title: The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease.
abstract: Serum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)-glucuronosyltransferase (UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase (HMOX1), a rate-limiting enzyme upstream of UGT1A in the haem catabolic pathway, and alpha-thalassaemia could explain some of the inconsistent effects. The UGT1A1 [TA](n) and HMOX1 [GT](n) promoter polymorphisms and alpha globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/beta(0), 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects (P < 0.0001 and P < 0.01, respectively). While HMOX1 genotype had no effect, co-inheritance of alpha-thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD.
authors.affiliation: King's College London School of Medicine, Division of Gene and Cell Based Therapy, London, UK.
authors.forename: Nisha
authors.initials: N
authors.lastname: Vasavda
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.forename: Sheila
authors.initials: S
authors.lastname: Kondaveeti
authors.forename: Emma
authors.initials: E
authors.lastname: Maytham
authors.forename: Moji
authors.initials: M
authors.lastname: Awogbade
authors.forename: Sybil
authors.initials: S
authors.lastname: Bannister
authors.forename: Juliette
authors.initials: J
authors.lastname: Cunningham
authors.forename: Andrew
authors.initials: A
authors.lastname: Eichholz
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Daniel
authors.forename: Iheanyi
authors.initials: I
authors.lastname: Okpala
authors.forename: Tony
authors.initials: T
authors.lastname: Fulford
authors.forename: Swee Lay
authors.initials: SL
authors.lastname: Thein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics*; D001663:Bilirubin / Q000097:blood; D002648:Child; D005260:Female; D042882:Gallstones / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D005838:Genotype; D005914:Globins / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics*; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006450:Hemoglobin SC Disease / Q000150:complications / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic; D018570:Risk Assessment / Q000379:methods; D014463:Ultrasonography; D017085:alpha-Thalassemia / Q000150:complications / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D005914:Globins; D014453:Glucuronosyltransferase; D051547:Heme Oxygenase-1; D000099148:UGT1A1 Enzyme; C496541:HMOX1 protein, human