title: Genetic influences on serum bilirubin in American Indians: The Strong Heart Family Study.
abstract: OBJECTIVE
  To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians.
  
  
  METHODS
  Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota.
  
  
  RESULTS
  Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10⁻⁶) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10⁻⁵). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21.
  
  
  CONCLUSIONS
  Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.
authors.affiliation: Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 78245, USA. pmelton@sfbrgenetics.org
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Melton
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.forename: Harald H
authors.initials: HH
authors.lastname: Göring
authors.forename: Sandy
authors.initials: S
authors.lastname: Laston
authors.forename: Jason G
authors.initials: JG
authors.lastname: Umans
authors.forename: Elisa T
authors.initials: ET
authors.lastname: Lee
authors.forename: Richard R
authors.initials: RR
authors.lastname: Fabsitz
authors.forename: Richard B
authors.initials: RB
authors.lastname: Devereux
authors.forename: Lyle G
authors.initials: LG
authors.lastname: Best
authors.forename: Jean W
authors.initials: JW
authors.lastname: Maccluer
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
mesh_terms: D001663:Bilirubin / Q000097:blood*; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006932:Hyperbilirubinemia / Q000453:epidemiology / Q000235:genetics*; D007198:Indians, North American / Q000235:genetics* / Q000706:statistics & numerical data*; D008126:Lod Score; D008297:Male; D010375:Pedigree; D011110:Polymorphism, Genetic; D014481:United States / Q000453:epidemiology; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme