title: UGT1A1 variation and gallstone formation in sickle cell disease.
abstract: Pigment gallstones are a common clinical complication of sickle cell (SS) disease. Genetic variation in the promoter of uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) underlies Gilbert syndrome, a chronic form of unconjugated hyperbilirubinemia, and appears to be a risk factor for gallstone formation. We investigated the association between UGT1A1 (TA)(n) genotype, hyperbilirubinemia, and gallstones in a sample of Jamaicans with SS disease. Subjects were from the Jamaican Sickle Cell Cohort Study (cohort sample, n = 209) and the Sickle Cell Clinic at the University of the West Indies, Kingston, Jamaica (clinic sample, n = 357). The UGT1A1 (TA)(n) promoter region was sequenced in 541 SS disease subjects and 111 healthy controls (control sample). Indirect bilirubin levels for (TA)(7)/(TA)(7) and (TA)(7)/(TA)(8) genotypes were elevated compared with (TA)(6)/(TA)(6) (clinic sample, P < 10(-5); cohort sample, P < 10(-3)). The (TA)(7)/(TA)(7) genotype was also associated with symptomatic presentation and gallstones in the clinic sample (odds ratio [OR] = 11.3; P = 7.0 x 10(-4)) but not in the younger cohort sample. These unexpected findings indicate that the temporal evolution of symptomatic gallstones may involve factors other than the bilirubin level. Although further studies of the pathogenesis of gallstones in SS disease are required, the (TA)(7)/(TA)(7) genotype may be a risk factor for symptomatic gallstones in older people with SS disease.
authors.affiliation: Institute of Biological Anthropology and the Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom. eden@genetics.uchicago.edu
authors.forename: Eden V
authors.initials: EV
authors.lastname: Haverfield
authors.forename: Colin A
authors.initials: CA
authors.lastname: McKenzie
authors.forename: Terrence
authors.initials: T
authors.lastname: Forrester
authors.forename: Nourdine
authors.initials: N
authors.lastname: Bouzekri
authors.forename: Rosalind
authors.initials: R
authors.lastname: Harding
authors.forename: Graham
authors.initials: G
authors.lastname: Serjeant
authors.forename: Thomas
authors.initials: T
authors.lastname: Walker
authors.forename: Tim E A
authors.initials: TE
authors.lastname: Peto
authors.forename: Ryk
authors.initials: R
authors.lastname: Ward
authors.forename: David J
authors.initials: DJ
authors.lastname: Weatherall
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000375:Aging; D000755:Anemia, Sickle Cell / Q000150:complications*; D001483:Base Sequence; D002648:Child; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D042882:Gallstones / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D000099148:UGT1A1 Enzyme
chemical_list: D004247:DNA; D017931:DNA Primers; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme