The Influence of Uridine Diphosphate Glucuronosyl Transferase 1A Promoter Polymorphism, βS-Globin Gene Haplotype, Co-Inherited α-Thalassemia Trait and Hb F on Steady-State Serum Bilirubin Levels in Sickle Cell Anemia.
Authors: Adekile Adekunle D. , Kutlar Ferdane , McKie Kathleen , Addington Anthony , Elam Dedrey , Clair Betsy , Holley Leslie , Kutlar Abdullah 
Published: October 2019

Abstract
The chronic hemolysis of sickle cell anemia (SCA) produces hyperbilirubinemia but serum bilirubin level varies considerably and the modulating factors have not been fully elucidated. One identified genetic factor is the uridine diphosphate glucuronosyl transferase 1A (UGT1A) gene promoter polymorphism in which homozygosity for the (AT)7 allele has been associated with increased bilirubin levels in children with SCA. The same association has been reported in apparently healthy individuals, in β-thalassemia, G6PD deficiency, neonatal jaundice and hereditary spherocytosis. In the present study, in addition to UGT1A promoter genotype, serum bilirubin level was related to other genetic modifiers - βS-globin gene haplotype, Hb F, co-inherited α-thal trait, age and gender. The patients were randomly selected from the sickle cell clinic, Medical College of Georgia. UGT1A promoter genotypes were determined using automated sequencing and spreadex gel electrophoresis. Other investigations were with standard techniques. There were 67 SCA patients (41 males, 26 females), aged 2 to 44 years (mean of 20.6±10.7). Ten (14.9%) patients were homozygous for the (AT)6 UGT1A allele, 22 (32.8%) were homozygous for the (AT)7, while 35 (52.2%) were heterozygous for the two. Serum bilirubin was significantly higher in the homozygous (AT)7 group (3.7±1.5, 5.6±2.4 and 3.8±2.3 mg/dl respectively). It was also significantly higher in males than females (4.9±2.7 vs 3.7±1.7 mg/dl) and highest in patients aged >10 years. Co-inherited α-thal trait did not significantly affect the levels. There was a significant negative linear correlation (r = −0.304, p=0.016) of serum bilirubin with Hb F. Hb F was also significantly higher among females than males and when the different age groups were compared, it was highest in those <10 years old. Apart from UGT1A (AT)7 homozygosity, Hb F significantly influences serum bilirubin level in steady-state SCA. This is probably mediated via its hemolysis-sparing effect. Our (AT)7 homozygotes, including both children and adults, had significantly higher mean serum bilirubin level as previously reported by others. Indeed, when only the adults were analyzed, there was a distinct trimodal distribution among the 6/6, 6/7 and 7/7 UGT1A genotypes with serum bilirubin levels of 3.9 ± 0.9, 4.9 ± 2.2 and 5.8 ± 2.5 mg/dl respectively. Among children (<10 years), this trimodal distribution is lost, which supports the premise that a high Hb F is probably more important in modulating serum bilirubin levels in this age group.
Serum Bilirubin and Other Parameters Grouped According to UGT1A1 Genotype
UGT1A1 Genotype Age (yrs) Hb (g/dl) Retics (%) Hb F (%) Bilirubin (mg/dl) 6/6 (n=10) 18.1±8.7 7.9±1.2 11.3±4.7 8.4±6.4 3.7±1.5 6/7 (n=35) 17.9±10.9 8.7±1.3 11.4±4.2 10.9±8.6 3.8±2.3 7/7 (n=22) 26.1±9.3 8.3±2.1 10.9±4.8 6.6±5.4 5.6±2.4