UDP‐glucuronosyltransferase 1 gene promoter polymorphism is associated with increased serum bilirubin levels and cholecystectomy in patients with sickle cell anemia

To the Editor: A polymorphism in the TATAA element of the promoter region in the UDP-glucuronosyltransferase 1 (UGT1A) gene is associated with benign Gilbert’s syndrome (GS). The presence of seven thymine adenine (TA) repeats, rather than the six repeats found in the wild-type allele, is associated with a lower affinity of the IID transcription factor for the binding site at the TATAA element, leading to lower expression of the UGT1A enzyme which is responsible for bilirubin glucuronidation (1–3). This polymorphism has been associated with hyperbilirubinemia in several hereditary hemolytic anemias as well as increased neonatal jaundice in glucose-6 phosphate dehydrogenase (G6PD) deficiency and enhanced jaundice of newborns with hereditary spherocytosis (HS) (4–10). The aim of this study was to determine whether the co-inheritance of GS and sickle cell anemia (SCA) is associated with increased levels of bilirubin and cholelithiasis among adults and children from a Brazilian population with SCA. Sixty-seven patients with sickle cell anemia (mean age 28.5 10.7 years; range 5–51years) were clinically examined in a retrospective manner to determine mean serum bilirubin levels, the presence of gallstones and whether any patient had undergone cholecystectomy for chronic cholelithiasis. Detection of gallstones was based on biliary tree ultrasound. SCA was diagnosed as described previously (11). Patients were genotyped for the (TA) polymorphism by polymerase chain reaction (PCR) and electrophoresis on a 6%, silver-stained, denaturing polyacrylamide gel (8.3M urea), using primers described by Monaghan et al. (2). Significance for statistical analysis was defined as a p-value of<0.05. All data were analyzed by EpiInfo 6.04 using the chi-square test or Fisher’s exact test. Twenty-three (34.3%) of the SCA patients were homozygotes for the UGT1A wild-type allele (TA6/TA6) and 24 (35.8%) were heterozygotes (TA6/TA7). Thirteen (19.4%) patients were homozygotes for the mutated allele (TA7/TA7) associated with GS. Other alleles were also found in this population. Three patients (4.5%) were heterozygotes for the TA5 allele (TA5/TA6), three for the TA8 allele (TA8/TA6) and one patient had a TA5/TA7 genotype. Genotype distribution was similar to that found in African descendant populations in northeastern Brazil (12). Excluding the seven patients with rare alleles and 13 others whose complete clinical data were unavailable, 47 patients (age range 5–50years; four patients <15years of age) were subdivided into groups according to their genotype, and the clinical and laboratory data were analyzed (Table 1). In our study, higher mean serum bilirubin levels were observed in patients who were homozygotes for the UGT1A TA7/TA7 genotype when compared with normal controls (TA6/TA6) and with heterozygotes (TA6/TA7). Differences were statistically significant among the three groups, as observed by Miraglia del Giudice et al. (7), in patients with hereditary spherocytosis, and by Passon et al. (13), in children with SCA. Patients with the TA7/TA7 genotype also presented significantly higher unconjugated serum bilirubin levels than patients who were homozygotes for the normal genotype or who were heterozygotes. Similar results were reported in patients who were homozygotes for b-thalassemia (9). Although the prevalence of cholelithiasis was higher in the TA7/TA7 genotype, suggesting a Clin Genet 2003: 64: 160–162 Copyright # Blackwell Munksgaard 2003 Printed inDenmark. All rights reserved CLINICALGENETICS ISSN 0009-9163