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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 2  |  Page : 99-108

A systemic review of association between UDP glucuronosyltransferase family 1 member A1 (UGT1A1) polymorphisms in Gilbert's syndrome in Sickle Cell Disease


1 Amity University, Noida, Uttar Pradesh, India
2 Savitribai Phule Pune University, Pune, Maharashtra, India
3 Department of Transfusion Medicine and Haemotherapy, All India Institute of Medical Sciences, Mangalagiri, Andhra Pradesh, India

Date of Submission21-Sep-2021
Date of Decision17-Oct-2021
Date of Acceptance25-Oct-2021
Date of Web Publication14-Apr-2022

Correspondence Address:
Anand Bodade
Assistant Professor, Department of Transfusion Medicine and Hemotherapy, All India Institute of Medical Sciences, Mangalagiri 522503, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcsr.jcsr_56_21

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  Abstract 


Gilbert's syndrome (GS) is a benign hereditary disorder of bilirubin metabolism due to a mutation in the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) gene which results in hyperbilirubinaemia and related complications mainly cholelithiasis. It can be co-inherited along with sickle cell anaemia, thalassaemias and other haemoglobinopathies including glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis and cystic fibrosis. More than 100 mutations have been reported in UGT1A1 gene and the most common as insertion of extra (TA) nucleotides in the promoter region of TATA box. The more the number of TA repeats, the higher is the bilirubin levels. These mutations result in a 10%–35% reduction in the UGT1A1 enzyme activity resulting in mild to moderate unconjugated hyperbilirubinaemia and related complications. For diagnosis the mode of inheritance is more important than testing in the patients. However; the inheritance pattern of GS differs in ethnicities. For early diagnosis to prevent worsening of the symptoms and for timely management one should be aware of the inheritance pattern in patient. In this systemic analysis we studied the association between complications in GS with the genotypes and complications. It was found that TA7/7 is more significant in GS with sickle cell disease (SCD) group when compared to healthy controls with 2.2% chances of having this genotype in GS with SCD than healthy controls. The significance of having TA7/7 genotype is similar in GS with SCD and α-thalasaemia group. However, there is a high recommendation to carry out multicentre studies and conduct meta-analyses for establishing universal recommendations.

Keywords: Gilbert's syndrome, haemoglobinopathies, UGT1A1 polymorphisms


How to cite this article:
Sachdeva S, Bodade R, Bodade A. A systemic review of association between UDP glucuronosyltransferase family 1 member A1 (UGT1A1) polymorphisms in Gilbert's syndrome in Sickle Cell Disease. J Clin Sci Res 2022;11:99-108

How to cite this URL:
Sachdeva S, Bodade R, Bodade A. A systemic review of association between UDP glucuronosyltransferase family 1 member A1 (UGT1A1) polymorphisms in Gilbert's syndrome in Sickle Cell Disease. J Clin Sci Res [serial online] 2022 [cited 2022 May 21];11:99-108. Available from: https://www.jcsr.co.in/text.asp?2022/11/2/99/343248




  Introduction Top


Sickle cell disease (SCD) an autosomal recessive (AR) genetic disorder has become a public health issue in most of countries. Its genetic defect is a single nucleotide mutation (GAG codon changing to GTG) of the β-globin gene, which results in glutamate (E/Glu) being substituted by valine (V/Val) at position 6 (E6V substitution). The disorder manifests as a multi-system disorder and patients show varying degrees of anemia due to sickling of red cells leading to hypoxia. These sickle shaped Red cells get stuck in the blood vessels and block the blood flow that causes acute pain crisis and may lead to target organ damage as chronic complication. There are various genotypes observed in patients viz. HbSS, HbSC, HbSD, HbSE, HbSO, HbSβ0 thalassaemia and HbSβ+ thalassaemia.[1]

