title: UGT1A1 sequence variants and bilirubin levels in early postnatal life: a quantitative approach.
abstract: BACKGROUND
  Fundamental to definitively identifying neonates at risk of developing significant hyperbilirubinemia is a better understanding of the genetic factors associated with early bilirubin rise. Previous genetic studies have focused on the UGT1A1 gene, associating common variation in the coding or promoter regions with qualitative assessments of bilirubin (i.e. significantly elevated or not). These studies have had conflicting results and limited success. We chose to approach the problem by focusing on the quantitative (absolute) change in bilirubin levels early in post-natal life. We apply this approach to the UGT1A1 gene--exploring the contribution of both rare and common variants to early bilirubin changes.
  
  
  METHODS
  We sequenced the exons, PBREM, 5'-, and 3'- regions of the UGT1A1 gene in 80 otherwise healthy term neonates who had repeat bilirubin levels measured within the first five days of life.
  
  
  RESULTS
  Three novel coding variants were observed, but there was no clear relationship between rare coding variants and bilirubin rise. Adjusted linear regression models fit to evaluate the relationship between changing bilirubin levels and common UGT1A1variants found that among 39 neonates whose bilirubin was resampled within 33 hours, individuals homozygous for the mutant allele of a 3'UTR SNP had significantly smaller changes in bilirubin (P=0.003) than individuals carrying the wild-type allele.
  
  
  CONCLUSIONS
  Collectively, rare UGT1A1 coding variants do not appear to play a prominent role in determining early bilirubin levels; however common variants in the 3' UTR of UGT1A1 may modulate the early bilirubin rise. A quantitative approach to evaluating early bilirubin kinetics provides a more robust framework in which to better understand the genetics of neonatal hyperbilirubinemia.
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic and Foundation, 200 1stSt SW, Rochester, MN 55905, USA. neil.hanchard@green-oxford.com
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanchard
authors.forename: Jennifer
authors.initials: J
authors.lastname: Skierka
authors.forename: Amy
authors.initials: A
authors.lastname: Weaver
authors.forename: Brad S
authors.initials: BS
authors.lastname: Karon
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: Walter
authors.initials: W
authors.lastname: Cook
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: O'Kane
mesh_terms: D001663:Bilirubin / Q000097:blood / Q000235:genetics*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000097:blood / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme