ClinVar Genomic variation as it relates to human health

This variant has been designated UGT1A1*28 (Mackenzie et al., 1997). In 10 patients with Gilbert syndrome (143500), Bosma et al. (1995) identified a homozygous 2-bp insertion (TA) in the TATAA element of the 5-prime promoter region of the UGT1A1 gene. Normally, an A(TA)6TAA element is present between nucleotides -23 and -38. All 10 patients were homozygous for the sequence A(TA)7TAA; this resulted in reduced expression of the gene. The (TA)7 allele was found to have a frequency of 40% among normal controls, indicating that it is a polymorphism. Thus, the promoter mutation appeared to be a necessary but not sufficient factor in Gilbert syndrome. Bosma et al. (1995) found that 2 related individuals with Crigler-Najjar syndrome type II (606785) who were homozygous for a structural mutation in the UGT1A1 gene (Bosma et al., 1993) were also both homozygous for the wildtype A(TA)6TAA allele. Among 10 family members who were heterozygous for the coding mutation, the other allele contained the (TA)7 element in 6 and the (TA)6 element in 4. The 6 heterozygotes with the promoter abnormality had significantly higher serum bilirubin values than the 4 with the normal TATAA element. Kaplan et al. (1997) found that neonates with G6PD Mediterranean deficiency (305900.0006) who were heterozygous or homozygous for the variant (TA)7 UGT1A1 allele had a higher incidence of hyperbilirubinemia than corresponding controls. Among those normal for G6PD, the UGT1A1 polymorphism had no significant effect. Neither G6PD deficiency nor the variant UGT1A1 promoter alone increased the incidence of hyperbilirubinemia, but in combination both did. This gene interaction illustrated the paradigm of interaction of benign genetic polymorphisms in the causation of disease. Beutler et al. (1998) described this variant in the promoter of the UGT1A1 gene as responsible for most cases of Gilbert syndrome. In a patient with Crigler-Najjar syndrome type II, Yamamoto et al. (1998) identified an usual genotype consisting of heterozygosity for a P229Q mutation (191740.0010) and homozygosity for the 2-bp insertion mutation. The (TA)7 mutation of the UGT1A1 gene had been associated with increased bilirubin levels in normal persons (Bosma et al., 1995), in those with heterozygous beta-thalassemia (Galanello et al., 1997) or G6PD deficiency (Sampietro et al., 1997), and with neonatal icterus in G6PD deficiency (Kaplan et al., 1997) and hereditary spherocytosis (Iolascon et al., 1998). Beutler et al. (1998) examined the genotypes for the (TA)7 mutation in persons of Asian, African, and Caucasian ancestry. Although within the Caucasian ethnic group there was a strong correlation between promoter repeat number and bilirubin level, between ethnic groups they found that this relationship was inverse. Among people of African ancestry, there were, in addition to those with 6 and 7 repeats, also persons who had 5 or 8 repeats. Using a reporter gene they showed that there is an inverse relationship between the number of TA repeats and the activity of the promoter through the range of 5 to 8 TA repeats. An incidental finding was a polymorphism at nucleotide -106, tightly linked to the (TA)5 haplotype. Serum bilirubin levels are influenced by many factors, both genetic and environmental. Beutler et al. (1998) suggested that the unstable UGT1A1 polymorphism may serve to 'fine tune' the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants. In addition to the known common UGT1A1 TATA alleles (TA6 and TA7), Monaghan et al. (1999) identified a novel TATA allele (TA5) in a neonate with very prolonged jaundice. Statistical analysis of TATA genotype distributions within a group of breastfed neonates revealed significant differences among the acute, prolonged, and very prolonged subgroups: the incidence of familial hyperbilirubinemia genotypes (7/7 and 5/7) was 5 times greater in very prolonged cases (31%) relative to acute cases (6%). Neonates with prolonged jaundice from family pedigrees were observed to demonstrate the Gilbert syndrome phenotype as children or young adults. Kaplan et al. (2000) investigated whether the UGT promoter polymorphism would increase hyperbilirubinemia in direct Coombs-negative ABO (see 616093)-incompatible neonates, as seen in other combinations with this condition. Forty ABO-incompatible and 334 ABO-compatible controls had an allele frequency of 0.35 for the variant promoter gene. The incidence of hyperbilirubinemia was significantly higher only in the ABO-incompatible group who were also homozygous for the variant UGT promoter, compared with ABO-incompatible babies homozygous for the normal UGT promoter (43% vs 0.0; p of 0.02), and compared with ABO-compatible controls of all UGT genotypes combined (relative risk, 5.65; 95% CI, 2.23 to 14.31). Kaplan et al. (2000) concluded that Gilbert syndrome is a determining factor for neonatal hyperbilirubinemia in ABO incompatibility. Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Sequencing of UGT1A1 revealed that 1 infant was a compound heterozygote for this TATA box variant and the G71R missense mutation (191740.0016). Kadakol et al. (2001) found compound heterozygosity for the Gilbert-type promoter and a structural mutation of the UGT1A1 gene (191740.0020) in 18-month-old twins with severe neonatal hyperbilirubinemia resulting in kernicterus. They also found the promoter mutation in compound heterozygosity with a missense mutation resulting in mild hyperbilirubinemia. Homozygosity for both the Gilbert-type promoter and a missense mutation (191740.0021) resulted in Crigler-Najjar syndrome type II. In a young girl with Crigler-Najjar syndrome type II, Labrune et al. (2002) found homozygosity for a (TA)8 polymorphism and an asn400-to-asp mutation (191740.0022). In a study of 67 patients with sickle cell anemia (603903) in Brazil, Fertrin et al. (2003) found that TA6/TA7 heterozygotes and TA7/TA7 homozygotes had higher bilirubin levels; both groups had a higher probability of presenting symptomatic cholelithiasis (600803) than TA6/TA6 homozygotes, but this finding was only statistically significant in the TA6/TA7 heterozygotes. Using a novel PCR method termed fluorescence resonance energy transfer (FRET), Borlak et al. (2000) reported the (TA)6 and (TA)7 UGT1A1 genotypes of 265 unrelated healthy individuals from southern Germany. Genotype distribution was 43:45:12 for (TA)6/(TA)6, (TA)6/(TA)7, and (TA)7/(TA)7, respectively. Serum total bilirubin levels increased with presence of the (TA)7 allele; median micromoles per liter were 12.0, 14.0, and 20.5, respectively, which was a statistically significant difference. Prevalence for the homozygous (TA)7 genotype was 12.4%. Borlak et al. (2000) emphasized the clinical importance of the UGT1A1 genotype and function of the enzyme, particularly for drug metabolism. Roses (2004) pointed to an example of a mild adverse event with a clear genetic component that could be used as a model of the safe use of pharmacogenetics. Some patients in a trial of tranilast, a specific drug to retard coronary artery restenosis after surgery, under investigation by GlaxoSmithKline, developed hyperbilirubinemia. A screen for variants in candidate genes revealed that high levels of bilirubin were most common in patients who were homozygous for the 7-repeat UGT1A1 allele. Breaking the placebo- versus the drug-treated codes at the end of the trial showed that all 7-7 patients who developed hyperbilirubinemia received the drug, whereas none of the 7-7 patients treated with the placebo developed the adverse event. Several drug-treated patients with the 6-7 genotype also developed mildly elevated levels of bilirubin, but no treated or placebo patients with the 6-6 genotype became hyperbilirubinemic. A study of UGT1A1 gene polymorphism by Edison et al. (2005) showed that the TA(7) variant was associated with hyperbilirubinemia in homozygous HbE patients homozygous for the hemoglobin E gene (HBE; 141900.0071). The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. French et al. (2005) genotyped 126 children with newly diagnosed acute lymphoblastic leukemia at 16 well-characterized functional polymorphisms. The UGT1A1*28 polymorphism was a significant predictor of global gene expression, dividing patients based on their germline genotypes. Genes whose expression distinguished the TA 7/7 genotype from the other UGT1A1 genotypes included HDAC1 (601241), RELA (164014) and SLC2A1 (138140). Although UGT1A1 expression is concentrated in liver, it is involved in the conjugation (and thus transport, excretion, and lipophilicity) of a broad range of endobiotics and xenobiotics, which French et al. (2005) suggested could plausibly have consequences for gene expression in different tissues. Using a competitive electrophoretic mobility shift assay (EMSA), Hsieh et al. (2007) demonstrated that mutant TA7 TATA-box-like sequence has reduced binding affinity for nuclear binding complex and for TATA-binding protein compared to wildtype TA6; quantitative EMSA showed that the binding affinity progressively decreases as the number of TA repeats in the TATA-box-like sequence increases. Hsieh et al. (2007) stated that this decrease in binding affinity causes the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome. In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism and rs4148323 (191740.0016) (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the TA(7) allele was 0.134 in Han Chinese, 0.256 in the Uygur, and 0.277 in the Kazakh, which was lower than that reported for Caucasian populations (0.357 to 0.415; Beutler et al., 1998). (less)

