UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia

Abstract

Genetic modifiers contribute to phenotypic variability in patients with sickle cell anemia (SCA). The influence of the bilirubin UDP-glucuronosyltransferase (UGT) 1A1 (TA) n TAA promoter polymorphism on bilirubin levels and gallbladder disease in SCA was examined using prospectively collected data from the Cooperative Study of Sickle Cell Disease. A total of 324 children with HbSS (median age 6.9 years) had UGT1A1 genotyping; 243 (75%) had common (TA) 6 or (TA) 7 alleles, whereas 81 (25.0%) had variant (TA) 5 or (TA) 8 alleles. The UGT1A1 genotype significantly influenced average bilirubin levels for the common alleles: 6/6 genotype 5 2.36 ± 1.13 mg/dL, 6/7 genotype 5 2.90 ± 1.54 mg/dL, and 7/7 genotype 5 4.24 ± 2.11 mg/dL (P < 0.0001). Thirty-nine percent of children with the 7/7 genotype had documented gallbladder disease, compared with 18.2% with the 6/7 genotype and only 9.9% with the wildtype 6/6 UGT1A1 genotype (P 5 0.001). To analyze the (TA) 5 and (TA) 8 variant alleles, three groups were generated, showing increasing bilirubin levels with increasing TA repeats and age. Group 3 (genotypes 6/8, 7/7, and 7/8) had a significantly greater rate of bilirubin change than Groups 1 (genotypes 5/6, 5/7, and 6/6) or 2 (genotype 6/7). These results validate previous smaller studies and confirm that the UGT1A1 promoter polymorphism exerts a powerful influence on bilirubin levels and the development of gallbladder disease in children with SCA. UGT1A1 genotyping should be considered as a screening tool for predicting children most likely to develop gallbladder disease at a young age. Am. J. Hematol. 83:800-803, 2008. V

The Search for Genetic Modifiers of Disease Severity in the -Hemoglobinopathies

“…Importantly, these associations are more compelling because they were first very robustly confirmed with phenotypes in non-SCD populations. Polymorphisms in the promoter of the UGT1A1 gene are associated with serum bilirubin levels in many studies and different populations, including patients with SCD; the same polymorphisms are also associated with the risk of formation of gallstones in SCD patients (Passon et al 2001;Fertrin et al 2003;Chaar et al 2005Chaar et al , 2006Haverfield et al 2005;Carpenter et al 2008;Milton et al 2012). Renal failure is one of the major complications of SCD and is a strong predictor of mortality in SCD (Platt et al 1994).…”

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

“…There is a negative association between UGT1A1 expression and repeat length of the four alleles, attributable to decreasing promoter activity acting via altered affinity for the TATA-binding protein (Beutler et al, 1998;Hsieh et al, 2007). Although the (TA) n alleles appear to have similar effects on bilirubin levels in people of recent African descent (Chaar et al, 2005;Hong et al, 2007;Carpenter et al, 2008) and low-activity alleles confer significantly raised risk of developing gallstones requiring surgery (Passon et al, 2001;Heeney et al, 2003), Gilbert's syndrome is rarely diagnosed in Africa (Bougouma et al, 1999).…”

High rates of recurrent biliary tract obstruction in children with sickle cell disease

“…We used total bilirubin as a proxy for risk secondary to polymorphisms in bilirubin UDP-glucuronosyltransferase 1A1 (UGT1A1) gene, as promoter polymorphisms in this gene have been implicated in the development of hepatobiliary disease in children with SCD, but no association was seen with bilirubin and recurrent BTD in our series. (16) It seems likely that other unidentified factors, genetic, environmental and anatomic factors, may be associated with recurrent BTD in SCD.…”