The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease.
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.
Vasavda
Nisha
N
King's College London School of Medicine, Division of Gene and Cell Based Therapy, London, UK.
Menzel
Stephan
S
Kondaveeti
Sheila
S
Maytham
Emma
E
Awogbade
Moji
M
Bannister
Sybil
S
Cunningham
Juliette
J
Eichholz
Andrew
A
Daniel
Yvonne
Y
Okpala
Iheanyi
I
Fulford
Tony
T
Thein
Swee Lay
SL
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
D001663:Bilirubin; D005914:Globins; D014453:Glucuronosyltransferase; D051547:Heme Oxygenase-1; D000099148:UGT1A1 Enzyme; C496541:HMOX1 protein, human