This variant has been designated UGT1A1*28 (Mackenzie et al., 1997). In 10 patients with Gilbert syndrome (143500), Bosma et al. (1995) identified a homozygous 2-bp insertion (TA) in the TATAA element of the 5-prime promoter region of the UGT1A1 gene. Normally, an A(TA)6TAA element is present between nucleotides -23 and -38. All 10 patients were homozygous for the sequence A(TA)7TAA; this resulted in reduced expression of the gene. The (TA)7 allele was found to have a frequency of 40% among normal controls, indicating that it is a polymorphism. Thus, the promoter mutation appeared to be a necessary but not sufficient factor in Gilbert syndrome. Bosma et al. (1995) found that 2 related individuals with Crigler-Najjar syndrome type II (606785) who were homozygous for a structural mutation in the UGT1A1 gene (Bosma et al., 1993) were also both homozygous for the wildtype A(TA)6TAA allele. Among 10 family members who were heterozygous for the coding mutation, the other allele contained the (TA)7 element in 6 and the (TA)6 element in 4. The 6 heterozygotes with the promoter abnormality had significantly higher serum bilirubin values than the 4 with the normal TATAA element. Kaplan et al. (1997) found that neonates with G6PD Mediterranean deficiency (305900.0006) who were heterozygous or homozygous for the variant (TA)7 UGT1A1 allele had a higher incidence of hyperbilirubinemia than corresponding controls. Among those normal for G6PD, the UGT1A1 polymorphism had no significant effect. Neither G6PD deficiency nor the variant UGT1A1 promoter alone increased the incidence of hyperbilirubinemia, but in combination both did. This gene interaction illustrated the paradigm of interaction of benign genetic polymorphisms in the causation of disease. Beutler et al. (1998) described this variant in the promoter of the UGT1A1 gene as responsible for most cases of Gilbert syndrome. In a patient with Crigler-Najjar syndrome type II, Yamamoto et al. (1998) identified an usual genotype consisting of heterozygosity for a P229Q mutation (191740.0010) and homozygosity for the 2-bp insertion mutation. The (TA)7 mutation of the UGT1A1 gene had been associated with increased bilirubin levels in normal persons (Bosma et al., 1995), in those with heterozygous beta-thalassemia (Galanello et al., 1997) or G6PD deficiency (Sampietro et al., 1997), and with neonatal icterus in G6PD deficiency (Kaplan et al., 1997) and hereditary spherocytosis (Iolascon et al., 1998). Beutler et al. (1998) examined the genotypes for the (TA)7 mutation in persons of Asian, African, and Caucasian ancestry. Although within the Caucasian ethnic group there was a strong correlation between promoter repeat number and bilirubin level, between ethnic groups they found that this relationship was inverse. Among people of African ancestry, there were, in addition to those with 6 and 7 repeats, also persons who had 5 or 8 repeats. Using a reporter gene they showed that there is an inverse relationship between the number of TA repeats and the activity of the promoter through the range of 5 to 8 TA repeats. An incidental finding was a polymorphism at nucleotide -106, tightly linked to the (TA)5 haplotype. Serum bilirubin levels are influenced by many factors, both genetic and environmental. Beutler et al. (1998) suggested that the unstable UGT1A1 polymorphism may serve to 'fine tune' the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants. In addition to the known common UGT1A1 TATA alleles (TA6 and TA7), Monaghan et al. (1999) identified a novel TATA allele (TA5) in a neonate with very prolonged jaundice. Statistical analysis of TATA genotype distributions within a group of breastfed neonates revealed significant differences among the acute, prolonged, and very prolonged subgroups: the incidence of familial hyperbilirubinemia genotypes (7/7 and 5/7) was 5 times greater in very prolonged cases (31%) relative to acute cases (6%). Neonates with prolonged jaundice from family pedigrees were observed to demonstrate the Gilbert syndrome phenotype as children or young adults. Kaplan et al. (2000) investigated whether the UGT promoter polymorphism would increase hyperbilirubinemia in direct Coombs-negative ABO (see 616093)-incompatible neonates, as seen in other combinations with this condition. Forty ABO-incompatible and 334 ABO-compatible controls had an allele frequency of 0.35 for the variant promoter gene. The incidence of hyperbilirubinemia was significantly higher only in the ABO-incompatible group who were also homozygous for the variant UGT promoter, compared with ABO-incompatible babies homozygous for the normal UGT promoter (43% vs 0.0; p of 0.02), and compared with ABO-compatible controls of all UGT genotypes combined (relative risk, 5.65; 95% CI, 2.23 to 14.31). Kaplan et al. (2000) concluded that Gilbert syndrome is a determining factor for neonatal hyperbilirubinemia in ABO incompatibility. Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Sequencing of UGT1A1 revealed that 1 infant was a compound heterozygote for this TATA box variant and the G71R missense mutation (191740.0016). Kadakol et al. (2001) found compound heterozygosity for the Gilbert-type promoter and a structural mutation of the UGT1A1 gene (191740.0020) in 18-month-old twins with severe neonatal hyperbilirubinemia resulting in kernicterus. They also found the promoter mutation in compound heterozygosity with a missense mutation resulting in mild hyperbilirubinemia. Homozygosity for both the Gilbert-type promoter and a missense mutation (191740.0021) resulted in Crigler-Najjar syndrome type II. In a young girl with Crigler-Najjar syndrome type II, Labrune et al. (2002) found homozygosity for a (TA)8 polymorphism and an asn400-to-asp mutation (191740.0022). In a study of 67 patients with sickle cell anemia (603903) in Brazil, Fertrin et al. (2003) found that TA6/TA7 heterozygotes and TA7/TA7 homozygotes had higher bilirubin levels; both groups had a higher probability of presenting symptomatic cholelithiasis (600803) than TA6/TA6 homozygotes, but this finding was only statistically significant in the TA6/TA7 heterozygotes. Using a novel PCR method termed fluorescence resonance energy transfer (FRET), Borlak et al. (2000) reported the (TA)6 and (TA)7 UGT1A1 genotypes of 265 unrelated healthy individuals from southern Germany. Genotype distribution was 43:45:12 for (TA)6/(TA)6, (TA)6/(TA)7, and (TA)7/(TA)7, respectively. Serum total bilirubin levels increased with presence of the (TA)7 allele; median micromoles per liter were 12.0, 14.0, and 20.5, respectively, which was a statistically significant difference. Prevalence for the homozygous (TA)7 genotype was 12.4%. Borlak et al. (2000) emphasized the clinical importance of the UGT1A1 genotype and function of the enzyme, particularly for drug metabolism. Roses (2004) pointed to an example of a mild adverse event with a clear genetic component that could be used as a model of the safe use of pharmacogenetics. Some patients in a trial of tranilast, a specific drug to retard coronary artery restenosis after surgery, under investigation by GlaxoSmithKline, developed hyperbilirubinemia. A screen for variants in candidate genes revealed that high levels of bilirubin were most common in patients who were homozygous for the 7-repeat UGT1A1 allele. Breaking the placebo- versus the drug-treated codes at the end of the trial showed that all 7-7 patients who developed hyperbilirubinemia received the drug, whereas none of the 7-7 patients treated with the placebo developed the adverse event. Several drug-treated patients with the 6-7 genotype also developed mildly elevated levels of bilirubin, but no treated or placebo patients with the 6-6 genotype became hyperbilirubinemic. A study of UGT1A1 gene polymorphism by Edison et al. (2005) showed that the TA(7) variant was associated with hyperbilirubinemia in homozygous HbE patients homozygous for the hemoglobin E gene (HBE; 141900.0071). The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. French et al. (2005) genotyped 126 children with newly diagnosed acute lymphoblastic leukemia at 16 well-characterized functional polymorphisms. The UGT1A1*28 polymorphism was a significant predictor of global gene expression, dividing patients based on their germline genotypes. Genes whose expression distinguished the TA 7/7 genotype from the other UGT1A1 genotypes included HDAC1 (601241), RELA (164014) and SLC2A1 (138140). Although UGT1A1 expression is concentrated in liver, it is involved in the conjugation (and thus transport, excretion, and lipophilicity) of a broad range of endobiotics and xenobiotics, which French et al. (2005) suggested could plausibly have consequences for gene expression in different tissues. Using a competitive electrophoretic mobility shift assay (EMSA), Hsieh et al. (2007) demonstrated that mutant TA7 TATA-box-like sequence has reduced binding affinity for nuclear binding complex and for TATA-binding protein compared to wildtype TA6; quantitative EMSA showed that the binding affinity progressively decreases as the number of TA repeats in the TATA-box-like sequence increases. Hsieh et al. (2007) stated that this decrease in binding affinity causes the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome. In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism and rs4148323 (191740.0016) (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the TA(7) allele was 0.134 in Han Chinese, 0.256 in the Uygur, and 0.277 in the Kazakh, which was lower than that reported for Caucasian populations (0.357 to 0.415; Beutler et al., 1998). (less)