Gilbert's syndrome (GS) is a benign hereditary disorder of bilirubin metabolism due to a mutation in the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) gene which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme.[1],[2] It is typically inherited as autosomal recessive (AR) and occasionally as autosomal dominant pattern depending on the type of mutation. It can be co-inherited along with SCD, thalassaemias, glucose-6-phosphate dehydrogenase (G6PD) deficiency, cystic fibrosis and hereditary spherocytosis (HS). Bilirubin is a toxic product, formed by the breakdown of haem moiety from red cells and haemoproteins. Free bilirubin is conjugated with glucuronic acid, converted into soluble form and eliminated from the body by UDP-glucuronosyltransferase 1A1 (UGT1A1), a liver enzyme responsible for glucuronidation of bilirubin. The normal range of serum bilirubin is 0.3–1.2 mg/dL.[2],[3],[4],[5],[6]

More than 100 mutations have been reported in UGT1A1 gene which includes different replacement, deletion and insertion of amino acids, but the most common mutation is the insertion of extra (TA) nucleotides in the promoter region of the TATA box. The wild type genotype of the UGT1A1 promoter TATA box contains six repetitions, A (TA) 6TAA, however, the (TA) repeats representing GS can vary between 5 and 8. The more the number of TA repeats, the higher is the bilirubin levels. These mutations result in a 10%–35% reduction in the UGT1A1 enzyme activity, resulting in mild/moderate unconjugated hyperbilirubinaemia (bilirubin levels vary between normal ranges to 6 mg/dL), jaundice and risk of gallstones.[3],[5],[7] Most patients with this syndrome are asymptomatic except for fatigue, abdominal pain, fat intolerance, tiredness, headaches, dizziness or depression and episodes of jaundice.[2],[3],[5],[7],[8]

Usually diagnosis of GS is done by testing unconjugated bilirubin on fasting and bilirubin levels are normal. Alternatively, testing of unconjugated bilirubin levels after the administration of 50 mg nicotinic acid by overnight fasting or calorie restriction of 400-kcal can be done. Later, unconjugated bilirubin is measured after 30–60 min for 5 h after the administration of nicotinic acid (or rifampicin/phenobarbital). Bilirubin levels are increased in patients with GS. At present, these classical tests are being replaced by molecular testing of UGT1A1 through polymerase chain reaction to find the number of repeats and further predicting the manifestations.[4],[9]

The mode of inheritance is more important in the patients. The inheritance pattern of GS differs depending on the ethnicities. It is important to find the co-inheritance pattern of GS in SCD patients and its most common genotypes to sketch a road of early diagnosis to prevent worsening of the symptoms and for timely management.

We, therefore, attempted a systemic review of previously published case–control studies to compare the genotypes of UGT1A1 in SCD patients, thalassaemia compare with healthy controls to find the most common genotypes. Furthermore, we studied the association between complications in GS with the genotype to find the detection through clinical results.


  Material and Methods Top


We conducted a systemic analysis of previously published different studies on GS in SCD associated with thalassaemia. For our literature search, we used keywords such as UGT1A1, Sickle Cell Disease and Gilbert's Syndrome. Eligible studies were retrieved from PubMed, Science Direct and Google Scholar databases. All the references related to GS, gallstone and hyperbilirubinaemia were included. Searching was limited to publications in English language with no restriction of publication period. The reference lists of all potentially eligible articles were searched through PubMed and Google scholar.

Published case–control and observational studies were included provided they met the following criteria: (i) contained the number of patients for the genotypes: TA6/6, TA6/7 and TA7/7; (ii) Included either GS patients with SCD or GS patients with SCD and α or β-thalassaemia; and (iii) reported complications and biological parameters related to GS including gallstones, total bilirubin levels, HbF and Hb levels.

The studies were excluded if the number of patients were not clearly differentiated according to genotype or haemoglobinopathies. Studies those included GS with any other mutations were also excluded.

