Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: A dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia

Michael Kaplan*, Paul Renbaum, Ephrat Levy-Lahad, Cathy Hammerman, Amnon Lahad, Ernest Beutler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

309 Scopus citations


Severe jaundice leading to kernicterus or death in the newborn is the most devastating consequence of glucose-6-phosphate dehydrogenase: (EC; G-6-PD) deficiency. We asked whether the TA repeat promoter polymorphism in the cane for uridinediphosphoglucuronate glucuronosyltransferase 1 (EC 2.4.1;17; UDPGT1), associated with benign jaundice in adults (Gilbert syndrome), increases the incidence of neonatal hyperbilirubinemia in G-6-PD deficiency. DNA from term neonates was analyzed for UDPGT1 polymorphism (normal homozygotes, heterozygotes, variant homozygotes), and for G-6-PD Mediterranean deficiency. The variant UDPGT1 promoter allele frequency was similar in G-6-PD-deficient and normal neonates. Thirty (22.9%) G6-PD deficient neonates developed serum total bilirubin ≤ 257 μmol/liter, vs. 22 (9.2%) normals (p = 0.0005). Of those with the normal homozygous UDPGT1 genotype, the incidence of hyperbilirubinemia was similar in G-6-PD-deficients and controls (9.7% and 9.9%). In contrast, in the G-6-PD-deficient neonates, those with the heterozygous or homozygous variant uDPGT1 genotype had a higher incidence of hyperbilirubinemia than corresponding controls (heterozygotes: 31.6% vs. 6.7%, P < 0.0001; variant homozygotes: 50% vs. 14.7%, P = 0.02). Among G-6- PD-deficient infants the incidence of hyperbilirubinemia was greater in those with the heterozygous (31.6%, P = 0.006) or variant homozygous (50%, P = 0.003) UDPGT1 genotype than in normal homozygotes. In contrast, among those normal for G-6-PD, the UDPGT1 polymorphism had no significant effect (heterozygotes: 6.7%; variant homozygotes: 14.7%). Thus, neither G-6-PD deficiency nor the variant UDPGT1 promoter, alone, increased the incidence of hyperbilirubinemia, but both in combination did. This gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease.

Original languageAmerican English
Pages (from-to)12128-12132
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number22
StatePublished - 28 Oct 1997


  • Bilirubin conjugation
  • Gene interaction
  • Hemolysis
  • Neonatal jaundice
  • UDP- glucurosyltransferase 1


Dive into the research topics of 'Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: A dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia'. Together they form a unique fingerprint.

Cite this