UDP-glucuronosyltransferase 1A1 Gene Research Articles

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.

Lack of association between the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and the risk of benign prostatic hyperplasia in Caucasian men

Glucuronidation, mediated by the UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme, is an important metabolic process during which steroids are converted to more easily excreted compounds in steroid target tissues, such as the prostate. The aim of our study was to investigate the possible correlation between UGT1A1 promoter gene polymorphism and benign prostatic hyperplasia. 421 blood samples were obtained from 138 consecutive patients diagnosed with benign prostatic hypeplasia (BPH group) and 283 healthy volunteers (control group). A(TA)6TAA promoter polymorphism of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/7, heterozygous 6/7 and normal homozygous 6/6) were identified. No significant differences were observed between the BPH group and controls regarding the genotyping distribution of the three UGT1A1 promoter genotypes (P=0.39). Also, no association was found between overall disease risk and the presence of the polymorphic homozygous genotype (TA(7)/TA)7) vs. TA(6)/TA(7)+TA(6)/TA(6)) (P=0.31). Our data suggest that the TA repeat polymorphism of UGT1A1 is not associated with increased BPH risk susceptibility in Caucasian men.

UGT1A1 promoter polymorphism associated with serum bilirubin level in Saudi patients with sickle cell disease

BACKGROUND AND OBJECTIVESPolymorphism in (TA)n of the UGT1A1 promoter influences bilirubin level and risk of gallstones in patients with sickle cell disease (SCD) of African descent. Modifiers of bilirubin level and gallstones in Saudi patients with SCD are not known.DESIGN AND SETTINGSPatients with SCD presenting to participating institutions between July 2009 and July 2012 were enrolled in our study.METHODSA total of 223 SCD patients were enrolled. Laboratory workup at steady state included complete blood count, reticulocytes, serum bilirubin, lactate dehydrogenase (LDH), G6PD level, and hemoglobin (Hb) electrophoresis. The (TA)n UGT1A1 promoter polymorphism and presence of α-thalassemia were also determined.RESULTSTA6/6 in the UGT1A1 promoter was identified in 189 patients (84.7%), TA7/7 in 26 (11.7%), TA5/5 in 6 (2.7%), and TA5/6 in 2 (0.9%). Increased (TA)n of the UGT1A1 promoter (P<.0001), male gender (P=.02), higher LDH (P=.001), and lower Hb level (P=.009) were associated with higher bilirubin level, while the co-inheritance of α-thalassemia (P=.003) was linked with lower bilirubin level. UGT1A1 (TA)n (P<.0001) and Hb level (P=.005) remained significant on multivariate analysis. Gallstones were more frequent in patients with TA7/7 (72%) compared to patients with TA6/6 (57%) and TA5/5 or 5/6 (37%); however, this difference was not statistically significance (P=.18). Older age (P=.0001) and absence of α-thalassemia (P=.03) were associated with higher risk of gallstones.CONCLUSION(TA)n in the UGT1A1 promoter and intensity of hemolysis modify steady-state serum bilirubin level in SCD. Co-inheritance of α-thalassemia reduces the risk of gallstones in Saudi patients with SCD.

Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: a novel mechanism involved in inflammation-associated hyperbilirubinaemia

Jaundice or hyperbilirubinaemia is a common complication of sepsis. UGT1A1 (UDP-glucuronosyltransferase 1A1) is a critical gene for bilirubin metabolism and irinotecan detoxification. However, the molecular pathogenesis of hyperbilirubinaemia during inflammation needs to be further clarified. Human hepatic UGT1A1 expression was analysed by RT (reverse transcription)-PCR, qRT-PCR (quantitative real-time PCR) and Western blotting in response to LPS (lipopolysaccharide) stimulation. Transcription regulatory elements in the upstream promoter region of the human UGT1A1 gene were determined using EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). The important role of the transcription regulatory element was examined using a luciferase assay, and was determined by qRT-PCR using a transcription factor activation inhibitor. LPS down-regulated the UGT1A1 mRNA expression in human hepatoma cell lines. A newly identified NF-κB (nuclear factor κB)-binding site was located on the upstream promoter region (-725/-716) of the human UGT1A1 gene. LPS-induced NF-κB activation and specific binding to the NF-κB-binding site can suppress human UGT1A1 promoter activity and human UGT1A1 expression. We demonstrated that LPS mediates the suppression of human UGT1A1 expression through specific binding of NF-κB to this newly identified NF-κB-binding site in the upstream promoter of the human UGT1A1 gene. The present study may partly explain the molecular pathogenesis of inflammation-associated hyperbilirubinaemia.