This variant has been designated UGT1A1*28 (Mackenzie et al., 1997). In 10 patients with Gilbert syndrome (143500), Bosma et al. (1995) identified a homozygous 2-bp insertion (TA) in the TATAA element of the 5-prime promoter region of the UGT1A1 gene. Normally, an A(TA)6TAA element is present between nucleotides -23 and -38. All 10 patients were homozygous for the sequence A(TA)7TAA; this resulted in reduced expression of the gene. The (TA)7 allele was found to have a frequency of 40% among normal controls, indicating that it is a polymorphism. Thus, the promoter mutation appeared to be a necessary but not sufficient factor in Gilbert syndrome. Bosma et al. (1995) found that 2 related individuals with Crigler-Najjar syndrome type II (606785) who were homozygous for a structural mutation in the UGT1A1 gene (Bosma et al., 1993) were also both homozygous for the wildtype A(TA)6TAA allele. Among 10 family members who were heterozygous for the coding mutation, the other allele contained the (TA)7 element in 6 and the (TA)6 element in 4. The 6 heterozygotes with the promoter abnormality had significantly higher serum bilirubin values than the 4 with the normal TATAA element. Kaplan et al. (1997) found that neonates with G6PD Mediterranean deficiency (305900.0006) who were heterozygous or homozygous for the variant (TA)7 UGT1A1 allele had a higher incidence of hyperbilirubinemia than corresponding controls. Among those normal for G6PD, the UGT1A1 polymorphism had no significant effect. Neither G6PD deficiency nor the variant UGT1A1 promoter alone increased the incidence of hyperbilirubinemia, but in combination both did. This gene interaction illustrated the paradigm of interaction of benign genetic polymorphisms in the causation of disease. Beutler et al. (1998) described this variant in the promoter of the UGT1A1 gene as responsible for most cases of Gilbert syndrome. In a patient with Crigler-Najjar syndrome type II, Yamamoto et al. (1998) identified an usual genotype consisting of heterozygosity for a P229Q mutation (191740.0010) and homozygosity for the 2-bp insertion mutation. The (TA)7 mutation of the UGT1A1 gene had been associated with increased bilirubin levels in normal persons (Bosma et al., 1995), in those with heterozygous beta-thalassemia (Galanello et al., 1997) or G6PD deficiency (Sampietro et al., 1997), and with neonatal icterus in G6PD deficiency (Kaplan et al., 1997) and hereditary spherocytosis (Iolascon et al., 1998). Beutler et al. (1998) examined the genotypes for the (TA)7 mutation in persons of Asian, African, and Caucasian ancestry. Although within the Caucasian ethnic group there was a strong correlation between promoter repeat number and bilirubin level, between ethnic groups they found that this relationship was inverse. Among people of African ancestry, there were, in addition to those with 6 and 7 repeats, also persons who had 5 or 8 repeats. Using a reporter gene they showed that there is an inverse relationship between the number of TA repeats and the activity of the promoter through the range of 5 to 8 TA repeats. An incidental finding was a polymorphism at nucleotide -106, tightly linked to the (TA)5 haplotype. Serum bilirubin levels are influenced by many factors, both genetic and environmental. Beutler et al. (1998) suggested that the unstable UGT1A1 polymorphism may serve to 'fine tune' the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants. In addition to the known common UGT1A1 TATA alleles (TA6 and TA7), Monaghan et al. (1999) identified a novel TATA allele (TA5) in a neonate with very prolonged jaundice. Statistical analysis of TATA genotype distributions within a group of breastfed neonates revealed significant differences among the acute, prolonged, and very prolonged subgroups: the incidence of familial hyperbilirubinemia genotypes (7/7 and 5/7) was 5 times greater in very prolonged cases (31%) relative to acute cases (6%). Neonates with prolonged jaundice from family pedigrees were observed to demonstrate the Gilbert syndrome phenotype as children or young adults. Kaplan et al. (2000) investigated whether the UGT promoter polymorphism would increase hyperbilirubinemia in direct Coombs-negative ABO (see 616093)-incompatible neonates, as seen in other combinations with this condition. Forty ABO-incompatible and 334 ABO-compatible controls had an allele frequency of 0.35 for the variant promoter gene. The incidence of hyperbilirubinemia was significantly higher only in the ABO-incompatible group who were also homozygous for the variant UGT promoter, compared with ABO-incompatible babies homozygous for the normal UGT promoter (43% vs 0.0; p of 0.02), and compared with ABO-compatible controls of all UGT genotypes combined (relative risk, 5.65; 95% CI, 2.23 to 14.31). Kaplan et al. (2000) concluded that Gilbert syndrome is a determining factor for neonatal hyperbilirubinemia in ABO incompatibility. Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Sequencing of UGT1A1 revealed that 1 infant was a compound heterozygote for this TATA box variant and the G71R missense mutation (191740.0016). Kadakol et al. (2001) found compound heterozygosity for the Gilbert-type promoter and a structural mutation of the UGT1A1 gene (191740.0020) in 18-month-old twins with severe neonatal hyperbilirubinemia resulting in kernicterus. They also found the promoter mutation in compound heterozygosity with a missense mutation resulting in mild hyperbilirubinemia. Homozygosity for both the Gilbert-type promoter and a missense mutation (191740.0021) resulted in Crigler-Najjar syndrome type II. In a young girl with Crigler-Najjar syndrome type II, Labrune et al. (2002) found homozygosity for a (TA)8 polymorphism and an asn400-to-asp mutation (191740.0022). In a study of 67 patients with sickle cell anemia (603903) in Brazil, Fertrin et al. (2003) found that TA6/TA7 heterozygotes and TA7/TA7 homozygotes had higher bilirubin levels; both groups had a higher probability of presenting symptomatic cholelithiasis (600803) than TA6/TA6 homozygotes, but this finding was only statistically significant in the TA6/TA7 heterozygotes. Using a novel PCR method termed fluorescence resonance energy transfer (FRET), Borlak et al. (2000) reported the (TA)6 and (TA)7 UGT1A1 genotypes of 265 unrelated healthy individuals from southern Germany. Genotype distribution was 43:45:12 for (TA)6/(TA)6, (TA)6/(TA)7, and (TA)7/(TA)7, respectively. Serum total bilirubin levels increased with presence of the (TA)7 allele; median micromoles per liter were 12.0, 14.0, and 20.5, respectively, which was a statistically significant difference. Prevalence for the homozygous (TA)7 genotype was 12.4%. Borlak et al. (2000) emphasized the clinical importance of the UGT1A1 genotype and function of the enzyme, particularly for drug metabolism. Roses (2004) pointed to an example of a mild adverse event with a clear genetic component that could be used as a model of the safe use of pharmacogenetics. Some patients in a trial of tranilast, a specific drug to retard coronary artery restenosis after surgery, under investigation by GlaxoSmithKline, developed hyperbilirubinemia. A screen for variants in candidate genes revealed that high levels of bilirubin were most common in patients who were homozygous for the 7-repeat UGT1A1 allele. Breaking the placebo- versus the drug-treated codes at the end of the trial showed that all 7-7 patients who developed hyperbilirubinemia received the drug, whereas none of the 7-7 patients treated with the placebo developed the adverse event. Several drug-treated patients with the 6-7 genotype also developed mildly elevated levels of bilirubin, but no treated or placebo patients with the 6-6 genotype became hyperbilirubinemic. A study of UGT1A1 gene polymorphism by Edison et al. (2005) showed that the TA(7) variant was associated with hyperbilirubinemia in homozygous HbE patients homozygous for the hemoglobin E gene (HBE; 141900.0071). The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. French et al. (2005) genotyped 126 children with newly diagnosed acute lymphoblastic leukemia at 16 well-characterized functional polymorphisms. The UGT1A1*28 polymorphism was a significant predictor of global gene expression, dividing patients based on their germline genotypes. Genes whose expression distinguished the TA 7/7 genotype from the other UGT1A1 genotypes included HDAC1 (601241), RELA (164014) and SLC2A1 (138140). Although UGT1A1 expression is concentrated in liver, it is involved in the conjugation (and thus transport, excretion, and lipophilicity) of a broad range of endobiotics and xenobiotics, which French et al. (2005) suggested could plausibly have consequences for gene expression in different tissues. Using a competitive electrophoretic mobility shift assay (EMSA), Hsieh et al. (2007) demonstrated that mutant TA7 TATA-box-like sequence has reduced binding affinity for nuclear binding complex and for TATA-binding protein compared to wildtype TA6; quantitative EMSA showed that the binding affinity progressively decreases as the number of TA repeats in the TATA-box-like sequence increases. Hsieh et al. (2007) stated that this decrease in binding affinity causes the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome. In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism and rs4148323 (191740.0016) (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the TA(7) allele was 0.134 in Han Chinese, 0.256 in the Uygur, and 0.277 in the Kazakh, which was lower than that reported for Caucasian populations (0.357 to 0.415; Beutler et al., 1998). (less)

