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Gene May 2021Gilbert's syndrome (GS) is a mild condition characterized by periods of hyperbilirubinemia, which results in variations in the UDP-glucuronosyltransferase 1 (UGT1A1)...
Gilbert's syndrome (GS) is a mild condition characterized by periods of hyperbilirubinemia, which results in variations in the UDP-glucuronosyltransferase 1 (UGT1A1) gene. Variant genotypes of UGT1A1 vary in different populations in the world. The present study aimed to determine the genotype of the UGT1A1 promoter and exon that are related to the serum total bilirubin (STB) level in the Chinese Han population. A total of 120 individuals diagnosed with GS (GS group) and 120 healthy individuals (non-GS group) were enrolled. Routine blood, liver function tests, and antibodies associated with autoimmune liver diseases were assessed. Blood samples were collected for DNA purification. Sequencing of the UGT1A1 promoter and exons was conducted for post segment amplification by PCR. Compound heterozygous UGT1A1*28 and UGT1A1*6 (25/120, 20.83%), single homozygous UGT1A1*28 (24/120, 20.00%) and single heterozygous UGT1A1*6 (18/120, 15.00%) were the most frequent genotypes in the GS group. However, single heterozygous UGT1A1*6 (30/120, 25.00%) and single heterozygous UGT1A1*28 (19/120, 15.83%) were the most frequent genotypes in the non-GS group. Further, the frequencies of single homozygous UGT1A1*28, compound heterozygous UGT1A1*28 and UGT1A1*6, and compound heterozygous UGT1A1*28, UGT1A1*6 and UGT1A1*27 were significantly higher in the GS group than those in the non-GS group. The STB levels of GS patients with the homozygous UGT1A1*28 genotype were remarkably higher than those of patients with other genotypes. Homozygous UGT1A1*28 and heterozygous UGT1A1*6 variants were associated with the highest and lowest risks of hyperbilirubinemia, respectively. Our study revealed that compound heterozygous UGT1A1*28 and UGT1A1*6, or single homozygous UGT1A1*28 are major genotypes associated with GS in Chinese Han people. These findings might facilitate the precise genomic diagnosis of Gilbert's syndrome.
Topics: Adult; Asian People; Bilirubin; China; Female; Genotype; Gilbert Disease; Glucuronosyltransferase; Heterozygote; Homozygote; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic
PubMed: 33631237
DOI: 10.1016/j.gene.2021.145526 -
Stem Cell Research Mar 2021Human fibroblasts cells from a Crigler-Najjar Syndrome (CNS) patient were used to generate integration-free induced pluripotent stem cells (iPSCs) by over-expressing...
Human fibroblasts cells from a Crigler-Najjar Syndrome (CNS) patient were used to generate integration-free induced pluripotent stem cells (iPSCs) by over-expressing episomal-based plasmids expressing OCT4, SOX2, NANOG, KLF4, c-MYC and LIN28. The derived CNS705-iPSC line is homozygous for the UGT1A1 c.877_890delTACATTAATGCTTCinsA mutation. Pluripotency was confirmed by the expression of associated markers and embryoid body-based differentiation into cell types from all three germ layers. Comparative transcriptome analysis of the iPSC and the human embryonic stem cell line H9 revealed a Pearson's correlation of 0.9468.
Topics: Cell Differentiation; Cell Line; Cellular Reprogramming; Crigler-Najjar Syndrome; Embryoid Bodies; Fibroblasts; Humans; Induced Pluripotent Stem Cells; Kruppel-Like Factor 4
PubMed: 33485181
DOI: 10.1016/j.scr.2021.102167 -
American Journal of Physiology.... Feb 2021Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene... (Review)
Review
Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as "hypobilirubinemia," are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.
Topics: Animals; Bilirubin; Energy Metabolism; Gene Expression Regulation; Gilbert Disease; Heme; Hormones; Humans; Hyperbilirubinemia; Metabolic Networks and Pathways; PPAR alpha
PubMed: 33284088
DOI: 10.1152/ajpendo.00405.2020 -
Cureus Oct 2020Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common red blood cell enzyme deficiency worldwide. The disease is widely distributed in...
Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common red blood cell enzyme deficiency worldwide. The disease is widely distributed in regions where malaria is prevalent, affecting mostly males because the enzyme is inherited as an X-link recessive pattern. In Saudi Arabia, we lack newborn screening (NBS) for G6PD deficiency, despite early reports about high prevalence. Methods This is a 10-year retrospective study of children who were screened for G6PD deficiency during their hospitalization between January 2008 to December 2017. The test was carried out using a qualitative fluorescence test suitable for mass screening to determine the prevalence of G6PD deficiency among the admitted children between 0 and 14 years of age. Results A total of 48,889 patients were screened which included 27,634 (56.5%) males and 21,255 (43.5%) females with a mean age of 1.93 + 3.98 years. The overall prevalence of G6PD deficiency was 25%, whereas it was 33.8% in the male subset and 13.2% in the female subset. Male sex was significantly correlated with G6PD deficiency. A total of 25,628 newborns were screened, with 14,219 (55.5%) males and 11,409 (44.5%) females, who had a G6PD deficiency prevalence of 18.8%. There was a G6PD deficiency prevalence of 26% in males and 9.9% in females. Conclusion The present study confirms the high prevalence of G6PD deficiency in our community. Therefore, we need to establish an NBS program to screen for G6PD deficiency in order to prevent neonatal hyperbilirubinemia encephalopathy, avoidable hemolytic episodes, and to increase awareness among health practitioners.
PubMed: 33269163
DOI: 10.7759/cureus.11235 -
JGH Open : An Open Access Journal of... Oct 2020Crigler-Najjar syndrome (CNs) is a rare hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin Uridine (UDP) glucuronosyltransferase family 1...
Crigler-Najjar syndrome (CNs) is a rare hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin Uridine (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1, ENSG00000241635) gene. Two patients were clinically diagnosed with Crigler-Najjar Syndrome types II (CNs-II) can be clinically diagnosed which were based on the level of total bilirubin, efficacy of phenobarbital treatment, normal liver architecture and exclusion of hemolysis. Diagnosis was also confirmed by UGT1A1 gene mutations, which by sequencing the coding region for UGT1A1 gene mutations, which were the homozygous mutations c.668G > A/p.Cys223Tyr and which caused less than 10% of activity of the enzyme. No data have been reported about this mutate in the population. These patients have a good prognosis and require no active intervention, indicating that an early accurate diagnosis is necessary for disease management and genetic counseling.
PubMed: 33102778
DOI: 10.1002/jgh3.12355 -
Experimental and Therapeutic Medicine Nov 2020Gilbert syndrome (GS) is a hereditary unconjugated hyperbilirubinemia that results from mutations in the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1)...
Gilbert syndrome (GS) is a hereditary unconjugated hyperbilirubinemia that results from mutations in the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene. To the best of our knowledge, there are currently no reports that focus on patients with systemic lupus erythematosus (SLE) coexisting with GS. The present study aimed to evaluate the clinical characteristics and genotype of UGT1A1 in a Chinese patient with SLE and GS. Complete medical records and laboratory data were reviewed for a patient with SLE referred to Ruijin Hospital (Shanghai, China) for treatment between March 2016 and January 2020. Genetic analysis of the UGT1A1 gene was performed by PCR amplification and Sanger sequencing. The serum total bilirubin and unconjugated bilirubin concentrations on admission were 96.2 and 86.8 µmol/l, respectively. The homozygous mutation c.1456T>G (p.Y486D) in exon 5 was detected in this patient. The patient had a good response to phenobarbital orally at a dose of 30 mg/day and a decrease in serum bilirubin was observed. Elevated unconjugated hyperbilirubinemia in SLE needs to be differentiated from other diseases, such as GS, which can be diagnosed by UGT1A1 genetic sequencing.
PubMed: 32973940
DOI: 10.3892/etm.2020.9219 -
Thorax Nov 2020Moderately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect...
BACKGROUND
Moderately raised serum bilirubin levels are associated with lower rates of lung cancer, particularly among smokers. It is not known whether these relationships reflect antioxidant properties or residual confounding.
OBJECTIVE
This study aimed to investigate potential causal relationships between serum total bilirubin and lung cancer incidence using one-sample Mendelian randomisation (MR) and UK Biobank.
METHODS
We instrumented serum total bilirubin level using two variants (rs887829 and rs4149056) that together explain ~40% of population-level variability and are linked to mild hereditary hyperbilirubinaemia. Lung cancer events occurring after recruitment were identified from national cancer registries. Observational and genetically instrumented incidence rate ratios (IRRs) and rate differences per 10 000 person-years (PYs) by smoking status were estimated.
RESULTS
We included 377 294 participants (median bilirubin 8.1 μmol/L (IQR 6.4-10.4)) and 2002 lung cancer events in the MR analysis. Each 5 μmol/L increase in observed bilirubin levels was associated with 1.2/10 000 PY decrease (95% CI 0.7 to 1.8) in lung cancer incidence. The corresponding MR estimate was a decrease of 0.8/10 000 PY (95% CI 0.1 to 1.4). The strongest associations were in current smokers where a 5 μmol/L increase in observed bilirubin levels was associated with a decrease in lung cancer incidence of 10.2/10 000 PY (95% CI 5.5 to 15.0) and an MR estimate of 6.4/10 000 PY (95% CI 1.4 to 11.5). For heavy smokers (≥20/day), the MR estimate was an incidence decrease of 23.1/10 000 PY (95% CI 7.3 to 38.9). There was no association in never smokers and no mediation by respiratory function.