Microarray with LNA-probes for genotyping of polymorphic variants of Gilbert’s syndrome gene UGT1A1(TA)n

Gilbert's syndrome is a common metabolic dysfunction characterized by elevated levels of unconjugated bilirubin in the bloodstream. This condition is usually caused by additional (TA) insertions in a promoter region of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene, which instead of the sequence А(TА)6TАА contains А(TА)7TАА. While the condition itself is benign, it presents elevated risk for patients treated with irinotecan, a common chemotherapy drug. The technique is based on hybridization analysis of a pre-amplified segment of the UGT1A1 gene promoter performed on a microarray. Specific probes containing locked nucleic acids (LNA) were designed and immobilized on the microarray to provide accurate identification. A microarray has been developed to identify both common and rare variants of UGT1A1(TA)n polymorphisms. In total, 108 individuals were genotyped. Out of these, 47 (43.5%) had homozygous wild-type genotypes (TA)6/(TA)6; 41(38%) were heterozygotes (TA)6/(TA)7; and 18 (16.7%)--homozygotes (TA)7/(TA)7. In two cases (1.8%), rare genotypes (TA)5/(TA)7 and (TA)5/(TA)6 were found. The results were in full agreement with the sequencing. In addition, synthetic fragments corresponding to all human allelic variants [(TA)5, (TA)6, (TA)7, (TA)8] were successfully tested. The developed microarray-based approach for identification of polymorphic variants of the UGT1A1 gene is a promising and reliable diagnostic tool that can be successfully implemented in clinical practice.

UDP-glucuronosyltransferase 1A1 (UGT1A1) gene haplotypes and their effect on serum bilirubin concentration in healthy Indian adults

The aim of the present study was to investigate the allele and genotype frequencies and haplotype structures of the variants in the UGT1A1 gene and their association with serum bilirubin levels in healthy adults. Total serum bilirubin levels were measured in 300 healthy adults (normal hematology and liver function test) and genotyping of seven SNPs was performed by PCR-RFLP, Gene Scan analysis and direct sequencing on the ABI Prism 310 Genetic Analyzer. Of the seven SNPs, four were found to be polymorphic and the frequencies of minor alleles were 0.336, 0.431, 0.353 and 0.066 for −53(TA)7, −3279G, −3156A and 211A respectively. Individuals who carried the −53(TA)7, −3279G and −3156A mutant alleles in homozygous or heterozygous states had significantly higher mean serum bilirubin levels. Five major promoter haplotypes were observed: −53(TA)6/−3279T/−3156G was the most common haplotype, followed by −53(TA)7/−3279G/−3156A, −53(TA)6/−3279G/−3156G, −53(TA)6/−3279G/−3156A and −53(TA)7/−3279T/−3156G with an estimated frequency of 0.445, 0.230, 0.083, 0.065 and 0.050 respectively. Furthermore, the mutant haplotype (−53(TA)7/−3279G/−3156A) was found to have a significant effect on bilirubin concentrations. Promoter polymorphisms and a common haplotype of the UGT1A1 gene are associated with serum bilirubin concentrations and could be a genetic risk factor for hyperbilirubinemia in Indians.

Implication of genetic variation at the promoter and exon1 of UGT1A1 in occurrence of cholelithiasis in Tunisia

Bilirubin is conjugated with glucoronic acid in the liver by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms at the promoter region or exon1 of UGT1A1 gene result in unconjugated hyperbilirubinemia and could be at the origin of gallstone formation. The purpose of this study is to determine whether polymorphisms in the promoter area and exon 1 of UGT1A1 can be considered as a risk factor for lithogenesis. Our study involved 76 patients with cholelithiasis as well as 141 unaffected subjects. For each subject an analysis of the bilirubin parameters was performed. We screened genetic variation in the promoter and exon1 UGT1A1 namely the A (TA) nTAA and the six following SNPs: 44T>G, 101C>A, 115C>G, 145C>T, 211G>A and 222 C>A by PCR/sequencing. Our findings show that subjects with (TA)(7) or (TA)(8) variant in their genotypes are associated with high bilirubin level. Furthermore, the comparison between patients and controls according to A(TA)nTAA variation demonstrated that (TA)(6)/(TA)(7) and (TA)(7)/(TA)(7) genotype and (TA)(7) and (TA)(8) alleles were significantly associated with an increased risk of gallstone diseases p=0.0017, p= 6.1 10(-6), p=1.5 10(-6) and p=0.025 respectively. However, polymorphisms in exon1 were normal in all studied subjects except for the 211G>A which appears to be associated with a protective effect p=7.910(-9); OR=0.03, CI95% (0.001-0.158).

