Association of HMOX1 gene promoter polymorphisms with hyperbilirubinemia in the early neonatal period

Background Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of human heme oxygenase-1 (HMOX1) contains a polymorphic (GT)_n repeat that can regulate gene expression. Here, we investigated the association of (GT)_n repeat length in the HMOX1 promoter region with neonatal hyperbilirubinemia in a population of Japanese term neonates. Methods Using polymerase chain reaction and fragment analysis, we determined the number of (GT)_n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in uridine diphosphoglucuronosyltransferase on hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case-control study. Allele and genotype frequencies of (GT)_n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates. Results The prevalence of short alleles (<22 (GT)_n repeats) was significantly higher in hyperbilirubinemic than in control neonates (18% vs 7%, P = 0.015). Hyperbilirubinemia was more frequent in homozygous or heterozygous short allele carriers than control neonates (28% vs 11%, respectively, P = 0.03). Possession of short alleles was significantly associated with the development of neonatal hyperbilirubinemia (OR, 3.1; 95%CI: 1.03-9.53). Conclusions Infants carrying short alleles (<22 (GT)_n repeats) in the HMOX1 gene promoter region appear to be at a higher risk for developing neonatal hyperbilirubinemia.