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

Abstract

Background: Heme oxygenase (HO) is the initial, rate-limiting enzyme in the conversion of heme to bilirubin. Dinucleotide (GT)_n repeat length in the promoter region of the encoding gene modulates transcription: shorter alleles, in contrast with longer allele counterparts, are associated with greater gene expression and should result in increased heme catabolism. Objective: We compared the rates of heme catabolism and plasma total bilirubin (TB) between HO-1 promoter genotypes of varying (GT)_n repeat lengths in glucose-6-phosphate dehydrogenase (G6PD)-normal and -deficient neonates. Methods:HO-1 promoter length was determined from genomic DNA from previous studies by size discrimination of fluorescently-labeled PCR products with capillary electrophoresis. Sizing was confirmed by sequencing homozygote samples. Alleles were categorized as: short (≤24 GT repeats), medium (25-33 GT repeats), and long (≥34 GT repeats). Previously determined values for blood carboxyhemoglobin, corrected for inspired carbon monoxide (COHbc), and TB were used to determine the rate of heme catabolism and 3rd day TB values for each HO-1 promoter length genotype, respectively. G6PD Mediterranean was determined by PCR analysis. Results: Neither COHbc nor TB values were significantly different between various HO-1 promoter genotypes for either G6PD-normal or -deficient neonates. Conclusions: In the steady state, HO-1 promoter genotypes, based on the length of (GT)_n repeats, do not modulate heme catabolism or 3rd day TB values in either G6PD-normal or -deficient neonates.

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

“…9 Kaplan et al also showed that (GT)n repeat length did not regulate TB level in a population of Israeli neonates. 24 Both studies, however, categorized (GT)n repeat length into three classes and also used a higher cut-off number in their S classification (26 and 24, respectively) compared with that in the present study (<22). The present S classification is similar to that chosen by Tiwari et al (<21).…”

Decreased Glutathione S-transferase Level and Neonatal Hyperbilirubinemia Associated with Glucose-6-phosphate Dehydrogenase Deficiency: A Perspective Review

“…6,24 For that reason, a group of researchers recently reanalyzed stored deoxyribonucleic acid for heme oxygenase-1 promoter variants from neonates enrolled in a previous study 25 with the implicit aim of identifying another mechanism for G6PD deficiency-associated hyperbilirubinemia. 26 The results from this post hoc study were negative, but the findings should be interpreted cautiously because of the small sample size as acknowledged by the authors. 26 The relationship between G6PD deficiency-associated hyperbilirubinemia and Gilbert syndrome is confounded by an observation that Gilbert syndrome itself may be associated with increased hemolysis.…”

“…26 The results from this post hoc study were negative, but the findings should be interpreted cautiously because of the small sample size as acknowledged by the authors. 26 The relationship between G6PD deficiency-associated hyperbilirubinemia and Gilbert syndrome is confounded by an observation that Gilbert syndrome itself may be associated with increased hemolysis. 27 This observation is possibly due to that people with Gilbert syndrome may have increased hematocrit levels and hemoglobin levels as it has been shown in male adolescents and adults with Gilbert syndrome.…”

Bilirubin Production Is Increased in Newborn Mice Exposed to Isoflurane

“…In the human promoter region of the HO-1 gene, there is a polymorphic (GT)n repeat that regulates gene expression [23], with short (GT)n repeats associated with high HO-1 expression. In a cohort of infants from Israel, no association was observed between the rate of heme catabolism or plasma total bilirubin levels and HO-1 promoter genotypes in the steady state [24]. However, in a Japanese population of nonhemolytic term infants, we found that the presence of short (GT)n alleles was significantly higher in hyperbilirubinemic (18%) than in control neonates (7%) [25].…”