Tocilizumab-induced hyperbilirubinemia in Japanese patients with rheumatoid arthritis: its association with UDP glucuronosyltransferase 1A1 gene polymorphisms

This study was performed to explore the possibility of an association between polymorphisms within the uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) and hyperbilirubinemia arising during tocilizumab therapy. We examined the distributions of 3 variant alleles, UGT1A1*6, *28, and *27, in 46 Japanese patients with rheumatoid arthritis (RA) who had received tocilizumab therapy for at least 24 weeks, grouped the patients according to their carriage status of these UGT1A1 variants, and determined the frequency of hyperbilirubinemia in each of the groups. Of the 46 patients treated with tocilizumab, 34 maintained normal bilirubin levels after 24 weeks, whereas the remaining 12 developed mild or moderate hyperbilirubinemia. Patients carrying 2 copies of UGT1A1*28 (*28/*28) were more likely to develop hyperbilirubinemia than those without UGT1A1*28. In addition, patients carrying 2 copies of variant alleles, either as homozygotes (UGT1A1*6/*6 or *28/*28) or as compound heterozygotes (UGT1A1*6/*28), were at higher risk of hyperbilirubinemia as compared with those without either UGT1A1*6 or UGT1A1*28 (odds ratio [OR] 28.33; 95% confidence interval [CI] 2.39–336.00; p = 0.005). Multivariate logistic regression analysis confirmed the strong association of tocilizumab-induced hyperbilirubinemia with the presence of 2 copies of variant alleles (OR 25.51; 95% CI 2.35–276.53; p = 0.008), yielding an area under the receiver operating characteristics curve of 0.78 (95% CI 0.60–0.95, p = 0.005). Tocilizumab can induce hyperbilirubinemia in RA patients, especially those carrying UGT1A1*6/*6, *6/*28, and *28/*28 genotypes. Considering this genetic association, it may be unnecessary to withdraw this drug from RA patients in the absence of other signs of hepatic injury. Given that tocilizumab has the potential to inhibit UGT1A1-mediated glucuronidation, however, it may inhibit not only bilirubin metabolism but also UGT1A1-dependent detoxification of drugs, thereby increasing the risk of unwanted adverse events during RA therapy.

UGT1A1predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

To evaluate effects of UDP-glucuronosyltransferase1A1 (UGT1A1) and thymidylate synthetase (TS) gene polymorphisms on irinotecan in metastatic colorectal cancer (mCRC). Two irinotecan- and fluorouracil-based regimens, FOLFIRI and IFL, were selected as second-line therapy for 138 Chinese mCRC patients. Genomic DNA was extracted from peripheral blood samples before treatment. UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism, respectively. Gene polymorphisms of UGT1A1*28, UGT1A1*6 and promoter enhancer region of TS were analyzed. The relationship between genetic polymorphisms and clinical outcome, that is, response, toxicity and survival were assessed. Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes. Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography. Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared. One hundred and eight patients received the FOLFIRI regimen, 29 the IFL regimen, and one irinotecan monotherapy. One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation. One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS. Patients showed a higher frequency of wild-type UGT1A1*28 (TA6/6) compared with a Caucasian population (69.9% vs 45.2%). No significant difference was found between response rates and UGT1A1 genotype, although wild-type showed lower response rates compared with other variants (17.9% vs 24.2% for UGT1A1*28, 15.7% vs 26.8% for UGT1A1*6). When TS was considered, the subgroup with homozygous UGT1A1*28 (TA7/7) and non-3RG genotypes showed the highest response rate (33.3%), while wild-type UGT1A1*28 (TA6/6) with non-3RG only had a 13.6% response rate, but no significant difference was found. Logistic regression showed treatment duration was closely linked to clinical response. In toxicity comparison, UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea (27.8% vs 100%), and significantly reduced the risk of grade 4 neutropenia compared with TA7/7 (7.8% vs 37.5%). Wild-type UGT1A1*6 (G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant (A/A) genotype (13.0% vs 40.0%). Taking UGT1A1 and TS genotypes together, lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes, when TA6/6 was compared with TA7/7 (35.3% vs 100.0%). No significant association with time to progression (TTP) and overall survival (OS) was observed with either UGT1A1 or TS gene polymorphisms, although slightly longer TTP and OS were found with UGT1A1*28 (TA6/6). Irinotecan PK was investigated in 34 patients, which showed high area under concentration curve (AUC) of irinotecan and SN-38, but low AUC ratio (SN-38G / SN-38) in those patients with UGT1A1*28 TA7/7. A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

