Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of Human Uridine Diphosphate Glucuronosyltransferase Genes

Di, Yuan Ming; Chan, Eli; Wei, Ming Q.; Liu, Junping; Zhou, Shu‐Feng

doi:10.1208/s12248-009-9126-z

Cited by 22 publications

(22 citation statements)

References 79 publications

(125 reference statements)

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“…These variants were not associated to hyperbilirubinemia. The potential effect of 63 known UGTs non-synonymous (ns) SNPs on protein function was previously evaluated [40] and data obtained showed that SIFT and Polyphen had a correct prediction rate of 51.1% and 66.7%, respectively. However, we noticed, in the present study, that SIFTS and Polyphen were in divergence, comparing to the other methods, in five of the nine identified variants.…”

Section: Amino Acid Conservationmentioning

confidence: 99%

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

Rodrigues¹,

Vieira²,

Santos³

et al. 2012

Blood Cells, Molecules, and Diseases

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The Gilbert syndrome is a benign form of unconjugated hyperbilirubinemia, mainly associated with alterations in UGT1A1 gene. This work investigated the effect of UGT1A1 variants on total bilirubin levels in Gilbert patients (n = 45) and healthy controls (n = 161). Total bilirubin levels were determined using a colorimetric method; molecular analysis of exons 1-5 and two UGT1A1 promoter regions were performed by direct sequencing and automatic analysis of fragments. Five in silico methods predicted the effect of new identified variants. A significant different allelic distribution, in Gilbert patients and in controls, was found for two promoter polymorphisms. Among patients, 82.2% were homozygous and 17.8% heterozygous for the c.−41_−40dupTA allele; in control group, 9.9% were homozygous and 43.5% heterozygous for this promoter variant, while 46.6% (n = 75) presented the [A(TA) 6 TAA]. For the T>G transition at c.−3279 promoter region, in patients, 86.7% were homozygous and 13.3% heterozygous; in control group, 33.5% were homozygous for the wild type allele, 44.1% were heterozygous and 22.4% homozygous for the mutated allele. The two polymorphisms were in Hardy-Weinberg equilibrium in both groups. Sequencing of UGT1A1 coding region identified nine novel variants, five in patients and four in controls. In silico analysis of these amino acids replacements predicted four of them as benign and three as damaging.In conclusion, we demonstrated that total bilirubin levels are mainly determined by the TA duplication in the TATA-box promoter and by the c.−3279T>G variant. Alterations in the UGT1A1 coding region seem to be associated with increased bilirubin levels, and, therefore, with Gilbert syndrome.

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Section: Amino Acid Conservationmentioning

confidence: 99%

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

Rodrigues¹,

Vieira²,

Santos³

et al. 2012

Blood Cells, Molecules, and Diseases

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“…Recently, 39-43% of nsSNPs in human cytochromes P450 genes were predicted to have functional impacts on enzyme activities in our previous study [122]. In our another study, SIFT predicted 35.5% of the nsSNPs in 21 human uridine diphosphate glucuronosyltransferase genes as deleterious, whereas PolyPhen identified 46.0% of the nsSNPs as potentially damaging and damaging [123]. We also found that both SIFT and PolyPhen classified 60.9-65.4% of nsSNPs in human nuclear receptor genes as being deleterious [124].…”

Section: Discussionmentioning

confidence: 84%

Phenotype Prediction of Non‐Synonymous Single‐Nucleotide Polymorphisms in Human ATP‐Binding Cassette Transporter Genes

Wang

Liu

Meng

et al. 2010

Basic Clin Pharma Tox

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A large number of non-synonymous single-nucleotide polymorphisms (nsSNPs) have been found in human genome, but there is poor knowledge on the relationship between the genotype and phenotype of these nsSNPs. Human ATP-binding cassette (ABC) transporters are able to transport a number of important substrates including endogenous and exogenous compounds. This study aimed to predict the phenotypical impact of nsSNPs of human ABC transporter genes, and the predicted results were further validated by reported phenotypical data from site-directed mutagenesis and clinical genetic studies. One thousand and six hundred thirty-two nsSNPs were found from 49 human ABC transporter genes. Using the PolyPhen and SIFT algorithms, 41.8-53.6% of nsSNPs in ABC transporter genes were predicted to have an impact on protein function. The prediction accuracy was up to 63-85% when compared with known phenotypical data from in vivo and in vitro studies. There was a significant concordance between the prediction results using SIFT and PolyPhen. Of nsSNPs predicted as deleterious, the prediction scores by SIFT and PolyPhen were significantly related to the number of nsSNPs with known phenotypes confirmed by experimental and human studies. The amino acid substitution variants are supposed to be the pathogenetic basis of increased susceptibility to certain diseases with Mendelian or complex inheritance, altered drug resistance and altered drug clearance and response. Predicting the phenotypic consequence of nsSNPs using computational algorithms may provide a better understanding of genetic differences in susceptibility to diseases and drug response. The prediction of nsSNPs in human ABC transporter genes would be useful hints for further genotype-phenotype studies.

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“…The list included four missense mutations, all of which were predicted by Polyphen-2 to be possibly or probably damaging. While Polyphen-2 normally compares favourably with other mutation prediction programs when tested alongside experimental functional data (Di et al 2009;Adzhubei et al 2010;Wei et al 2010), no in silico prediction programs are 100% accurate. With estimated correct prediction rates ranging from 91.7% (Zou et al 2011) to 66.7% (Di et al 2009), a Polyphen-2 deleterious prediction alone is not confirmation a variant is functional.…”

Section: Next Stepsmentioning

confidence: 99%

“…Often, to achieve this validation, variant and wild type versions of the protein are expressed in a relevant cell line, and the function of the protein (e.g. enzymatic activity) is measured (Brunham et al 2005;Di et al 2009;Zou et al 2011). However, for PICALM and CR1, it is not known what aspect of the protein's function is actually implicated in AD pathology, so it would not be obvious what parameter to measure.…”

Section: Next Stepsmentioning

confidence: 99%

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

Lord

Turton

Braae

et al. 2014

Alzheimer's & Dementia

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In 2009, two large genome wide association studies (GWAS) found associations between common single nucleotide polymorphisms (SNPs) at three loci (CLU, PICALM and CR1) and Alzheimer's disease (AD) risk. The causal variants underlying these associations and how these impact on AD susceptibility remain unclear. Target enrichment and next generation sequencing (NGS) were used to completely resequence the three associated loci in 96 AD patients in an attempt to uncover potentially causative and rare variants that may explain the observed association signals. A pipeline was developed for the handling of pooled NGS data following a comparison of several different combinations of programs. 33 exonic SNPs were found within the three genes, along with over 1000 non-coding variants. To identify the variants most likely to be affecting AD risk, a two pronged approach was adopted. The variants were imputed in a large case-control cohort (2067 cases, 7376 controls) to test for association with AD, and the likely functional consequences of the variants were assessed using in silico resources. Several of the analysed variants showed suggestive or significant association with AD in the imputed data, and/or were predicted to have consequences on the function or regulation of the genes, suggesting avenues for future research in AD genetics. The whole method of pooled, targeted NGS and prioritisation using imputed data for association testing and in silico resources for functional analysis represents a new strategy for tracking down the illusive causation of GWAS signals. PublicationsNext generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions. Lord J,

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Prediction of Deleterious Non-synonymous Single-Nucleotide Polymorphisms of Human Uridine Diphosphate Glucuronosyltransferase Genes

Cited by 22 publications

References 79 publications

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

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

Phenotype Prediction of Non‐Synonymous Single‐Nucleotide Polymorphisms in Human ATP‐Binding Cassette Transporter Genes

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

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