Published online June 16, 2008
PEDIATRICS (doi:10.1542/peds.2007-3249)
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ARTICLE

Coexpression of Gene Polymorphisms Involved in Bilirubin Production and Metabolism

Zhili Lin, PhDa, Jamie Fontaine, BSa and Jon F. Watchko, MDb

a Pediatrix Screening, Inc, Bridgeville, Pennsylvania
b Division of Newborn Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. The potential for genetically determined conditions to modulate the risk for developing neonatal hyperbilirubinemia is increasingly being recognized. The aims of this investigation were to (1) develop genotyping assays for an expanded panel of mutations and polymorphisms across 3 genes that are involved in bilirubin production and metabolism (glucose-6-phosphate dehydrogenase [G6PD], uridine diphosphate glucuronosyl transferase 1A1 [UGT1A1], and organic anion transporter polypeptide 1B1 [OATP1B1]) and (2) determine their allele frequencies in 450 anonymous DNA samples of US residents with ancestry from all of the major regions of the world.

METHODS. Genotyping assays were developed on the basis of allele-specific hybridization and melting peak analysis of the probe set and the match or mismatch template. Allele frequencies and the complexity of coinheritance of multiple genetic variants across G6PD, UGT1A1, and OATP1B1 genes in DNA samples from the DNA Polymorphism Discovery Resource of the National Human Genome Research Institute were determined by using this expanded panel.

RESULTS. Genetic polymorphisms of the UGT1A1 promoter, specifically the T-3279G phenobarbital responsive enhancer module and the (thymidine-adenine)7 dinucleotide repeat TATAA box variants, were common. Similarly, OATP1B1 coding sequence gene variants were frequently observed. Moreover, in more than three quarters of the samples, ≥2 variants were detected, reflecting a high degree of polymorphism coexpression across these genes, including those who carried the African A– G6PD mutation.

CONCLUSIONS. We conclude that this expanded panel of mutations and polymorphisms can serve as an effective instrument to study the genetic architecture of hyperbilirubinemia and speculate an important role for genetic polymorphism coinheritance in determining hyperbilirubinemia risk in newborns.

Key Words: genetics • glucose-6-phosphate dehydrogenase • hyperbilirubinemia • organic anion transporter polypeptide 1B1 • uridine diphosphate glucuronosyl transferase 1A1 • phenobarbital responsive enhancer module

Abbreviations: G6PD—glucose-6-phosphate dehydrogenase • UGT1A1—uridine diphosphate glucuronosyl transferase 1A1 • OATP1B1—organic anion transporter polypeptide 1B1 • PBREM—phenobarbital responsive enhancer module • PCR—polymerase chain reaction


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hyperbilirubinemia is the most common clinical condition in the newborn that requires evaluation and management1 and the most frequent reason for hospital readmission during the first week of postnatal life.2 Although generally a benign transitional phenomenon of no overt clinical impact, in a select few, the total serum bilirubin may rise to hazardous levels that pose a direct threat of brain damage. Acute bilirubin encephalopathy, an uncommon disorder,3 may ensue, frequently evolving into kernicterus, a devastating, chronic, disabling neurologic condition.3,4

Although both genetic and environmental factors contribute to the development of neonatal hyperbilirubinemia, increasingly, the importance of genetically determined conditions is being recognized.5–13 Gene variants reported in association with an increased risk for neonatal hyperbilirubinemia include those of (1) the red blood cell enzyme glucose-6-phosphate dehydrogenase (G6PD),7,10,11,14,15 (2) the hepatic bilirubin-conjugating enzyme uridine-diphosphate glucuronosyl transferase 1A1 (UGT1A1),7–10 and (3) the hepatic organic anion transporter polypeptide 1B1 (OATP1B1).12,13,16 G6PD gene variants may predispose to neonatal hyperbilirubinemia via either an acute hemolytic event with or without an identifiable environmental trigger14,15 or a low-grade hemolysis coupled with UGT1A1 gene polymorphisms.10,17 UGT1A1 promoter and coding sequence gene variants8–10,13,17,18 may predispose to neonatal hyperbilirubinemia via decreased hepatic bilirubin conjugation. More recent findings suggested that gene polymorphisms of OATP1B1,12,13 a putative bilirubin transporter19,20 localized to the sinusoidal membrane of hepatocytes (ie, the blood–hepatocyte interface), may predispose to neonatal hyperbilirubinemia by possibly limiting hepatic bilirubin uptake.