A functional polymorphism in UGT1A1 related to hyperbilirubinemia is associated with a decreased risk for Crohn's disease

BackgroundAn imbalance between the production of reactive oxygen species (ROS) and their capturing by antioxidants results in oxidative stress, this may play an important role in the pathogenesis of inflammatory bowel disease (IBD). Since bilirubin is an important endogenous antioxidant, increased levels of bilirubin may protect against IBD. UDP-glucuronosyltransferase 1A1 (UGT1A1) is the only enzyme involved in the conjugation of bilirubin and the common UGT1A1*28 allele in the UGT1A1 gene, which is strongly associated with Gilbert's syndrome in Caucasians, results in elevated plasma bilirubin levels. AimsTo test the hypothesis that the UGT1A1*28 allele is associated with lower disease susceptibility to, and disease behavior within, IBD. In addition, a possible altered risk for developing IBD-drug related side-effects was explored. MethodologyGenomic DNA of 751 patients with IBD (209 patients with ulcerative colitis and 542 patients with Crohn's disease) and 930 healthy controls was genotyped for the UGT1A1*28 promoter polymorphism, and genotype distribution was compared between patients and controls. Genotype phenotype interactions were also investigated. ResultsPatients with Crohn's disease significantly less often bear the UGT1A1*28 homozygous genotype compared to the control group, with an odds ratio of 0.64, 95% CI: 0.42–0.98. The ulcerative colitis group showed no significant differences compared to controls. ConclusionThe homozygous state of the UGT1A1*28 polymorphism, associated with higher serum bilirubin levels, may be protective for the development of Crohn's disease, suggesting that the anti-oxidant capacity of bilirubin may play a part.

Study of irinotecan-induced toxicity and its correlation to UGT1A1 gene promoter polymorphisms

To investigate the distribution of uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphism and its relation to the toxicities caused by irinotecan in Chinese patients with cervical cancer and ovarian cancer. Sixty-four blood samples were taken from the patients with ovarian cancer and cervical cancer. The DNA was extracted and amplified with PCR. Then, the sequences of UGT1A1 gene promoter were detected by capillary electrophoresis allele fragment analysis (size-based analysis) methods. The relationship between UGT1A1 gene promoter polymorphism and the toxicity caused by irinotecan was analyzed. In all the patients, TA 6/6 was the most common genotype of UGT1A1 gene promoter (44 cases), accounting for 69% (44/64), followed by genotype of TA 6/7 (17 cases, 27%, 17/64), while genotype TA 7/7 was rare (3 cases, 5%, 3/64). The genotypes of UGT1A1 gene promoter was an independent factor for the occurrence of delayed diarrhea (P = 0.040, OR = 4.228, 95%CI: 1.065 - 16.785) but not for neutropenia (P = 0.068, OR = 3.659, 95%CI: 0.911 - 14.700). The patients with both genotype TA 6/7 and TA 7/7 presented much higher risk of delayed diarrhea and neutropenia than those with TA 6/6 (all P = 0.001). UGT1A1 gene promoter polymorphism may be a significant influencing factor for delayed diarrhea. The patients with both genotype TA 6/7 and TA 7/7 could present much higher risk for delayed diarrhea than those with TA 6/6, while genotype TA 6/6 may be the most common UGT1A1 promoter type in Chinese patients with cervical or ovarian cancer.