Data extraction

For all shortlisted studies, the following data was extracted from the original publications: the place of research, year of publication, haemoglobinopathies, genotypes and the number of patients for each genotype, number of patients having gallstones according to genotype, total bilirubin level (mg/dL), HbF (%) and Hb levels (g/dL). The process adopted for retrieval and selection of papers in this analysis is shown in [Figure 1].
Figure 1: Flow diagram for literature searching

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Statistical analysis

The significance of each genotype in GS with SCD was evaluated. The pooled estimate and corresponding 95% confidence interval (CI) limits were calculated based on random effect model to find the association between UGT1A1 polymorphism with SCD and complications related to GS including gallstones, total bilirubin levels, HbF and Hb levels as per the genotypes.

To compare the significance of each genotype in different haemoglobinopathies, high-resolution forest plots were prepared to depict both odds ratio (OR) and 95% CI limits. By forest plot, we evaluated heterogeneity among studies using Q statistic and I2 index, assuming that I2 values of 25%, 50% and 75% represented as low, medium and high heterogeneity, respectively. We considered an I2 value of >50% as indicative of substantial heterogeneity. Pooled estimate was calculated based on the fixed-effects model which was reported using the Woolf's (inverse variance) method. Publication bias was evaluated using Begg's funnel plot and Egger's test. P < 0.05 is considered to be statistically significant.

The analysis was performed using 'R' version 1.0.136 (RStudio Team (2019]). RStudio: Integrated Development for R. RStudio, Inc., Boston, MA URL (http://www.rstudio.com) and 'Meta' R package for (version 4.9-7).


  Observations and Results Top


In our analysis, based on the inclusion criteria, number of patients and their complications were extracted from seventeen studies.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] A total of 2387 GS phenotypes were included in this analysis, 1897 patients having GS with SCD, 95 patients having GS with SCD and α-thalassaemia, 97 patients having GS with SCD and β-thalassaemia and 350 healthy controls. Thus, the above-mentioned studies were divided into four arms for the analysis.

The numbers of patients extracted from each study are documented in [Table 1][10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] according to the genotype and haemoglobinopathies. For complications GS with SCD, out of 17 studies, 11 studies 533 patients having gallstones, 9 studies reported bilirubin levels, 6 studies reported HbF and Hb levels in different genotypes. The extracted data for same has been documented in [Table 2].
Table 1: Description of various studies and cases considered for comparison in different arms

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Table 2: No of patients with gallstones, total bilirubin levels, HbF and Hb levels in patients having GS with SCD

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Significance of UGT1A1 polymorphism in Gilbert's syndrome with sickle cell disease and their complications

Incidence of the pooled estimate for TA6/6 in patients having GS with SCD had the pooled estimate of 16% (12%–21%) and complication of cholelithiasis had the pooled estimate of 28% (13%–50%) as shown in [Figure 2]a and [Figure 2]b, respectively. The pooled mean of total bilirubin levels (mg/dL), HbF (%) and Hb (g/dL) at 95% CI was 3.68 (3.58–3.78), 10.50 (9.93–11.06) and 7.74 (7.33–8.54), respectively, in TA6/TA6 [Figure 2]c, [Figure 2]d and [Figure 2]e.
Figure 2: Forest plots for incidence of TA6/6 in Gilbert's syndrome with sickle cell disease (a), incidence of gallstone in TA6/6 (b), mean total bilirubin levels in TA6/6 (c), mean HbF levels in TA6/6 (d) and mean Hb levels in TA6/6 (e)
>Hb = haemoglobin; CI = confidence intervals; GS = Gilbert's syndrome; SCD = Sickle cell disease; IV = Inverse-Variance weighting;
GLMM = Generalised linear mixed model


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Incidence of the pooled estimate for TA6/7 in patients having GS with SCD had a pooled estimate of 25% (19%–31%) [Figure 3]a. Incidence for cholelithiasis had the pooled estimate of 44% (26%–63%) [Figure 3]b. The pooled mean of total bilirubin levels (mg/dL), HbF (%) and Hb (g/dL) was 3.28 (3.14–3.42), 10.27 (7.93–12.60) and 8.21 (7.90–8.53), respectively, in TA6/TA7 [Figure 3]c, [Figure 3]d and [Figure 3]e.
Figure 3: Forest plots for incidence of TA6/7 in GS with SCD (a), incidence of gallstone in TA6/7 (b), mean total bilirubin levels in TA6/7 (c), mean HbF levels in TA6/7 (d) and mean Hb levels in TA6/7 (e)
Hb = Haemoglobin; CI = Confidence intervals; GS = Gilbert's syndrome; SCD = Sickle cell disease; IV = Inverse Variance weighting;
GLMM = Generalised linear mixed model


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Incidence of the pooled estimate for TA7/7 was 14% (10%–19%) in patients having GS with SCD [Figure 4]a. The pooled estimate was 76% (53%–90%) for incidence of cholelithiasis [Figure 4]b. For TA7/TA7 genotype, the pooled mean total bilirubin levels (mg/dL), HbF (%) and Hb (g/dL) were 6.50 (6.41–6.59), 9.23 (6.39–12.07), 8.02 (7.65–8.39), respectively [Figure 4]c, [Figure 4]d and [Figure 4]e
Figure 4: Forest plots for incidence of TA7/7 in GS with SCD (a), incidence of gallstones in TA7/7 (b), mean total bilirubin levels in TA7/7 (c), mean HbF levels in TA7/7 (d) and (e) mean Hb levels in TA7/7
Hb = haemoglobin; GS = Gilbert's syndrome; SCD = Sickle cell disease; IV = Inverse variance; GLMM = Generalised linear mixed model


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The analysis results for pooled estimated showed that TA6/7 was more significant in patients having GS with SCD (with OR 25% and range of 19%–31% at 95% CI). However, patients with TA7/7 had increased risk of cholelithiasis and so raised bilirubin levels whereas HbF levels were high in patients with TA6/6.

Comparison of different arms

Gilbert's syndrome with sickle cell disease versus healthy controls

The comparative analysis of five studies results indicated an overall pooled OR of 0.96 (P = 0.850) for subgroup analysis of TA6/TA6 [Table 3]. The results concluded that there was no significant association between GS with SCD and healthy control in TA6/TA6, with heterogeneity (I2 = 51.4%, P = 0.083; [Figure 5]a). Whereas, in TA6/TA7, the overall pooled OR was 1.63 (P = 0.067). These results concluded that, there was no any significant association between GS with SCD and healthy control in TA6/TA7, with significant heterogeneity (I2 = 66.7%, P = 0.017; [Figure 5]b). No considerable publication bias was detected by Egger's tests and Begg's correlation test.
Table 3: Statistical Analysis of Studies to compare genotypes between different arms

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Figure 5: Comparison of studies between GS with SCD and Healthy control. (Forest plot using fixed effect model. Horizontal bars indicate the amount of variation (95% confidence intervals of the parameter estimates). Sizes of square indicate weight in the pooled effect size, (a) for TA6/6, (b) TA6/7 and (c) TA7/7)
SCD = Sickle cell disease; CI = Confidence intervals; IV = Inverse-variance weighting


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However, in TA7/TA7 group, the overall pooled OR was 2.18 (95% CI; 1.44–3.41, P = 0.006). These results concluded that, there was a significant association between GS with SCD and healthy control in TA7/TA7, with significant heterogeneity (I2 = 79.1%, P = 0.006). No considerable publication bias detected by Egger's tests and Begg's correlation test [Figure 5]c. Thus TA7/7 is more significant in GS with SCD group when compared to healthy controls. There are 2.18% chances of having this genotype in GS with SCD than healthy controls.

