comparable to *28/*28 homozygotes. For irinotecan dosing, compound heterozygotes should be treated as poor metabolizers with dose reduction.

SLCO1B1 (rs4149056, OATP1B1*5): This transporter gene variant reduces hepatic uptake of drugs including irinotecan and statins. The combination of UGT1A1*6 (reduced metabolism) and SLCO1B1*5 (reduced liver uptake) creates synergistic toxicity risk¹⁸¹⁸ synergistic toxicity risk
the case report of life-threatening irinotecan toxicity with combined UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes demonstrates the danger. If you have both variants, irinotecan dose should be reduced even further (possibly to 50% of standard dose) with intensive monitoring.

CYP2D6 and Other Phase I Enzymes: Some prodrugs require CYP450 enzymes for activation before UGT1A1 glucuronidation. Interactions are drug-specific but generally, having reduced activity in both Phase I (CYP450) and Phase II (UGT1A1) pathways can either prolong active drug exposure (if CYP activates) or provide partial compensation (if CYP inactivates). Discuss polypharmacy with a clinical pharmacist if you're on multiple medications.

Rifampin and Other UGT1A1 Inducers: Rifampin (an antibiotic) induces UGT1A1 expression, potentially compensating for reduced *6 enzyme activity. Conversely, discontinuing rifampin after chronic use can unmask Gilbert syndrome. Other inducers include phenobarbital, carbamazepine, and St. John's Wort.