Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects

Rodrigues, Carina; Vieira, Emília; Santos, Rosário; Carvalho, João M. S.; Santos-Silva, Alice; Costa, Elı́sio; Bronze-da-Rocha, Elsa

doi:10.1016/j.bcmd.2012.01.004

Cited by 25 publications

(21 citation statements)

References 36 publications

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“…In previous studies, the UGT1A1 rs4124874 (c.-3279T>G) has been found to have an individual effect on bilirubin concentration [6], [7], however, in our study the presence of the rs4124874 G-allele alone was not associated with increased bilirubin concentration. Therefore, our results strongly indicate that the TA 7 -allele of rs8175347 is the predominant UGT1A1 variant being responsible for increased bilirubin concentrations in our population, and not rs4124874.…”

Section: Discussioncontrasting

confidence: 93%

Serum Bilirubin Concentration in Healthy Adult North-Europeans Is Strictly Controlled by the UGT1A1 TA-Repeat Variants

Kringen

Piehler²,

Grimholt

et al. 2014

PLoS ONE

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The major enzyme responsible for the glucuronidation of bilirubin is the uridine 5′-diphosphoglucose glucuronosyltransferase A1 (UGT1A1) enzyme, and genetic variation in the UGT1A1 gene is reported to influence the bilirubin concentration in the blood. In this study, we have investigated which gene-/haplotype variants may be useful for genetic testing of Gilbert's syndrome. Two groups of samples based on serum bilirubin concentrations were obtained from the Nordic Reference Interval Project Bio-bank and Database (NOBIDA): the 150 individuals with the highest bilirubin (>17.5 µmol/L) and the 150 individuals with normal bilirubin concentrations (<17.5 µmol/L). The individuals were examined for the TA6>TA7 variant in the UGT1A1 promoter and 7 tag-SNPs in an extended promoter region of UGT1A1 (haplotype analysis) and in selected SNPs in candidate genes (SLCO1B3, ABCC2 and NUP153). We found significant odds ratios for high bilirubin level for all the selected UGT1A1 variants. However, in stepwise multivariate logistic regression analysis of all genetic variants together with age, sex, country of origin and fasting time, the repeat variants of UGT1A1 TA6>TA7 and SLCO1B3 rs2117032 T>C were the only variants significantly associated with higher bilirubin concentrations. Most individuals with high bilirubin levels were homozygous for the TA7-repeat (74%) while only 3% were homozygous for the TA7-repeat in individuals with normal bilirubin levels. Among individuals heterozygous for the TA7-repeat, a low frequent UGT1A1-diplotype harboring the rs7564935 G-variant was associated with higher bilirubin levels. In conclusion, our results demonstrate that in testing for Gilbert's syndrome, analyzing for the homozygous TA7/TA7-genotype would be appropriate.

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Section: Discussioncontrasting

confidence: 93%

Serum Bilirubin Concentration in Healthy Adult North-Europeans Is Strictly Controlled by the UGT1A1 TA-Repeat Variants

Kringen

Piehler²,

Grimholt

et al. 2014

PLoS ONE

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“…However, the distribution of subjects with respect to UGT1A1 genotypes was similar to that found in previous studies involving Portuguese children with Hereditary Spherocytosis, with a 7/7 frequency of 8.8%(28), as well as Portuguese healthy subjects, with frequencies observed in two studies of 6.3 and 9.9% [28], [31]. Thus, it seems reasonable to assume that the frequency of 7/7 homozygotes in the Portuguese population may be lower than that observed in other Caucasian populations.…”

Section: Discussionsupporting

confidence: 86%

Body Fat Percentage Is a Major Determinant of Total Bilirubin Independently of UGT1A1*28 Polymorphism in Young Obese