Tocilizumab-induced hyperbilirubinemia in Japanese patients with rheumatoid arthritis: its association with UDP glucuronosyltransferase 1A1 gene polymorphisms

This study was performed to explore the possibility of an association between polymorphisms within the uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) and hyperbilirubinemia arising during tocilizumab therapy. We examined the distributions of 3 variant alleles, UGT1A1*6, *28, and *27, in 46 Japanese patients with rheumatoid arthritis (RA) who had received tocilizumab therapy for at least 24weeks, grouped the patients according to their carriage status of these UGT1A1 variants, and determined the frequency of hyperbilirubinemia in each of the groups. Of the 46 patients treated with tocilizumab, 34 maintained normal bilirubin levels after 24weeks, whereas the remaining 12 developed mild or moderate hyperbilirubinemia. Patients carrying 2 copies of UGT1A1*28 (*28/*28) were more likely to develop hyperbilirubinemia than those without UGT1A1*28. In addition, patients carrying 2 copies of variant alleles, either as homozygotes (UGT1A1*6/*6 or *28/*28) or as compound heterozygotes (UGT1A1*6/*28), were at higher risk of hyperbilirubinemia as compared with those without either UGT1A1*6 or UGT1A1*28 (odds ratio [OR] 28.33; 95% confidence interval [CI] 2.39-336.00; p=0.005). Multivariate logistic regression analysis confirmed the strong association of tocilizumab-induced hyperbilirubinemia with the presence of 2 copies of variant alleles (OR 25.51; 95% CI 2.35-276.53; p=0.008), yielding an area under the receiver operating characteristics curve of 0.78 (95% CI 0.60-0.95, p=0.005). Tocilizumab can induce hyperbilirubinemia in RA patients, especially those carrying UGT1A1*6/*6, *6/*28, and *28/*28 genotypes. Considering this genetic association, it may be unnecessary to withdraw this drug from RA patients in the absence of other signs of hepatic injury. Given that tocilizumab has the potential to inhibit UGT1A1-mediated glucuronidation, however, it may inhibit not only bilirubin metabolism but also UGT1A1-dependent detoxification of drugs, thereby increasing the risk of unwanted adverse events during RA therapy.

Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case–control study followed by systematic review of existing evidence

To determine whether the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) Gly71Arg (211G>A) mutation is associated with neonatal hyperbilirubinemia. The study consisted of two parts. The case-control study included 112 hyperbilirubinemic infants and 105 control subjects from the Fifth People's Hospital of Shenzhen. Polymerase chain reaction, restriction fragment length polymorphisms and agarose gel electrophoresis techniques were used to detect the UGT1A1 211G>A mutation. Meta-analyses was performed to assess the association between neonatal hyperbilirubinemia and UGT1A1 211G>A. Our case-control study revealed that the likelihood of developing neonatal hyperbilirubinemia was 2.65 times higher in the infants with the A allele in the UGT1A1 211G>A than in the infants with the G allele (95% CI, 1.60-4.39). Meta-analyses (including data from our study) revealed that UGT1A1 211G>A is associated with an increased risk of neonatal hyperbilirubinemia [odds ratio (OR), 2.37; 95% CI, 2.05-2.74]. In the subgroup analyses based on ethnicity, significantly elevated risks were found in Asian populations (OR, 2.45; 95% CI, 2.10-2.84), but no significant associations were present in Caucasian populations (OR, 1.54; 95% CI, 0.87-2.75). The UGT1A1 211G>A mutation is associated with neonatal hyperbilirubinemia in Asians, but not in Caucasians.

211 G to A Variation of UDP-Glucuronosyl Transferase 1A1 Gene and Neonatal Breastfeeding Jaundice

Breastfeeding jaundice is a common problem in neonates who were exclusively breastfed, but its pathogenesis is still unclear. The uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphism was shown to contribute to the development of neonatal hyperbilirubinemia. We hypothesize that the variation of UGT1A1 gene may contribute to neonatal breastfeeding jaundice. We prospectively enrolled 688 near-term and term infants who were exclusively breastfed (BF group) or were supplemented by infant formula partially (SF group) before onset of hyperbilirubinemia. Genotyping of the promoter and exon1 of UGT1A1 was performed in all neonates. Neonates in BF group had a significantly higher maximal body weight loss ratio, peak bilirubin level, and a greater incidence of hyperbilirubinemia than those in SF group. Neonates with nucleotide 211 GA or AA variation in UGT1A1 genotypes had higher peak serum bilirubin levels and higher incidence of hyperbilirubinemia than WTs (GG). This phenomenon was only seen in BF group but not in SF group when subset analysis was performed. This suggests that neonates who carry the nucleotide 211 GA or AA variation within coding region in UGT1A1 gene are more susceptible to develop early-onset neonatal breastfeeding jaundice.

