Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism

Abstract

Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA) n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in a group of 153 young SCD patients (mean age 12.0 ± 9.0 years) predominantly of Bantu beta S haplotype. The concomitant effect of alpha thalassaemia was also analysed. Among the several UGT1A1 genotypes found, the most frequent were the (TA) 6 /(TA) 6 (n = 37), (TA) 6 /(TA) 7 (n = 60) and (TA) 7 /(TA) 7 (n = 29). These groups of patients did not significantly differ in age, gender ratio and haemoglobin, foetal haemoglobin and reticulocyte levels. On the other hand, total bilirubin levels were significantly different between groups, with an increased (TA) repeat number being associated with higher bilirubinaemia. Furthermore, both cholelithiasis and cholecystectomy were more frequent in groups with higher (TA) repeat number, although the former association was not statistically significant. None of the mentioned parameters is statistically different within UGT1A1 groups with the presence of alpha thalassaemia. Thus, the UGT1A1 promoter polymorphism may represent an important nonglobin genetic modifier of Bantu SCD patients' clinical manifestations, even at a young age.

A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia

“…Genetic studies of these patients have identified a dinucleotide repeat polymorphism (TA) 5–8 in the TATA box of the UGT1A1 gene promoter that is associated with reduced UGT expression and produces hyperbilirubinemia [30]–[31], [37], [46]–[47]. This polymorphism has also been observed in small cohorts of sickle cell anemia patients suggesting a common pathogenic link between ethnically divergent etiologies of indirect hyperbilirubinemia [5], [10]–[15], [33]. In the current study, genome-wide genetic screening of a large cohort of sickle cell anemia patients not only confirmed these findings but also supported their biological relevance.…”

“…However, sequencing of UGT1A1 has been undertaken in SCD cohorts in Guadeloupe, Portugal, Jamaica, India and the United States; genotyping of 324 SCD children from the Cooperative Study of Sickle Cell Disease (CSSCD) revealed that the common (TA)6 and (TA)7 alleles were present in 75% [10]–[15]. The (TA)7/(TA)7 genotype was associated with increased serum bilirubin levels and cholelithiasis risk compared with the (TA)6/(TA)7 and (TA)6/(TA)6 genotypes across cohorts with suggestions that those with a (TA)8 allele are at highest risk, suggesting a similar pattern of inheritance as observed in Caucasians [10]–[15]. Treatment with hydroxyurea, known to decrease the hemolytic rate in sickle cell anemia patients, was unable to decrease bilirubin levels to normal levels in those with the (TA)7/(TA)7 genotype suggesting that this genetic defect may represent a new pharmacologic target for these patients [14].…”

Protector effect of α-thalassaemia on cholecystitis and cholecystectomy in sickle cell disease

“…Our data showed that the frequency of cholelithiasis was not affected by -α 3.7 deletion. In line with these results, two studies found a similar prevalence of cholelithiasis between SCD patients with and without -α 3.7 deletion [10,12]. In contrast, Vasavda et al [11] observed a reduced risk of cholelithiasis in the positive α-thal patients.…”

“…Nevertheless, the role of α-thalassaemia in bilirubin levels and cholelithiasis is controversial in SCD [8][9][10][11][12][13]. Furthermore, there is a lack of information about complications from cholelithiasis in SCD patients with coinheritance of α-thalassaemia.…”

Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment

“…In sickle cell patients, the number of TA repetitions has been shown to exert an important influence on serum bilirubin levels [122]. Homozygosity for the 7 alelle has been associated with earlier and increased incidence of gallstones in children, and a higher need for cholecystectomy in adults with symptomatic biliary disease [123][124][125][126][127]. Coinheritance of a-thalassemia decreases hemolysis and, therefore, can decrease bilirubin levels, but data are contradictory in defining whether it is sufficient to compensate for the effect of the 7/7 genotype [128,129].…”