Neonatal Hyperbilirubinemia in Japanese Neonates: Analysis of the Heme Oxygenase-1 Gene and Fetal Hemoglobin Composition in Cord Blood

Abstract

Neonatal hyperbilirubinemia is frequent and severe in Japanese infants. Although the G71R mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene is associated with severe neonatal hyperbilirubinemia in this population, it accounts for only half of the neonates with severe hyperbilirubinemia. It was suggested that increased bilirubin production would also be associated with severe neonatal hyperbilirubinemia in Japanese infants. To elucidate the genetic factors causing severe hyperbilirubinemia in these patients, we studied two notable factors associated with bilirubin production: heme oxygenase-1, a key enzyme of heme metabolism, and fetal Hb composition, a factor possibly associated with heme load in neonates. We first determined the sequences of promoter and all coding regions of the heme oxygenase-1 gene in Japanese neonates who had undergone phototherapy, but found no mutation except for the polymorphic (GT) n repeats in the promoter region. These repeats modulate the transcription of the heme oxygenase-1 gene, and the longer repeat sequences are known to reduce the transcription. We detected a significant difference in the allele frequencies of each number of (GT) n repeats between Japanese and German populations. However, we could not find a relation between those polymorphisms and neonatal hyperbilirubinemia. We next analyzed the state of Hb switching of the ␥-to ␤-globin chain and the phenotype of ␥-globin chain isoforms in cord blood. We found no relation between fetal Hb composition and neonatal hyperbilirubinemia. Further studies are required to elucidate genetic or environmental factors in neonatal hyperbilirubinemia in Japanese infants. (Pediatr Res 54: 165-171, 2003) Abbreviations B-UGT, bilirubin uridine diphosphate-glucuronosyltransferase (EC 2.4.1.17) HO-1, heme oxygenase-1 (EC 1.14.99.3) CO, carbon monoxide HbF, fetal hemoglobin TCBR, transcutaneous bilirubinometer reading Unconjugated hyperbilirubinemia in the neonate is a physiologic and transitional phenomenon that is very common. Physiologic unconjugated hyperbilirubinemia of the neonate is called neonatal hyperbilirubinemia or neonatal jaundice. The term physiologic means that the neonate has no evidence of diseases causing unconjugated hyperbilirubinemia such as hemolytic anemias and does not carry variable risk factors associated with neonatal unconjugated hyperbilirubinemia such as maternal diabetes, prematurity, and so on (1).Bilirubin production is increased in the neonate because of larger erythrocyte volume, shortened erythrocyte life span, heme and heme precursors degraded from the fetal extramedullary hematopoietic tissue, and, possibly, increased turnover of cytochromes (2). In addition, the ability to conjugate bilirubin is extremely low in the neonate; the B-UGT activity of neonates at term is about 1% of adult values (3). Neonatal hyperbilirubinemia is also probably associated with other factors such as an immaturity of hepatic uptake and intracellular transport, and increased enterohepatic circulation. Thu...

Reduced Expression of Heme Oxygenase-1 in Patients with Coronary Atherosclerosis

“…2). These findings were all consistent with previous observations in both Cauca- sian and Japanese populations (22,23,34). We divided the subjects into three genotype groups (S/S, S/L, and L/L) as described above, then compared the basal and stimulated levels of HO-1 mRNA among them.…”

“…As in the previous studies (22,23,34), the (GT)n repeat length ranged from 16 to 41 and showed a bimodal distribution, with the median length of the short repeat being around 23 pairs and that of the long repeat being around 30 pairs. Thus, as in the previous studies, each of the two alleles of the gene was classified as a long (L) or short (S) genotype based on whether the repeat length was more or less than 26 pairs, respectively.…”

Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms

“…To identify other predisposing factors for neonatal hyperbilirubinemia, we studied the effect of polymorphisms in the enhancer sequence (-3483/-3194) (phenobarbital response enhancer module) of the UGT1A1 gene, polymorphic (GT)n repeats in the promoter region of the hemeoxygenase-1 (a rate-limiting enzyme in heme metabolism) gene and the composition of fetal hemoglobin (a probable major source of bilirubin in neonates). 18,19 However, we could not find any predisposing factors. There has been an increase in reports that UGT1A1 211G4A genotype is associated with unconjugated hyperbilirubinemia in breast-fed neonates.…”

<b><i>Heme Oxygenase-1</i></b> Promoter Polymorphisms and Neonatal Jaundice

“…In Japanese infants who had undergone phototherapy, no relationship was found by Kanai et al [5] between these polymorphisms and neonatal hyperbilirubinemia. Similarly, Bozkaya et al [6] did not detect significant differences in HO-1 promoter allele lengths between Turkish newborns with TB values >12.9 mg/dl and those with lower values.…”

“…Short allele HO-1 promoter polymorphisms may therefore play an important genetic role in upsetting the equilibrium between bilirubin production and elimination thereby facilitating the development of neonatal hyperbilirubinemia [2,3,4]. To date, limited studies have evaluated this possibility with inconclusive results [5,6,7]. …”