Gilbert's syndrome with sickle cell disease versus Gilbert's syndrome with sickle cell disease and α-thalassaemia

The analysis of three studies indicated an overall pooled OR 0.88 (P = 0.655) for TA6/TA6 with no significant difference between GS with SCD and GS with SCD and α-thalassaemia with less heterogeneity (I2 = 0.0%, P = 0.790; [Figure 6]a).
Figure 6: comparison of studies between GS with SCD and GS with SCD and α-thalassemia.
(Forest plot using fixed effect model. Horizontal bars indicate the amount of variation (95% confidence intervals of the parameter estimates). Sizes of square indicate weight in the pooled effect size, (a) for TA6/6, (b) TA6/7 and (c) TA7/7)
; IV = Inverse-Variance weighting


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In patients with TA6/TA7, the overall pooled OR 1.10 (P = 0.723) with no significant association between GS with SCD and GS with SCD and α-thalassaemia in TA6/TA7, with less significant heterogeneity (I2 = 0%, P = 0.017). No considerable publication bias was detected by Egger's tests and Begg's correlation test [Figure 6]b.

However, in TA7/TA7 group, there was an overall pooled OR 1.01 (P = 0.984) with no significant association between GS with SCD and GS with SCD and α-thalassaemia in TA7/TA7, with significant heterogeneity (I2 = 0%, P = 0.418; [Figure 6]c). The significance of having TA7/7 genotype is similar in GS with SCD and GS with SCD and α-thalasaemia group.


  Discussion Top


Our systemic analysis on the UGT1A1 genetic association with various complications of GS in SCD in 2387 patients having GS with SCD retrieved from 17 studies revealed that TA6/7 is more significant in patients having GS with SCD. However, patients having TA7/7 have increased risk of having high bilirubin levels and cholelithiasis.

From India, only three types of genotypes related DNA polymorphisms in the promoter region of UGT1A1 have been reported: (TA) 6/(TA) 6, (TA) 6/(TA) 7 and (TA) 7/(TA) 7.[20],[21] Other countries such as Africa and America have reported cases of five and eight TA repeats in the promoter region of UGT1A1.[27]

In the Slovenian population, no statistically significant difference was found in genotype frequencies between males and females (P = 0.446). A rare genotype (TA) 7/8 was observed in one Caucasian individual. On family analysis of this patient, it was seen that father had genotype (TA) 6/8 and was the carrier of the (TA) 8 allele. The sister had the genotype (TA) 6/8 and the two brothers had (TA) 7/8.[28]

In an article, three ethnic groups including Caucasians, Africans and Parkana Indians were studied. The homozygous and heterozygous genotypes were significantly different from the two former groups (p = 0.0318).[29] Another study[13] from Nigeria on a group of young SCA patients and healthy controls reported 10 genotypes including TA5/5, 5/6, 5/7, 5/8, 6/6, 6/7, 6/8, 7/7, 7/8 and 8/8. Genotype distributions of the patients and control group were not significantly different (P = 0.09 and P = 0.22, respectively) in them.[13]

The role of the TA repeats and the influence of some other relevant genetic modifiers, βS haplotype, α-thalassaemia and HbF levels were studied in patients with SCD. HbF had a significant negative linear correlation with serum bilirubin (r = −0.304, P = 0.016). There was a significant influence of the βS-globin haplotype and co-existing α-thalassaemia trait on serum bilirubin levels.[26]

TA insertion in the promoter of UGT1A1 can be used as a molecular marker for GS is associated with hyperbilirubinaemia, β-thalassaemia, G6PD deficiency, HS, risk of gallbladder abnormalities and jaundice.