CONCLUSION
Genetically raised serum bilirubin, common across human populations, may protect people exposed to high levels of smoke oxidants against lung cancers.
Topics: Adult; Aged; Bilirubin; Biological Specimen Banks; Causality; Female; Humans; Incidence; Lung Neoplasms; Male; Mendelian Randomization Analysis; Middle Aged; Registries; Smoking; United Kingdom
PubMed: 32855344
DOI: 10.1136/thoraxjnl-2020-214756 -
Circulation Journal : Official Journal... Sep 2020The potential antiatherogenic role of bilirubin is generally acknowledged, so the aim of this study was to determine serum bilirubin concentrations and the prevalence of...
BACKGROUND
The potential antiatherogenic role of bilirubin is generally acknowledged, so the aim of this study was to determine serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in the Czech general population with particular reference to its relationship to the risk of myocardial infarction (MI).Methods and Results:Biochemical markers were analyzed in 2 independent Czech post-MONICA studies (in total, n=3,311), and in 741 male MI patients. TheUGT1A1promoter gene variant (rs81753472) was analyzed in these MI patients and in the first control population cohort (n=717). Medians of serum bilirubin concentrations in the 2 Czech general population cohorts were 9.6 and 9.8 μmol/L (10.7 and 11.3 μmol/L in males, and 8.3 and 8.8 μmol/L in females; P<0.01). The prevalence of GS was 8.9%, twice as high in males compared with females (11.6 vs. 6.1%; P<0.01). TheUGT1A1(TA)promoter repeats significantly influenced serum bilirubin concentrations in the controls, but not in the MI patients. Serum bilirubin concentrations were significantly lower in MI patients (7.7 vs. 10.7 μmol/L; P<0.01), with almost 5-fold lower prevalence of GS.
CONCLUSIONS
Serum bilirubin concentrations and the prevalence of GS were determined in the Czech general population. Significantly lower serum bilirubin concentrations were observed in male MI patients.
Topics: Adult; Bilirubin; Cross-Sectional Studies; Czech Republic; Female; Genotype; Gilbert Disease; Glucuronosyltransferase; Humans; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Prevalence; Promoter Regions, Genetic; Prospective Studies; Retrospective Studies; Risk Factors; Sex Factors
PubMed: 32848115
DOI: 10.1253/circj.CJ-20-0192 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... May 2020A case of Gilbert syndrome (GS) with a heterozygous mutation in the gene is reported. The patient had no symptoms except for recurrent sclera icterus since childhood....
A case of Gilbert syndrome (GS) with a heterozygous mutation in the gene is reported. The patient had no symptoms except for recurrent sclera icterus since childhood. Laboratory examinations revealed an elevated unconjugated bilirubin. Biliary obstruction, hemolysis and other diseases that might cause jaundice were excluded. *28 and c.211G>A heterozygous mutations in gene were found, which may be another type of mutation causing GS in Chinese population.
Topics: Asian People; Bilirubin; Gilbert Disease; Glucuronosyltransferase; Heterozygote; Humans; Mutation
PubMed: 32762156
DOI: 10.3785/j.issn.1008-9292.2020.04.13 -
BMC Pediatrics Aug 2020Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder presenting as isolated direct hyperbilirubinemia.DJS is rarely diagnosed in the neonatal period. The...
BACKGROUND
Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder presenting as isolated direct hyperbilirubinemia.DJS is rarely diagnosed in the neonatal period. The purpose of this study was to clarify the clinical features of neonatal DJS and to analyze the genetic mutation of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2).
METHODS
From 2013 to 2018, 135 infants with neonatal cholestasis at Seoul National University Hospital were enrolled. Genetic analysis was performed by neonatal cholestasis gene panel. To clarify the characteristics of neonatal DJS, the clinical and laboratory results of 6 DJS infants and 129 infants with neonatal cholestasis from other causes were compared.
RESULTS
A total of 8 different ABCC2 variants were identified among the 12 alleles of DJS. The most common variant was p.Arg768Trp (33.4%), followed by p.Arg100Ter (16.8%). Three novel variants were identified (p.Gly693Glu, p.Thr394Arg, and p.Asn718Ser). Aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in infants with DJS than in infants with neonatal cholestasis from other causes. Direct bilirubin and total bilirubin were significantly higher in the infants with DJS.
CONCLUSIONS
We found three novel variants in 6 Korean infants with DJS. When AST and ALT levels are normal in infants with neonatal cholestasis, genetic analysis of ABCC2 permits an accurate diagnosis.
Topics: Bilirubin; Cholestasis; Humans; Hyperbilirubinemia; Infant; Infant, Newborn; Jaundice, Chronic Idiopathic; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mutation
PubMed: 32758197
DOI: 10.1186/s12887-020-02260-0