title: A genome-wide association study of total bilirubin and cholelithiasis risk in sickle cell anemia.
abstract: Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5 × 10(-8)). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08 × 10(-25)). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15 × 10(-4)). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities.
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Milton
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Nadia
authors.initials: N
authors.lastname: Solovieff
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hartley
authors.forename: Pallav
authors.initials: P
authors.lastname: Bhatnagar
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Dworkis
authors.forename: James F
authors.initials: JF
authors.lastname: Casella
authors.forename: Emily
authors.initials: E
authors.lastname: Barron-Casella
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bean
authors.forename: W Craig
authors.initials: WC
authors.lastname: Hooper
authors.forename: Michael R
authors.initials: MR
authors.lastname: DeBaun
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Garrett
authors.forename: Karen
authors.initials: K
authors.lastname: Soldano
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
authors.forename: Allison
authors.initials: A
authors.lastname: Ashley-Koch
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Klings
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000235:genetics*; D001663:Bilirubin / Q000097:blood* / Q000235:genetics; D002769:Cholelithiasis / Q000097:blood* / Q000209:etiology*; D015331:Cohort Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D012307:Risk Factors; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D000099148:UGT1A1 Enzyme