This variant has been designated UGT1A1*28 (Mackenzie et al., 1997). In 10 patients with Gilbert syndrome (143500), Bosma et al. (1995) identified a homozygous 2-bp insertion (TA) in the TATAA element of the 5-prime promoter region of the UGT1A1 gene. Normally, an A(TA)6TAA element is present between nucleotides -23 and -38. All 10 patients were homozygous for the sequence A(TA)7TAA; this resulted in reduced expression of the gene. The (TA)7 allele was found to have a frequency of 40% among normal controls, indicating that it is a polymorphism. Thus, the promoter mutation appeared to be a necessary but not sufficient factor in Gilbert syndrome. Bosma et al. (1995) found that 2 related individuals with Crigler-Najjar syndrome type II (606785) who were homozygous for a structural mutation in the UGT1A1 gene (Bosma et al., 1993) were also both homozygous for the wildtype A(TA)6TAA allele. Among 10 family members who were heterozygous for the coding mutation, the other allele contained the (TA)7 element in 6 and the (TA)6 element in 4. The 6 heterozygotes with the promoter abnormality had significantly higher serum bilirubin values than the 4 with the normal TATAA element. Kaplan et al. (1997) found that neonates with G6PD Mediterranean deficiency (305900.0006) who were heterozygous or homozygous for the variant (TA)7 UGT1A1 allele had a higher incidence of hyperbilirubinemia than corresponding controls. Among those normal for G6PD, the UGT1A1 polymorphism had no significant effect. Neither G6PD deficiency nor the variant UGT1A1 promoter alone increased the incidence of hyperbilirubinemia, but in combination both did. This gene interaction illustrated the paradigm of interaction of benign genetic polymorphisms in the causation of disease. Beutler et al. (1998) described this variant in the promoter of the UGT1A1 gene as responsible for most cases of Gilbert syndrome. In a patient with Crigler-Najjar syndrome type II, Yamamoto et al. (1998) identified an usual genotype consisting of heterozygosity for a P229Q mutation (191740.0010) and homozygosity for the 2-bp insertion mutation. The (TA)7 mutation of the UGT1A1 gene had been associated with increased bilirubin levels in normal persons (Bosma et al., 1995), in those with heterozygous beta-thalassemia (Galanello et al., 1997) or G6PD deficiency (Sampietro et al., 1997), and with neonatal icterus in G6PD deficiency (Kaplan et al., 1997) and hereditary spherocytosis (Iolascon et al., 1998). Beutler et al. (1998) examined the genotypes for the (TA)7 mutation in persons of Asian, African, and Caucasian ancestry. Although within the Caucasian ethnic group there was a strong correlation between promoter repeat number and bilirubin level, between ethnic groups they found that this relationship was inverse. Among people of African ancestry, there were, in addition to those with 6 and 7 repeats, also persons who had 5 or 8 repeats. Using a reporter gene they showed that there is an inverse relationship between the number of TA repeats and the activity of the promoter through the range of 5 to 8 TA repeats. An incidental finding was a polymorphism at nucleotide -106, tightly linked to the (TA)5 haplotype. Serum bilirubin levels are influenced by many factors, both genetic and environmental. Beutler et al. (1998) suggested that the unstable UGT1A1 polymorphism may serve to 'fine tune' the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants. In addition to the known common UGT1A1 TATA alleles (TA6 and TA7), Monaghan et al. (1999) identified a novel TATA allele (TA5) in a neonate with very prolonged jaundice. Statistical analysis of TATA genotype distributions within a group of breastfed neonates revealed significant differences among the acute, prolonged, and very prolonged subgroups: the incidence of familial hyperbilirubinemia genotypes (7/7 and 5/7) was 5 times greater in very prolonged cases (31%) relative to acute cases (6%). Neonates with prolonged jaundice from family pedigrees were observed to demonstrate the Gilbert syndrome phenotype as children or young adults. Kaplan et al. (2000) investigated whether the UGT promoter polymorphism would increase hyperbilirubinemia in direct Coombs-negative ABO (see 616093)-incompatible neonates, as seen in other combinations with this condition. Forty ABO-incompatible and 334 ABO-compatible controls had an allele frequency of 0.35 for the variant promoter gene. The incidence of hyperbilirubinemia was significantly higher only in the ABO-incompatible group who were also homozygous for the variant UGT promoter, compared with ABO-incompatible babies homozygous for the normal UGT promoter (43% vs 0.0; p of 0.02), and compared with ABO-compatible controls of all UGT genotypes combined (relative risk, 5.65; 95% CI, 2.23 to 14.31). Kaplan et al. (2000) concluded that Gilbert syndrome is a determining factor for neonatal hyperbilirubinemia in ABO incompatibility. Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Sequencing of UGT1A1 revealed that 1 infant was a compound heterozygote for this TATA box variant and the G71R missense mutation (191740.0016). Kadakol et al. (2001) found compound heterozygosity for the Gilbert-type promoter and a structural mutation of the UGT1A1 gene (191740.0020) in 18-month-old twins with severe neonatal hyperbilirubinemia resulting in kernicterus. They also found the promoter mutation in compound heterozygosity with a missense mutation resulting in mild hyperbilirubinemia. Homozygosity for both the Gilbert-type promoter and a missense mutation (191740.0021) resulted in Crigler-Najjar syndrome type II. In a young girl with Crigler-Najjar syndrome type II, Labrune et al. (2002) found homozygosity for a (TA)8 polymorphism and an asn400-to-asp mutation (191740.0022). In a study of 67 patients with sickle cell anemia (603903) in Brazil, Fertrin et al. (2003) found that TA6/TA7 heterozygotes and TA7/TA7 homozygotes had higher bilirubin levels; both groups had a higher probability of presenting symptomatic cholelithiasis (600803) than TA6/TA6 homozygotes, but this finding was only statistically significant in the TA6/TA7 heterozygotes. Using a novel PCR method termed fluorescence resonance energy transfer (FRET), Borlak et al. (2000) reported the (TA)6 and (TA)7 UGT1A1 genotypes of 265 unrelated healthy individuals from southern Germany. Genotype distribution was 43:45:12 for (TA)6/(TA)6, (TA)6/(TA)7, and (TA)7/(TA)7, respectively. Serum total bilirubin levels increased with presence of the (TA)7 allele; median micromoles per liter were 12.0, 14.0, and 20.5, respectively, which was a statistically significant difference. Prevalence for the homozygous (TA)7 genotype was 12.4%. Borlak et al. (2000) emphasized the clinical importance of the UGT1A1 genotype and function of the enzyme, particularly for drug metabolism. Roses (2004) pointed to an example of a mild adverse event with a clear genetic component that could be used as a model of the safe use of pharmacogenetics. Some patients in a trial of tranilast, a specific drug to retard coronary artery restenosis after surgery, under investigation by GlaxoSmithKline, developed hyperbilirubinemia. A screen for variants in candidate genes revealed that high levels of bilirubin were most common in patients who were homozygous for the 7-repeat UGT1A1 allele. Breaking the placebo- versus the drug-treated codes at the end of the trial showed that all 7-7 patients who developed hyperbilirubinemia received the drug, whereas none of the 7-7 patients treated with the placebo developed the adverse event. Several drug-treated patients with the 6-7 genotype also developed mildly elevated levels of bilirubin, but no treated or placebo patients with the 6-6 genotype became hyperbilirubinemic. A study of UGT1A1 gene polymorphism by Edison et al. (2005) showed that the TA(7) variant was associated with hyperbilirubinemia in homozygous HbE patients homozygous for the hemoglobin E gene (HBE; 141900.0071). The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. French et al. (2005) genotyped 126 children with newly diagnosed acute lymphoblastic leukemia at 16 well-characterized functional polymorphisms. The UGT1A1*28 polymorphism was a significant predictor of global gene expression, dividing patients based on their germline genotypes. Genes whose expression distinguished the TA 7/7 genotype from the other UGT1A1 genotypes included HDAC1 (601241), RELA (164014) and SLC2A1 (138140). Although UGT1A1 expression is concentrated in liver, it is involved in the conjugation (and thus transport, excretion, and lipophilicity) of a broad range of endobiotics and xenobiotics, which French et al. (2005) suggested could plausibly have consequences for gene expression in different tissues. Using a competitive electrophoretic mobility shift assay (EMSA), Hsieh et al. (2007) demonstrated that mutant TA7 TATA-box-like sequence has reduced binding affinity for nuclear binding complex and for TATA-binding protein compared to wildtype TA6; quantitative EMSA showed that the binding affinity progressively decreases as the number of TA repeats in the TATA-box-like sequence increases. Hsieh et al. (2007) stated that this decrease in binding affinity causes the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome. In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism and rs4148323 (191740.0016) (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the TA(7) allele was 0.134 in Han Chinese, 0.256 in the Uygur, and 0.277 in the Kazakh, which was lower than that reported for Caucasian populations (0.357 to 0.415; Beutler et al., 1998). (less)