To identify genetic risk factors for marked hyperbilirubinemia in a US-based population, we developed genotyping assays for an expanded panel of mutations and polymorphisms across the G6PD, UGT1A1, and OATP1B1 genes. Initial selection of genetic variants for this panel was based on information listed in the public domain. Four common G6PD mutations, the African A– (G202A; A376G), the Mediterranean (C563T), and 2 Chinese (G1376T and G1388A), were included. Several promoter polymorphisms and coding sequence mutations for the UGT1A1 gene were also examined, including the T-3279G phenobarbital responsive enhancer module (PBREM) promoter variant, the (TA)n dinucleotide repeat TATAA box promoter polymorphisms, and the coding sequence G211A, C686A, C1091T, and T1456G mutations. Most of these genetic variants have been reported in association with Gilbert's syndrome,13,17,18,21–28 a condition characterized by mild indirect hyperbilirubinemia in the absence of liver disease and clinically overt hemolysis. A total of 18 coding sequence OATP1B1 gene variants were studied, including the nonsynonymous T217C, T245C, A388G, A452G, G455A, C463A, A467G, T521C, T578G, G721A, C1007G,T1058C, A1294G, A1385G, G1454T, G1463C, A1964G, and A2000G polymorphisms.12,13,29–34 Other polymorphisms of the UGT1A1 and OATP1B1 genes were detected during the course of the study, and their genotypes were confirmed by DNA sequencing.

In this study, we determined the allelic frequencies and assessed the complexity of coinheritance of multiple genetic variants across G6PD, UGT1A1, and OATP1B1 genes in DNA samples from the DNA Polymorphism Discovery Resource of the National Human Genome Research Institute35 by using this expanded panel. The Polymorphism Discovery Resource is composed of anonymous DNA samples of 450 US residents with ancestry from all of the major geographic regions of the world.35 These data suggest that coinheritance of multiple genetic variants in >1 of these 3 genes is relatively common in US residents.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
DNA Samples
A total of 450 anonymous DNA samples from the DNA Polymorphism Discovery Resource of the National Human Genome Research Institute35 were purchased from the Coriell Cell Repositories (www.coriell.org). Individuals gave informed consent explicitly to be part of this repository,35 and the University of Pittsburgh institutional review board designated this as an exempt project. This collection of DNA samples from unrelated individuals, male and female, represent 120 European American, 120 African American, 120 Asian American, 60 Mexican American, and 30 Native American individuals, reflecting ancestry from all of the major regions of the world.35 It included individuals with non-European ancestry at more than their frequency in the US population, a sampling strategy that facilitates the identification of genetic variants in the entire population.35 Given the anonymous nature of the repository, no medical, phenotypic, or ethnicity information was available for individual samples.

Polymerase Chain Reaction Setup and Cycling Condition
Sequences and concentrations of polymerase chain reaction (PCR) primers and fluorescent labeled probes used in the PCRs are available from the correspondence author on request. These were each synthesized and HPLC purified by Integrated DNA Technologies (Coralville, IA). PCR-amplification reactions (10 µL) were setup in a 384-well PCR plate. In addition to primer and probe concentrations, all PCRs contained 50 mM Tris (pH 8.5), 16 mM ammonium sulfate, 1.5 µg BSA, 3.5 mM MgCl, 200 µM dNTP, 0.5 to 1.0 U of Klen Taq polymerase (Ab Peptides, St Louis, MO), and 10 ng of DNA. With the exception of the cycling condition for G6PD mutations,36 the same cycling protocol was used for all other PCRs, namely 45 cycles of 94°C for 20 seconds, 60°C for 1 minute, and 72°C for 30 seconds, then hold at 94°C for 2 minutes. All reaction mixtures were covered with 8 µL of mineral oil before PCR amplification in a PrimusHT Multiblock thermal cycler (MWG Biotech, High Point, NC).

