Association between neonatal hyperbilirubinemia and UDP‐glucuronosyltransferase 1A1 gene polymorphisms

Abstract

We read the meta-analysis by Long et al. in which the association between neonatal hyperbilirubinemia and UDPglucuronosyltransferase (UGT) 1A1 gene polymorphisms was analyzed, with great interest. We were particularly surprised by the authors’ conclusion that UGT1A1 TATA promoter polymorphisms were not associated with an increased risk of neonatal hyperbilirubinemia in Asian subjects and that results from Caucasian populations were conflicting. Our surprise emanates from the non-inclusion in the meta-analysis of a study in which the interaction between glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and UGT1A1 (TA)6/(TA)7 heterozygosity or (TA)7/(TA)7 homozygosity led to a dramatic and significant increase in the incidence of neonatal hyperbilirubinemia. In that study, hyperbilirubinemia was defined as serum total bilirubin (STB) 15.0 mg/dL (257 mmol/L) during the first week of life. DNA from term neonates born to Sephardic Jewish mothers was analyzed for the UGT1A1 TATA promoter polymorphism and for the G-6-PD Mediterranean mutation. The variant (TA)7 promoter allele frequency was similar among G-6-PDdeficient (n = 131) and normal neonates (n = 240). Overall, 30 G-6-PD-deficient neonates (22.9%) developed hyperbilirubinemia versus 22 normal neonates (9.2%; P = 0.0005). Among those normal for G-6-PD, the UGT1A1 polymorphism had no significant effect on the incidence of hyperbilirubinemia (normal homozygotes, 9.9%; heterozygotes, 6.7%; variant homozygotes, 14.7%, NS). Furthermore, of those with the normal homozygous UGT1A1 promoter genotype ((TA)6/(TA)6), the incidence of hyperbilirubinemia was similar in G-6-PD-deficient neonates and controls (9.7% and 9.9%). Among the G-6-PD-deficient infants, however, between UGT1A1 promoter subgroups, the incidence of hyperbilirubinemia increased in a stepwise fashion and was greater in those with the heterozygous (31.6%; P = 0.006) or variant homozygous (50%; P = 0.003) UGT1A1 promoter genotype compared with normal homozygotes. Furthermore, among the G-6-PD-deficient neonates, within UGT1A1 promoter subgroups, those with the heterozygous or homozygous variant UGT1A1 promoter genotype had a higher incidence of hyperbilirubinemia than corresponding G-6-PD normal controls (heterozygotes: 31.6% vs. 6.7%, P < 0.0001; variant homozygotes: 50% vs. 14.7%, P = 0.02). Thus, neither G-6-PD deficiency alone nor the variant UGT1A1 gene promoter alone, increased the incidence of hyperbilirubinemia, but both in combination did. We would like to bring this gene interaction, which may serve as a paradigm of interaction of benign genetic polymorphisms in the causation of disease, to the attention of readers who may have received the wrong impression of the role of (TA)n promoter polymorphism in the pathogenesis of neonatal hyperbilirubinemia from the meta-anaylsis.