In a similar study[30] from Hyderabad, India the authors had scanned the incidence of gallbladder disease in Indian patients with GS. From 1191 GS patients, 106 patients had cholelithiasis, 18 patients had polyps and 17 had gallbladder wall thickening and were co-related with (TA) repeats and bilirubin levels. The risk of gallstone disease in males and females was 9.0% and 7.1%, respectively.[30]

A study[9] assessed the associated genotypes with the occurrence of cholelithiasis after adjustment of age, sex and body mass index (BMI, kg/m2).[9] There was a significant difference observed in the distribution of the (TA) 7/(TA) 7 genotype between cases and controls (p = 0.02). Genotypes 6/7 and 7/7 show significant association (OR = 2.225, P = 0.001 and OR: 2.101, P = 0.013, respectively) with risk of cholelithiasis.[31] A Jamaican study[22] included the presence of (TA) 5/(TA) 8 repeats unlike in the Indian studies and co-related genotype with gallstone formation. Observed genotypes distributions of the three groups were not significantly different from the values expected under Hardy–Weinberg equilibrium. Patients with genotypes (TA) 7/(TA) 7 and (TA) 7/(TA) 8 were found to be at higher risk for gallstones (P = 7.0 × 10−4, P = 0.005 and P = 0.03).[22] A study[14] on children with SCD reported seven genotypes including (TA) 5/6, 6/6, 6/7, 7/7, 5/7, 7/8 and 8/8. In young children with SCD, (TA) 7/(TA) 7 and (TA) 7/(TA) 8 were significantly associated with gallstones (P = 8.1 × 10−8 and P = 0.01, respectively).

The impact of (TA) repeats on total bilirubin levels was proved in GS patients and healthy controls. In GS patients, the presence of (TA) repeats was associated with significantly increased bilirubin levels. In healthy controls, significant differences in bilirubin levels were obtained comparing individuals (TA) 6/(TA) 6 with (TA) 6/(TA) 7 (P < 0.03). Therefore, it was concluded that total bilirubin levels are dependent on the TA repeats in the TATA-box promoter region.[32]

A study[33] conducted in infants with genotypes (TA) 7/(TA) 7 showed a greater increase in jaundice index during the first 2 days of life than (TA) 6/(TA) 6. No differences were observed between jaundice index increases of (TA) 6/(TA) 6 and (TA) 6/(TA) 7 subjects.[33] A case–control study[34] from Iran concluded no significant difference between TA repeats and jaundice and showed that (TA) 7/(TA) 7 mutations of GS were higher in infants with prolonged jaundice than infants without jaundice.

Our systemic analysis helps to predict complications in patients having GS with SCD. According to the genotype, patient's risk to gallstone and other complications can be predicted. However, for establishing uniform conclusions, there are high recommendations that many multicentre studies should be conducted to know the inheritance pattern of GS in SCD in different regions of world. Future studies concerning the impact of the (TA) repeats in UGT1A1 on multifactor diseases such as gallbladder disorders, jaundice and cancer will help to value the individual risk and optimise therapy, leading to a decrease in the risk of side effects and improvement in the general condition of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sedrak A, Kondamudi NP. Sickle Cell Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482384/. [Last updated on 06 Sep 2021].  Back to cited text no. 1
    
2.
Thoguluva Chandrasekar V, John S. Gilbert Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470200/. [Last updated on 06 Sep 2021].  Back to cited text no. 2
    
3.
Wang X, Chowdhury JR, Chowdhury NR. Bilirubin metabolism: Applied physiology. Curr Paediatr 2006;16:70.  Back to cited text no. 3
    
4.
Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatr 2011;171:11-5.  Back to cited text no. 4
    
5.
Kulkarni RG, Lakshmidevi KB, Ronghe V, Dinesh US. Gilbert's syndrome in healthy blood donors what next?? Asian J Transfus Sci 2016;10:63.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Dabke PS, Colah RB, Ghosh KK, Nadkarni AH. Role of co-inherited Gilbert syndrome on hyperbilirubinemia in Indian beta thalassemia patients. Hematology 2014;19:388-92.  Back to cited text no. 6
    
