Hyperbilirubinaemia in heterozygous β‐thalassaemia is related to co‐inherited Gilbert's syndrome

Abstract

The reasons why heterozygotes for β‐thalassaemia have considerable variation in serum bilirubin levels are unkown. High levels of bilirubin could be related to the co‐inherited Gilbert's syndrome, determined either by mutations of the coding region or by variation in the A(TA)nTAA motif of the promoter of the bilirubin UDP‐glucuronosyltransferase gene (UGT‐1). We sequenced the coding and the promoter region of UGT‐1A or characterized the A(TA)nTAA motif of the promoter by denaturing gel electrophoresis of radioactive amplified products. The results were correlated with bilirubin levels in 49 β‐thalassaemia heterozygotes for codon 39 (CAG → TAG) nonsense mutation. 21 normal individuals and 32 unrelated patients with Gilbert's syndrome served as controls. The coding sequence region of the UGT‐1A was normal. Five β‐thalassaemia heterozygotes, who were homozygous for the extra (TA) bases in the A(TA)nTAA element of the promoter of UGT‐1A, the configuration present in homozygosity in Gilbert's syndrome, had higher bilirubin levels compared to those with the (TA)6/(TA)7 or (TA)6/(TA)6 configurations. In the group of 32 patients with Gilbert's syndrome, 31 of whom had the (TA)7/(TA)7 configuration, we detected 14 heterozygotes for β‐thalassaemia, a figure much higher than predicted on the basis of the carrier rate. Homozygosity for the (TA)7 motif, the typical promoter configuration of Gilbert's syndrome, is one of the factors determining hyperbilirubinaemia in heterozygous β‐thalassaemia.

Racial variability in the UDP-glucuronosyltransferase 1 ( UGT1A1 ) promoter: A balanced polymorphism for regulation of bilirubin metabolism?

“…These findings suggested that the prevalence of the (ta) 7 mutation might be low among people of African origin. However, we now report that contrary to expectation, the (ta) 7 form is more common among people of African origin than among Caucasians. Although Asians seem to have higher bilirubin levels than whites, the (ta) 7 is much less common in that population.…”

“…However, we now report that contrary to expectation, the (ta) 7 form is more common among people of African origin than among Caucasians. Although Asians seem to have higher bilirubin levels than whites, the (ta) 7 is much less common in that population. Among Africans not only the (ta) 6 and (ta) 7 forms are found, but there are also promoters that contain five or eight ta repeats [(ta) 5 and (ta) 8 ].…”

“…Here we use the designation (ta) n , where n is the number of repeats. The (ta) 7 mutation of the UGT1A1 gene has been found to be associated with increased bilirubin levels in normal persons (4), in those with heterozygous ␤-thalassemia (7) or glucose-6-phosphate dehydrogenase (G6PD) deficiency (8), and with neonatal icterus in G6PD deficiency (9) and hereditary spherocytosis (10).…”

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

“…in b-thalassaemia (Galanello et al 1997(Galanello et al , 1999b, G6PD deficiency (Galanello et al 1999a) and SCD (Adekile et al 2005;Chaar et al 2005;Fertrin et al 2003;Harverfield et al 2005;Passon et al 2001). In fact, in addition to the results presented here, the mentioned studies performed in SCD (Table 1).…”

Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler–Najjar syndromes

“…This predicted value is higher than that of patients with a clinical diagnosis of Gilbert syndrome, reflecting the existence of other inherited or acquired factors affecting bilirubin metabolism, in addition to reduced glucuronidation caused by the (TA) insertion. The awareness that the (TA) insertion is the most frequent cause of Gilbert syndrome prompted the study of its association with other pathologies, namely h-thalassemia [22,23], sickle cell anemia [24], ABO incompatibility [25], glucose-6-phosphate dehydrogenase deficiency [26 -28], hereditary spherocytosis [29,30,31] and neonatal icterus [32,33].…”