Melting Peak Analysis
Genotyping assays were developed on the basis of allele-specific hybridization and melting peak analysis using the LightTyper instrument (Roche Diagnostics, Indianapolis, IN).37–39 Allelic discrimination was achieved by the difference in melting temperature between the probe set and match or mismatch template. For most targeted genetic variants, probes were designed to match perfectly the targeted mutant template and provide a 1-bp mismatch to the wild-type template. Any other genetic variant within the probe-binding site was consequently a ≥2-bp mismatch to the probe. The degree difference of a mismatch generated melting peaks at different temperatures. Briefly, on completion of PCRs, the 384-well PCR plates were individually inserted into the instrument after centrifugation. The LCD camera exposure time was set at 1500 milliseconds, and the PCR plate was heated from 35°C to 80°C at 0.2°C/second ramp rate. Data were collected and analyzed by using the LightTyper Genotyping Software. The genotype was determined for each sample on the basis of the melting profile. Genotyping the UGT1A1 promoter (TA)n repeat polymorphism was performed using the same approach, however, with 4 possible (TA)n repeats, numbering from 5 to 8. For this assay, the probe was designed to match perfectly the (TA)8 repeats. In addition, because of the close proximity of possible melting peaks that can be detected, we analyzed the data within the temperature range of 59°C to 63°C instead of the reference range 35°C and 80°C to achieve maximum separation of all 4 possible melting peaks.

DNA Sequencing
DNA sequencing reactions were performed from selected DNA samples with genetic variants detected by the genotyping assays. Briefly, PCRs were performed under the same condition stated in the previous section without probes. PCR products were purified using the Qiagen mini kits (Qiagen, Valencia, CA) by following the recommended protocol. DNA sequencing reactions were performed at the DNA sequencing core facilities at the University of Pittsburgh.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The wild-type UGT1A1 PBREM promoter generated a single melting peak at 52.7°C, homozygous samples for the T-3279G polymorphism generated a single mutant peak at 62°C, and heterozygous samples generated both peaks. The melting peak profile for the UGT1A1 (TA)n dinucleotide repeat TATAA box promoter revealed peaks at 63.5°C for (TA)8, 60.8°C for (TA)7, 59.5°C for (TA)6 (wild-type allele), and 58.0°C for (TA)5; heterozygous samples evidenced 2 distinguishable peaks for (TA)5/(TA)7, (TA)6/(TA)8, and (TA)7/(TA)8 and a merged single peak for (TA)5/(TA)6 and (TA)6/(TA)7. The latter single peaks were distinguishable from each other and homozygous (TA)5/(TA)5, (TA)6/(TA)6 (wild type), and (TA)7/(TA)7 genotypes. The (TA)n genotyping assay further revealed a variant melting peak at 54.4°C, DNA sequencing of which identified a novel G to C substitution at position –49 in the UGT1A1 promoter.

Allele frequencies of panel-detected variants among the 450 DNA samples are listed in Table 1 and notable for (1) the (TA)7 UGT1A1 TATAA promoter variant at 33.9%, (2) the T-3279G UGT1A1 PBREM variant at 56.9%, and (3) the A388G OATP1B1 variant (OATP1B1*1b) at 47.1%. Indeed, 56 (12.4%) individuals were homozygous for the UGT1A1 (TA)7/(TA)7 genotype, considered the cause of Gilbert syndrome in white individuals18; a total of 160 (35.6%) individuals were homozygous for the UGT1A1 T-3279G PBREM promoter variant, and 116 (25.8%) were homozygous for the OATP1B1 A388G variant. Of additional note, all (TA)7 homozygous individuals were also homozygous for the T-3279G allele.


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  		TABLE 1 Allele Frequencies in the 450 DNA Samples

 
By contrast, a single G6PD A– mutant peak alone was detected in just 4 samples, these being either hemizygous male and/or homozygous female individuals given that G6PD is an X-linked gene. There were also 19 individuals who were heterozygous for the G6PD A– variant and 2 individuals who were heterozygous for the C563T (Mediterranean) variant, by definition, all female. No individual expressed either of the 2 G6PD Chinese mutations; the UGT1A1 T1456G mutation; or the OATP1B1 T217C, T245C, A452G, G455A, A467G, T578G, G721A, C1007G, T1058C, A1294G, A1385G, G1454T, A1964G, and A2000G mutations. UGT1A1 coding sequence variants were infrequent and limited to heterozygous expression, the most common being the G211A polymorphism. The novel UGT1A1 promoter variant (G-49C) and 3 novel OATP1B1 variants (G227A, A535G, and A1444G) were noted in the heterozygous state.