Hereditary Spherocytosis Coexisting with UDP-Glucuronosyltransferase Deficiency Highly Suggestive of Crigler-Najjar Syndrome Type II

Patients with co-existing hereditary spherocytosis (HS) and UDP-glucuronosyltransferase 1A1 (UGT1A1) deficiency as Gilbert's syndrome (GS) have been reported, and previous studies have demonstrated an increased risk for developing gallstones in patients with co-inheritance of GS and HS. We experienced an interesting case of HS showing persistent jaundice after splenectomy, and upon further evaluation, the 25-year-old female patient was found to have HS combined with UGT1A1 deficiency. Sequence analysis of the UGT1A1 gene revealed that she was a compound heterozygote with p.[G71R; Y486D] + [Y486D] mutations, which suggests Crigler-Najjar syndrome type II rather than GS. Careful evaluation of inappropriately elevated bilirubin level compared with the degree of hemolysis is important, reflecting the therapeutic implication of splenectomy and cholecystectomy.

Is Ceftriaxone-Induced Biliary Pseudolithiasis Influenced by UDP-Glucuronosyltransferase 1A1 Gene Polymorphisms?

Ceftriaxone (cfx), a third-generation cephalosporin antibiotic, leads to transient cholelithiasis in some children, also known as pseudolithiasis. However, the underlying pathogenetic mechanism of this adverse effect has not yet been elucidated. We describe 3 children with ceftriaxone-induced pseudolithiasis, who were also carriers of the A(TA)7TAA polymorphism of the UGT1A1 gene, implying that a cause and effect relation may exist.

Abstract P6-06-02: UGT1A1*28 and Breast Cancer: Increased Risk for Gilbert's Syndrome Patients

Abstract Introduction: Estrogens are essential for the initiation and development of breast cancer (BC). Among the enzymes involved in conjugation and inactivation of estrogens and its metabolites, there is the UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in the promoter region of the UGT1A1 gene are common in patients with Gilbert's syndrome (GS), reducing the enzyme activity by about 80%. Although considered benign, patients with Gilbert's Syndrome (GS) have lower activity of UGT1A1, which may lead to a higher risk for estrogen-dependent cancers, such as breast cancer (BC). Methods: Case control-study and meta-analysis. Setting: academic tertiary hospital in Brazil. Cases: Women with recently operated BC, no previous neoplasm or immunossuppression. Controls: Healthy women, older than 40 years old, mammography BIRADS 1 or 2 in the last 12 months, no previous neoplasm or immunossupression. Interventions: data collection; sequencing of the UGT1A1 gene. Literature search: PubMed, EMBASE, SciElo, hand search. Languages: English, German, Spanish, Portuguese. Studies: case-control studies, BC patients and healthy subjects, genetic diagnosis of GS. Results: From August 2008 to November 2009, 89 cases and 56 controls were enrolled. Patients were significantly older than controls (median 52 (46-64) vs 47 (43-50) y/o p=0.013), with comparable body mass index (median 27.55 vs 25.95 p=0.46), age at menarche (median 13 vs 13 p=0.68), age at menopause (median 48 vs 45, p=0.24), age at first full-term pregnancy (median 22 vs 23 p=o.46) and proportion of individuals with first degree-relatives with BC (22% vs 19%, p=0.68). The prevalence of GS was 19.1% in cases and 12.5% in controls (adjusted OR 1.65 CI95% 0.63-4.28 p=0.29), but the study was underpowered to detect differences smaller than 21%. The meta-analysis included 10 studies with 5815 BC patients and 8255 controls. There was a weak association between GS and BC (OR 1.13 CI95% 1.01-1.26 I2=2%), which was stronger for Caucasians (OR 1.14 CI95% 1.01-1,29 I2 = 20%), estrogen-receptor positive BC (OR 1.18 CI 95% 1.02-1.35 I2=0%) and individuals with a family history of BC (OR 1.4 CI95% 1.01-1.95 I2=0%). Conclusions: In our study, the polymorphism UGT1A1 *28/*28, present in most individuals with Gilbert's syndrome, was an important risk factor for developing breast cancer. Gilbert's syndrome, usually considered benign, may be a risk factor for breast cancer. There have been no studies evaluating the incidence of BC in patients with GS. Prospective studies with patients diagnosed with SG are needed to confirm this hypothesis and assess other patients subgroups. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-06-02.

