title: Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia.
abstract: Severe jaundice leading to kernicterus or death in the newborn is the most devastating consequence of glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G-6-PD) deficiency. We asked whether the TA repeat promoter polymorphism in the gene 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%) G-6-PD deficient neonates developed serum total bilirubin >/= 257 micromol/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.
authors.affiliation: Department of Neonatology, Shaare Zedek Medical Center, Jerusalem 91031, Israel. kaplan@cc.huji.ac.il
authors.forename: M
authors.initials: M
authors.lastname: Kaplan
authors.forename: P
authors.initials: P
authors.lastname: Renbaum
authors.forename: E
authors.initials: E
authors.lastname: Levy-Lahad
authors.forename: C
authors.initials: C
authors.lastname: Hammerman
authors.forename: A
authors.initials: A
authors.lastname: Lahad
authors.forename: E
authors.initials: E
authors.lastname: Beutler
mesh_terms: D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D005878:Gilbert Disease / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000453:epidemiology / Q000209:etiology*; D007231:Infant, Newborn; D007557:Israel / Q000453:epidemiology; D007565:Jaundice / Q000235:genetics; D007585:Jews / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D013577:Syndrome
chemical_list: D014453:Glucuronosyltransferase