The number of variants detected per sample ranged from 0 to 9 and are plotted versus total number of cohort samples in Fig 1. Eighteen samples had no variant detected, and 48 samples had only 1 variant detected, together accounting for 14.7% of the individuals. Thus, 85.3% of the samples had ≥2 variants, indicative of a high level of polymorphism coinheritance as shown in Table 2. Regarding the specifics of this coinheritance, 3 of the 4 G6PD African A– individuals coexpressed UGT1A1 promoter and/or OATP1B1 gene variants, including (1) 1 who was heterozygous for a (TA)7/(TA)5 UGT1A1 promoter variant and homozygous for both the A388G and A1463C OATP1B1 polymorphisms, the latter the putative loss of function OATP1B1*18 haplotype34; (2) 1 who was heterozygous for (TA)7/(TA)8 UGT1A1 promoter variant and homozygous for A388G OAT1B1 polymorphism; and (3) 1 who was heterozygous for the (TA)7/(TA)6 UGT1A1 promoter alone. Of the 19 heterozygous G6PD African A– female individuals, some of whom could evidence partial G6PD deficiency as a result of nonrandom X inactivation, 2 were homozygous for both the UGT1A1 (TA)7/(TA)7 promoter and OATP1B1 A388G variants, and another 7 were heterozygous for the (TA)7/(TA)6 UGT1A1 promoter polymorphism, 4 of whom were also homozygous for the OATP1B1 A388G genotype. Of additional note regarding coinheritance of UGT1A1 and OATP1B1 polymorphisms, 40 of the 56 individuals who were homozygous for the (TA)7/(TA)7 UGT1A1 promoter variant were either homozygous (n = 14) or heterozygous (n = 26) for the OATP1B1 A388G polymorphism, and another 2 were homozygous for the OATP1B1 C463A variant. Coexpression of different OATP1B1 variants among themselves was less frequent; of the 116 individuals who were homozygous for the A388G polymorphism, only 1 coexpressed homozygosity for the OATP1B1 T521C variant, the putative loss of function OATP1B1*15 haplotype,34 whereas another coexpressed homozygosity for the A1463C variant, a different putative loss of function OATP1B1*18 haplotype.34


Figure 1
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  		FIGURE 1 Distribution of the total number of samples as a function of the number of genetic variant(s) detected per sample. The number of genetic variants detected across all 3 genes was added together for each sample. Four genetic variants were excluded: the (TA)6 repeat for the UGT1A1 promoter designated as wild type; the (TA)5 repeat, which has been shown to express higher UGT1A1 activity than the wild type21; and the 2 synonymous OATP1B1 variants T571C and C1452T.

 

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  		TABLE 2 Coinheritance Among UGT1A1, OATP1B1, and G6PD Genes

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we developed genotyping assays for an expanded panel of mutations and polymorphisms across 3 genes that are involved in bilirubin metabolism, namely those that encode G6PD, UGT1A1, and OATP1B1. When applied to 450 anonymous DNA samples of US residents with ancestry from all of the major regions of the world,35 we detected a broad array of polymorphisms and a high degree of variant coexpression across these 3 genes.

Of the genes involved in bilirubin metabolism, UGT1A1 has been the most widely studied given its essential role in hepatic bilirubin glucuronization. A frequent polymorphism in the current cohort was the insertion of a seventh (TA) repeat (allele frequency of 33.9%) in the promoter sequence of UGT1A1, which normally consists of (TA)6 repeats. A seventh (TA) repeat in the repetitive TATAA element lessens the affinity of the TATAA binding protein, a transcription factor, to the TATAA box18 such that as the number of (TA)n repeats increase above the wild type (TA)6, UGT1A1 expression declines.21 Individuals who are homozygous for the (TA)7/(TA)7 promoter variant (12.4% of individuals in the cohort) evidence ~30% of wild-type UGT1A1 activity, and this genotype underlies the Gilbert syndrome phenotype in white individuals.18 The decreased hepatic bilirubin-conjugating capacity in Gilbert syndrome is associated with an accelerated early postnatal increase in neonatal jaundice,40 prolonged indirect hyperbilirubinemia, particularly in breastfed newborns,41 and an increased risk for marked neonatal hyperbilirubinemia when coupled with hemolytic conditions.7,10 In addition to individuals with (TA)7 repeat alleles, we identified 9 individuals who carried an eighth (TA) repeat (allele frequency of 1.0%), which was always observed in the heterozygous state and would further reduce UGT1A1 transcriptional activity when expressed with the (TA)7 promoter allele (3 of 9 individuals in this cohort).21 The (TA)8 UGT1A1 promoter sequence, originally reported in individuals of varying African heritage,21 has been noted, albeit rarely, in white individuals as well.7,42