781 Crigler-Najjar Syndrome Type Ii Caused by Homozygous Double Mutation [T1456G, G211A] of Ugt1A1 Gene in a Taiwanese Sibling

Objective: This study aimed to analyze the mutations of UDP-glucuronosyltransferase 1A1 (UGT1A1) gene in a Taiwanese family.Patients and Methods: Two brothers aged 24 and 2 months, respectively were born to a Chinese mother who married to a Taiwanese man. They had profound unconjugated hyperbilirubinemia in the newborn period (30.7 and 25.2 mg/dL, respectively). The liver function, hemoglobin and glucose-6-phosphate dehydrogenase levels were within normal limit. They both received intensive phototherapy and the serum bilirubin level gradually decreased to 6-10 mg/dL. The blood samples of the brothers and their parents were sent for DNA analysis including the promoter area of the UGT1A1 gene, exons 1-4, the coding region of exon 5, and their flanking intronic regions. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing were used.Results: The PCR results for the UGT1A1 gene showed homozygous G > A substitution at nucleotide 211 in exon 1 and homozygous T > G substitution at nucleotide 1456 in exon 5 (Gly71 Arg plus Tyr486 Asp) in both patients. No other variation was detected in the UGT1A1 gene. Analyzing the UGT1A1 gene of the parents showed a homozygous 211G > A plus a heterozygous 1456 T > G variations in their father and a heterozygous 211G > A plus a heterozygous 1456 T > G variations in their mother. All of the tests were confirmed by the direct gene sequence.Conclusion: Double homozygous mutation [T1456G, G211A] of UGT1A1 gene is rare in CN-2 and is a novel mutation in Taiwanese children.

The clinical application of UGT1A1pharmacogenetic testing: Gene-environment interactions

Over the past decade, the number of pharmacogenetic tests has increased considerably, allowing for the development of our knowledge of their clinical application. The uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) assay is an example of a pharmacogenetic test. Numerous variants have been found in UGT1A1, the main conjugating enzyme of bilirubin and drugs such as the anticancer drug irinotecan. Recently, the US Food and Drug Administration (FDA) recommended testing for the presence of UGT1A1*28, an allele correlated with decreased transcriptional activity, to predict patients at risk of irinotecan toxicity. The administration of other drugs -- such as inhibitors of the UGT1A1 enzyme -- can clinically mimic the *28 phenotype, whereas inducers of UGT1A1 can increase the glucuronidation rate of the enzyme. The *28 polymorphism is not present in all ethnicities at a similar frequency, which suggests that it is important to study different populations to determine the clinical relevance of testing for UGT1A1*28 and to identify other clinically relevant UGT1A1 variants. Environmental factors such as lifestyle can also affect UGT1A1 activity. This review is a critical analysis of studies on drugs that can be affected by the presence of UGT1A1*28, the distribution of this polymorphism around the globe, distinct variants that may be clinically significant in African and Asian populations and how lifestyle can affect treatment outcomes that depend on UGT1A1 activity.

Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and prostate cancer risk in Caucasian men

Background: Catechol-estrogen metabolites can induce carcinogenesis by acting as endogenous tumor initiators. Glucuronidation, mediated by the UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme, is a main metabolic pathway of estrogen detoxification in steroid target tissues, such as the prostate. The aim of our study was to investigate the possible correlation between UGT1A1 promoter gene polymorphisms and prostate cancer risk. Patients and methods: 129 patients with prostate cancer and 260 healthy controls were included in our study. A(TA)TAA promoter polymorphism of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/7, heterozygous 6/7 and normal homozygous 6/6) were identified. Results: No significant differences were observed between the cancer group and controls regarding the genotyping distribution of the three UGT1A1 promoter genotypes ( P > 0.05). Also, no association was found between overall disease risk and the presence of the polymorphic homozygous genotype (TA(7)/TA(7) vs TA(6)/TA(7) + TA(6)/TA(6)) ( P = 0.18). In addition, no association was revealed between UGT1A1 genotype distribution and Gleason score ( P = 0.55). Conclusion: Our data suggest that the TA repeat polymorphism of UGT1A1 gene does not seem to alter prostate cancer risk susceptibility in Caucasian men.