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, >or=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.