The T-3279G PBREM UGT1A1 promoter polymorphism was also frequently detected, and the T-3279G and (TA)7 UGT1A1 promoter variants were in linkage disequilibrium. Some investigators suggested that such linkage is essential to the pathogenesis of Gilbert syndrome,25 whereas others did not.43,44 Regardless, both promoter variants evidence lower UGT1A1 transcriptional activity.18,21,26,45 The G211A missense UGT1A1 coding sequence mutation that underlies Gilbert syndrome in Asian populations13,17,23,27,28 was observed in only 29 individuals and limited to the heterozygous state.

Coexpression of UGT1A1 variants with other genes was commonly observed: (1) ~70% of individuals who were homozygous for the (TA)7 UGT1A1 promoter variant were either homozygous or heterozygous for the OATP1B1 A388G polymorphism, and (2) ~50% of G6PD A– individuals coexpressed a (TA)7 variant on at least 1 allele. OATP1B1 polymorphism coexpression with UGT1A1 variants could couple diminished hepatic bilirubin uptake with decreased hepatic bilirubin-conjugating capacity, further impairing bilirubin clearance and increasing hyperbilirubinemia risk as recently reported by Huang et al13 in Taiwanese newborns. The prevalence of UGT1A1 promoter polymorphisms in this diverse population cohort is consistent with previous reports8–10,18,21 and suggested that bilirubin conjugation–limiting gene variants may prove to be important modulators of neonatal hyperbilirubinemia risk, particularly when coupled with other icterogenic conditions (eg, G6PD deficiency).

G6PD mutations are an important contributor to the risk for neonatal hyperbilirubinemia3,10,14,15 and account for ~22% of all cases in the US Pilot Kernicterus Registry, a database of voluntarily reported cases of kernicterus.3 The G6PD African A– variant was observed at an allele frequency of 3.4% and in both the hemizygous/homozygous and heterozygous states. The latter, in the context of nonrandom X-chromosome inactivation, can be G6PD deficient and at risk for development of severe hyperbilirubinemia.11,15,46 The (TA)7 repeat UGT1A1 promoter polymorphism was commonly coexpressed with the G6PD African A– mutation, a pattern previously reported with the G6PD Mediterranean variant10 where-in this gene interaction significantly enhanced the risk for neonatal hyperbilirubinemia10 in both the heterozygous (TA)7/(TA)6 and the homozygous (TA)7/(TA)7 forms. In this cohort, ~50% of G6PD African A– individuals coexpressed the (TA)7 repeat UGT1A1 promoter polymorphism on at least 1 allele, including 2 that coexpressed a (TA)7/(TA)8 UGT1A1 promoter genotype. The allele frequency of UGT1A1 promoter variants is highest in individuals of African origin [(TA)7 at 42.6% and (TA)8 at 6.9%],21 a proclivity that when coupled with G6PD mutations would be predicted to increase the risk for jaundice.21 Mirroring the high level of UGT1A1 promoter polymorphism coexpression, ~50% of G6PD African A– individuals coexpressed homozygosity for OATP1B1 variants, haplotypes (OATP1B1*1b or OATP1 B1*18) that theoretically could further impair hepatic bilirubin clearance and increase hyperbilirubinemia risk.