7.
Gil J, Sąsiadek MM. Gilbert syndrome: The UGT1A1*28 promoter polymorphism as a biomarker of multifactorial diseases and drug metabolism. Biomark Med 2012;6:223-30.  Back to cited text no. 7
    
8.
King D, Armstrong MJ. Overview of Gilbert's syndrome. Drug Ther Bull 2019;57:27-31.  Back to cited text no. 8
    
9.
Bartlett MG, Gourley GR. Assessment of UGT polymorphisms and neonatal jaundice. Semin Perinatol 2011;35:127-33.  Back to cited text no. 9
    
10.
Passon RG, Howard TA, Zimmerman SA, Schultz WH, Ware RE. Influence of bilirubin uridine diphosphate–glucuronosyltransferase 1a promoter polymorphisms on serum bilirubin levels and cholelithiasis in children with sickle cell anemia. J Pediatr Hematol Oncol 2001;23:448-51.  Back to cited text no. 10
    
11.
Carpenter SL, Lieff S, Howard TA, Eggleston B, Ware RE. UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia. Am J Hematol 2008;83:800-3.  Back to cited text no. 11
    
12.
Heeney MM, Howard TA, Zimmerman SA, Ware RE. UGT1A promoter polymorphisms influence bilirubin response to hydroxyurea therapy in sickle cell anemia. J Lab Clin Med 2003;141:279-82.  Back to cited text no. 12
    
13.
Olatunya OS, Albuquerque DM, Akanbi GO, Aduayi OS, Taiwo AB, Faboya OA, et al. Uridine diphosphate glucuronosyl transferase 1A (UGT1A1) promoter polymorphism in young patients with sickle cell anaemia: Report of the first cohort study from Nigeria. BMC Med Genet 2019;20:1-8.  Back to cited text no. 13
    
14.
Chaouch L, Talbi E, Moumni I, Ben Chaabene A, Kalai M, Chaouachi D, et al. Early complication in sickle cell anemia children due to A (TA) nTAA polymorphism at the promoter of UGT1A1 gene. Dis Markers 2013;35:67-72.  Back to cited text no. 14
    
15.
Chaouch L, Kalai M, Chaouachi D, Mallouli F, Hafsia R, Ben Ammar S, et al. Gilbert syndrome acts as a risk factor of developing gallstone among β hemoglobinopathy Tunisian patients. Tunis Med 2015;93:237-41.  Back to cited text no. 15
    
16.
Martins R, Morais A, Dias A, Soares I, Rolão C, Ducla-Soares JL, et al. Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism. J Human Genet 2008;53:524-8.  Back to cited text no. 16
    
17.
Chaar V, Kéclard L, Diara JP, Leturdu C, Elion J, Krishnamoorthy R, et al. Association of UGT1A1 polymorphism with prevalence and age at onset of cholelithiasis in sickle cell anemia. Haematologica 2005;90:188-99.  Back to cited text no. 17
    
18.
de Azevedo LA, Bonazzoni J, Wagner SC, Farias MG, Bittar CM, Daudt L, et al. Do alpha thalassemia, fetal hemoglobin, and the UGT1A1 polymorphism have an influence on serum bilirubin levels and cholelithiasis in patients with sickle cell disease? Mol Diagn Ther 2017;21:437-42.  Back to cited text no. 18
    
19.
Pandey S, Ranjan R, Firdos A, Shah V, Pandey SW, Mishra RM, et al. Relation between the uridine diphosphate glucuronosyltransferase 1a1 polymorphism and the bilirubin levels in sickle cell disease. J Clin Diagn Res 2012;6:821-4.  Back to cited text no. 19
    
20.
Farheen S, Sengupta S, Santra A, Pal S, Dhali GK, Chakravorty M, et al. Gilbert's syndrome: High frequency of the (TA) 7 TAA allele in India and its interaction with a novel CAT insertion in promoter of the gene for bilirubin UDP-glucuronosyltransferase 1 gene. World J Gastroenterol 2006;12:2269-75.  Back to cited text no. 20
    
