BACKGROUND AND OBJECTIVES: High levels of erythrocyte destruction in sickle cell anemia (SCA) result in chronic hyperbilirubinemia, with cholelithiasis occurring in a subset of patients. We investigated whether susceptibility to cholelithiasis in SCA was associated with the promoter polymorphism of the 5?-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene encoding a key enzyme in bilirubin catabolism. DESIGN AND METHODS: We determined the frequencies of UGT1A1 promoter alleles in 171 SCA children and 153 SCA adults regularly followed for a number of years at the Guadeloupe sickle cell center. These patients had undergone liver/biliary tree ultrasound scans every year. We analyzed the relationships between the various UGT1A1 promoter alleles and hemoglobin levels, steady-state total and unconjugated bilirubin concentrations and the frequency of cholelithiasis. RESULTS: In both children and adults, (TA)6 was less frequent and (TA)7 more frequent in patients with cholelithiasis than in those without this condition. Total and unconjugated bilirubin levels and the frequency of cholelithiasis were significantly higher in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes than in those with other genotypes. Those homozygous for (TA)6 or carrying at least one (TA)5 allele had the lowest total and unconjugated bilirubin levels and were least likely to have cholelithiasis. Patients with (TA)6/(TA)7 and (TA)6/(TA)8 genotypes presented intermediate values. Kaplan-Meier analysis of cholelithiasis-free survival in children demonstrated an early age-at-onset for cholelithiasis in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes. INTERPRETATIONS AND CONCLUSIONS: This study shows that the UGT1A1 gene promoter polymorphism is a major genetic risk factor modifying the frequency and age-at-onset of cholelithiasis in SCA patients.
BACKGROUND AND OBJECTIVES: High levels of erythrocyte destruction in sickle cell anemia (SCA) result in chronic hyperbilirubinemia, with cholelithiasis occurring in a subset of patients. We investigated whether susceptibility to cholelithiasis in SCA was associated with the promoter polymorphism of the 5?-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene encoding a key enzyme in bilirubin catabolism. DESIGN AND METHODS: We determined the frequencies of UGT1A1 promoter alleles in 171 SCA children and 153 SCA adults regularly followed for a number of years at the Guadeloupe sickle cell center. These patients had undergone liver/biliary tree ultrasound scans every year. We analyzed the relationships between the various UGT1A1 promoter alleles and hemoglobin levels, steady-state total and unconjugated bilirubin concentrations and the frequency of cholelithiasis. RESULTS: In both children and adults, (TA)6 was less frequent and (TA)7 more frequent in patients with cholelithiasis than in those without this condition. Total and unconjugated bilirubin levels and the frequency of cholelithiasis were significantly higher in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes than in those with other genotypes. Those homozygous for (TA)6 or carrying at least one (TA)5 allele had the lowest total and unconjugated bilirubin levels and were least likely to have cholelithiasis. Patients with (TA)6/(TA)7 and (TA)6/(TA)8 genotypes presented intermediate values. Kaplan-Meier analysis of cholelithiasis-free survival in children demonstrated an early age-at-onset for cholelithiasis in patients with (TA)7/(TA)7 and (TA)7/(TA)8 genotypes. INTERPRETATIONS AND CONCLUSIONS: This study shows that the UGT1A1 gene promoter polymorphism is a major genetic risk factor modifying the frequency and age-at-onset of cholelithiasis in SCA patients.
Authors: Betânia Lucena Domingues Hatzlhofer; Diego Antonio Pereira-Martins; Igor de Farias Domingos; Gabriela da Silva Arcanjo; Isabel Weinhäuser; Diego Arruda Falcão; Isabela Cristina Cordeiro Farias; Jéssica Vitória Gadelha de Freitas Batista; Luana Priscilla Laranjeira Prado; Jéssica Maria Florencio Oliveira; Thais Helena Chaves Batista; Marcondes José de Vasconcelos Costa Sobreira; Rodrigo Marcionilo de Santana; Amanda Bezerra de Sá Araújo; Manuela Albuquerque de Melo; Bruna Vasconcelos de Ancântara; Juan Luiz Coelho-Silva; Ana Beatriz Lucas de Moura Rafael; Danízia Menezes de Lima Silva; Flávia Peixoto Albuquerque; Magnun Nueldo Nunes Santos; Ana Cláudia Dos Anjos; Fernando Ferreira Costa; Aderson da Silva Araújo; Antonio Roberto Lucena-Araújo; Marcos André Cavalcanti Bezerra Journal: Ann Hematol Date: 2021-02-13 Impact factor: 3.673
Authors: Jéssica V G F Batista; Gabriela S Arcanjo; Thais H C Batista; Marcondes J Sobreira; Rodrigo M Santana; Igor F Domingos; Betânia L Hatzlhofer; Diego A Falcão; Diego A Pereira-Martins; Jéssica M Oliveira; Amanda S Araujo; Luana P M Laranjeira; Fernanda S Medeiros; Flávia P Albuquerque; Dulcinéia M Albuquerque; Magnun N Santos; Manuela F Hazin; Ana C Dos Anjos; Fernando F Costa; Aderson S Araujo; Antonio R Lucena-Araujo; Marcos A Bezerra Journal: Ann Hematol Date: 2021-02-01 Impact factor: 3.673
Authors: Jacqueline N Milton; Paola Sebastiani; Nadia Solovieff; Stephen W Hartley; Pallav Bhatnagar; Dan E Arking; Daniel A Dworkis; James F Casella; Emily Barron-Casella; Christopher J Bean; W Craig Hooper; Michael R DeBaun; Melanie E Garrett; Karen Soldano; Marilyn J Telen; Allison Ashley-Koch; Mark T Gladwin; Clinton T Baldwin; Martin H Steinberg; Elizabeth S Klings Journal: PLoS One Date: 2012-04-27 Impact factor: 3.240