Eight nonsynonymous OATP1B1 gene variants were detected, including the A388G (OATP1B1*1b [allele frequency of 47.1%]) and T521C (OATP1B1*5 [allele frequency of 9.8%]) polymorphisms previously reported in association with unconjugated hyperbilirubinemia12,13,47 and at allele frequencies intermediate to those of individuals of European American and African American descent.33 Coexpression among OATP1B1 gene variants resulting in putative OATP1B1 loss of function haplotypes34 was observed but, infrequently, in contrast to the more prevalent coexpression of individual OATP1B1 variants with UGT1A1 polymorphisms and/or the G6PD African A– mutation. Although more recent observations called into question a direct role of OATP1B1 in hepatic bilirubin uptake,33,48 Huang et al13 reported a significantly increased risk for bilirubinemia ≥20 mg/dL (≥342 µmol/L) in Taiwanese newborns who were homozygous for the A388G OATP1B1 variant, a risk that was further increased when coupled with coexpression of the UGT1A1 coding sequence G211A Gilbert syndrome polymorphism or breast milk feedings. Neonates with all 3 risk factors evidenced an adjusted odds ratio of 88.0 (95% confidence interval: 12.50–642.50) for a serum bilirubin of ≥20 mg/dL (≥342 µmol/L) as compared with formula-fed newborns with wild-type OATP1B1 and UGT1A1 genotypes.13 The high allele frequency of the OATP1B1 A388G variant in the current cohort suggests that this polymorphism alone does not account for an increased hyperbilirubinemia risk but may act in a manner analogous to the (TA)7 repeat UGT1A1 polymorphism by enhancing hyperbilirubinemia risk when coexpressed with other icterogenic conditions. Indeed, the novel findings by Huang et al add to a growing literature on the important contribution that gene variants make to the development of neonatal hyperbilirubinemia 5–7,9,10,13–17,24,28 and specifically the potential modulatory role of OATP1B1 variants in neonatal bilirubin clearance and, thereby, hyperbilirubinemia risk.13 Whether OATP1B1 polymorphisms exert a similar impact on hyperbilirubinemia risk in other populations is unknown but merits future study.

Severe neonatal hyperbilirubinemia is a prototypic pediatric complex trait or disorder that is both prevalent (>1%) in the newborn population (total serum bilirubin >20 mg/dL ~1:703,49) and the product of multiple gene loci each with relatively weak effects interacting with other genes and environmental contributors.50,51 The gene variants that underlie complex disorders are characteristically common in the population, often at allele frequencies of ~20 or higher,52 carried by affected and unaffected individuals alike. Such nonsynonymous polymorphisms are individually of little overt functional impact (ie, not physiologically disruptive but when coexpressed can collectively play an important modulatory role in defining phenotype and risk). It is the contribution of multiple different coexpressed susceptibility genes, individually conferring a small increase in risk, that is required coupled with environmental factors to generate complex disorder phenotypes. Severe neonatal hyperbilirubinemia is no exception, as evidenced by the reported allele frequencies of UGT1A1 and OATP1B1 polymorphisms* and their modulatory role in the genesis of marked neonatal hyperbilirubinemia when coexpressed with each other and/or other icterogenic conditions.10,13,17,24,28 In all likelihood, additional genes are involved beyond the 3 studied herein, and their identification is warranted. Knowledge of each susceptibility gene polymorphism is essential to understanding more fully the molecular pathogenesis of neonatal hyperbilirubinemia, providing genetic markers for clinical risk assessment, and characterizing potential novel therapeutic targets, all meritorious lines of future investigation. The degree of genetic heterogeneity and variant coexpression across OATP1B1, UGT1A1, and G6PD genes observed in this cohort underscore the likely complex polygenic nature of neonatal hyperbilirubinemia.


   ACKNOWLEDGMENTS
 
We are grateful for the support of the Mario Lemieux Centers for Patient Care and Research of the Mario Lemieux Foundation (Pittsburgh, PA) and the 25 Club of Magee-Womens Hospital (Pittsburgh, PA).


   FOOTNOTES
 
Accepted Jan 9, 2008.

Address correspondence to Jon F. Watchko, MD, Magee-Womens Hospital, Division of Newborn Medicine, Department of Pediatrics, 300 Halket St, Pittsburgh, PA 15213. E-mail: jwatchko{at}mail.magee.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Increasingly, evidence suggests that gene polymorphisms can contribute to the risk for neonatal hyperbilirubinemia (G6PD and/or UGT1A1 gene variants).

 

What This Study Adds

This study explores G6PD, UGT1A1, and OATP1B1 gene variant expression in a US-based DNA repository (450 individuals) with ancestry from all major regions of the world and documents a high degree of novel coexpression patterns across these 3 genes involved in bilirubin production and metabolism.

 

* Refs 7, 9, 10, 13, 17, 18, 21, 25, 27, 28, 33, and 34. Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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