21.
Italia KY, Jijina FF, Jain D, Merchant R, Nadkarni AH, Mukherjee M, et al. The effect of UGT1A1 promoter polymorphism on bilirubin response to hydroxyurea therapy in hemoglobinopathies. Clin Biochem 2010;43:1329-32.  Back to cited text no. 21
    
22.
Haverfield EV, McKenzie CA, Forrester T, Bouzekri N, Harding R, Serjeant G, et al. UGT1A1 variation and gallstone formation in sickle cell disease. Blood 2005;105:968-72.  Back to cited text no. 22
    
23.
AlFadhli S, Al-Jafer H, Hadi M, Al-Mutairi M, Nizam R. The effect of UGT1A1 promoter polymorphism in the development of hyperbilirubinemia and cholelithiasis in hemoglobinopathy patients. PLoS One 2013;8:e77681.  Back to cited text no. 23
    
24.
Kalotychou V, Antonatou K, Tzanetea R, Terpos E, Loukopoulos D, Rombos Y. Analysis of the A (TA)(n) TAA configuration in the promoter region of the UGT1 A1 gene in Greek patients with thalassemia intermedia and sickle cell disease. Blood Cells Mol Dis 2003;31:38-42.  Back to cited text no. 24
    
25.
Vasavda N, Menzel S, Kondaveeti S, Maytham E, Awogbade M, Bannister S, et al. The linear effects of α-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease. Br J Haematol 2007;138:263-70.  Back to cited text no. 25
    
26.
Adekile A, Kutlar F, McKie K, Addington A, Elam D, Holley L, et al. The influence of uridine diphosphate glucuronosyl transferase 1A promoter polymorphisms, βS-globin gene haplotype, co-inherited α-thalassemia trait and Hb F on steady-state serum bilirubin levels in sickle cell anemia. Eur J Haematol 2005;75:150-5.  Back to cited text no. 26
    
27.
Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: A balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998;95:8170-4.  Back to cited text no. 27
    
28.
Ostanek B, Furlan D, Mavec T, Lukac-Bajalo J. UGT1A1 (TA) n promoter polymorphism – A new case of a (TA) 8 allele in Caucasians. Blood Cells Mol Dis 2007;38:78-82.  Back to cited text no. 28
    
29.
Fertrin KY, Gonçalves MS, Saad ST, Costa FF. Frequencies of UDP-glucuronosyltransferase 1 (UGT1A1) gene promoter polymorphisms among distinct ethnic groups from Brazil. Am J Med Genet 2002;108:117-9.  Back to cited text no. 29
    
30.
Bale G, Avanthi US, Padaki NR, Sharma M, Duvvur NR, Vishnubhotla VR. Incidence and risk of gallstone disease in Gilbert's syndrome patients in Indian population. J Clin Exp Hepatol 2018;8:362-6.  Back to cited text no. 30
    
31.
Tsezou A, Tzetis M, Giannatou E, Spanos I, Roma E, Fretzayas A, et al. Gilbert syndrome as a predisposing factor for cholelithiasis risk in the Greek adult population. Genet Test Mol Biomarkers 2009;13:143-6.  Back to cited text no. 31
    
32.
Rodrigues C, Vieira E, Santos R, de Carvalho J, Santos-Silva A, Costa E, et al. Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects. Blood Cells Mol Dis 2012;48:166-72.  Back to cited text no. 32
    
33.
Bancroft JD, Kreamer B, Gourley GR. Gilbert syndrome accelerates development of neonatal jaundice. J Pediatr 1998;132:656-60.  Back to cited text no. 33
    
34.
Pasha YZ, Kacho MA, Niaki HA, Tarighati M, Alaee E. The association between prolonged jaundice and TATA box dinucleotide repeats in Gilbert's syndrome. J Clin Diagn Res 2017;11:C05-7.  Back to cited text no. 34
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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