et al. 2014

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ObjectivesBilirubin has potential antioxidant and anti-inflammatory properties. The UGT1A1*28 polymorphism (TA repeats in the promoter region) is a major determinant of bilirubin levels and recent evidence suggests that raised adiposity may also be a contributing factor. We aimed to study the interaction between UGT1A1 polymorphism, hematological and anthropometric variables with total bilirubin levels in young individuals.Methods350 obese (mean age of 11.6 years; 52% females) and 79 controls (mean age of 10.5 years; 59% females) were included. Total bilirubin and C-reactive protein (CRP) plasma levels, hemogram, anthropometric data and UGT1A1 polymorphism were determined. In a subgroup of 74 obese and 40 controls body composition was analyzed by dual-energy X-ray absorptiometry.ResultsThe UGT1A1 genotype frequencies were 49.9%, 42.7% and 7.5% for 6/6, 6/7 and 7/7 genotypes, respectively. Patients with 7/7 genotype presented the highest total bilirubin levels, followed by 6/7 and 6/6 genotypes. Compared to controls, obese patients presented higher erythrocyte count, hematocrit, hemoglobin and CRP levels, but no differences in bilirubin or in UGT1A1 genotype distribution. Body fat percentage was inversely correlated with bilirubin in obese patients but not in controls. This inverse association was observed either in 6/7 or 6/6 genotype obese patients. UGT1A1 polymorphism and body fat percentage were the main factors affecting bilirubin levels within obese patients (linear regression analysis).ConclusionIn obese children and adolescents, body fat composition and UGT1A1 polymorphism are independent determinants of total bilirubin levels. Obese individuals with 6/6 UGT1A1 genotype and higher body fat mass may benefit from a closer clinical follow-up.

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“…The establishment of a genotype–phenotype correlation for SNPs of the UGT1A1 gene may be challenging due to the presence of other frequent mutations at the promoter region that could also be associated with elevated bilirubin levels. In fact, in a previous work [Rodrigues et al., ], we identified nine heterozygous SNPs by sequencing analysis of the coding regions of the UGT1A1 gene. Three of these new variants were detected in GS patients (p.E180Q; p.M404T; p.R475C), four were detected in controls (p.I215V; p.M272V; p.V386I; p.I492T), and two were already described in the literature.…”

Section: Discussionmentioning

confidence: 99%

“…Three other variants were expected to have an effect on protein function, p.M404T, p.475C, and p.I492T, and individuals showed total bilirubin levels of 36.6, 51.3, and 5.8 μmol/L, respectively. However, in the presence of the two promoter polymorphisms, c.−41_−40dupTA and c.−3279T>G, higher total bilirubin levels were observed in GS patients and controls, both in heterozygotes and homozygotes [Rodrigues et al., ].…”

Section: Discussionmentioning

confidence: 99%

Performance of In Silico Tools for the Evaluation ofUGT1A1Missense Variants

et al. 2015

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Variations in the gene encoding uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) are particularly important because they have been associated with hyperbilirubinemia in Gilbert's and Crigler-Najjar syndromes as well as with changes in drug metabolism. Several variants associated with these phenotypes are nonsynonymous single-nucleotide polymorphisms (nsSNPs). Bioinformatics approaches have gained increasing importance in predicting the functional significance of these variants. This study was focused on the predictive ability of bioinformatics approaches to determine the pathogenicity of human UGT1A1 nsSNPs, which were previously characterized at the protein level by in vivo and in vitro studies. Using 16 Web algorithms, we evaluated 48 nsSNPs described in the literature and databases. Eight of these algorithms reached or exceeded 90% sensitivity and six presented a Matthews correlation coefficient above 0.46. The best-performing method was MutPred, followed by Sorting Intolerant from Tolerant (SIFT). The prediction measures varied significantly when predictors such us SIFT, polyphen-2, and Prediction of Pathological Mutations on Proteins were run with their native alignment generated by the tool, or with an input alignment that was strictly built with UGT1A1 orthologs and manually curated. Our results showed that the prediction performance of some methods based on sequence conservation analysis can be negatively affected when nsSNPs are positioned at the hypervariable or constant regions of UGT1A1 ortholog sequences.

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Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects

Cited by 25 publications

References 36 publications

Serum Bilirubin Concentration in Healthy Adult North-Europeans Is Strictly Controlled by the UGT1A1 TA-Repeat Variants

Serum Bilirubin Concentration in Healthy Adult North-Europeans Is Strictly Controlled by the UGT1A1 TA-Repeat Variants

Body Fat Percentage Is a Major Determinant of Total Bilirubin Independently of UGT1A1*28 Polymorphism in Young Obese

Performance of In Silico Tools for the Evaluation ofUGT1A1Missense Variants

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