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Serum Bilirubin Concentration in Healthy Adult North-Europeans Is Strictly Controlled by the UGT1A1 TA-Repeat Variants  [PDF]
Marianne K. Kringen, Armin P. Piehler, Runa M. Grimholt, Mimi S. Opdal, Kari Bente F. Haug, Petter Urdal
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090248
Abstract: 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.
Body Fat Percentage Is a Major Determinant of Total Bilirubin Independently of UGT1A1*28 Polymorphism in Young Obese  [PDF]
Luís Belo, Henrique Nascimento, Michaela Kohlova, Elsa Bronze-da-Rocha, Jo?o Fernandes, Elísio Costa, Cristina Catarino, Luísa Aires, Helena Ferreira Mansilha, Petronila Rocha-Pereira, Alexandre Quintanilha, Carla Rêgo, Alice Santos-Silva
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098467
Abstract: Objectives Bilirubin 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. Methods 350 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. Results The 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). Conclusion In 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.
The clinical application of UGT1A1 pharmacogenetic testing: Gene-environment interactions
Sara Marques, Ogechi N Ikediobi
Human Genomics , 2010, DOI: 10.1186/1479-7364-4-4-238
Abstract: The uridine diphosphate glucuronosyltransferase (UGT) enzymes are a superfamily of conjugating enzymes that aid in the excretion of several molecules by transferring one glucuronic acid to their substrates. This makes them more hydrophilic molecules and enables their biliary or renal elimination [1]. This superfamily consists of two families (UGT1, UGT2) and three subfamilies (UGT1A, UGT2A, UGT2B). The UGT2 family comprises eight different proteins encoded by individual genes located on chromosome 4q13, while the first subfamily (UGT1A) comprises nine proteins and is coded by the UGT1A gene, located on chromosome 2q37. This locus contains each isoform's unique exon 1 and the common exons 2-5, present in all transcripts [2]. Some UGT isoforms are tissue specific [3]. There is evidence of substrate overlap, although some substrates are specific for one particular isoform, such as the conjugation of bilirubin, which is mainly catalysed by UGT1A1 [1-3].UGT1A1 is the focus of this report.To date, more than 150 functional polymorphisms have been identified on the UGT1A locus, and 113 functional variants have been identified specifically in UGT1A1 [1,4]. These allelic variations were found in both the exonic and promoter sequences. The most thoroughly studied of these polymorphisms is UGT1A1*28, representing seven thymine-adenine (TA) repeats in the promoter region of UGT1A1. Individuals with this variant have an extra TA repeat in this sequence, whereas the wild-type allele comprises six repeats and is denoted as UGT1A1*1 [1,2,5]. The length of this TA repeat sequence is inversely correlated with the activity of the UGT1A1 enzyme; therefore, the *28 polymorphism results in reduced UGT1A1 activity, which affects the elimination of its drug substrates. When the *28 allele is present on only one chromosome, it results in a 25 per cent decrease in enzyme activity[6] and, when present in a homozygous fashion, UGT1A1 transcription is reduced by 70 per cent [1,2,4,5]. In additio
Relation of Prenatal and Postnatal Status to Calcaneus Quantitative Ultrasound in Adolescents  [PDF]
Acta Medica Okayama , 2012,
Abstract: This study aimed to elucidate the relationship of prenatal and/or postnatal factors, including acquired factors, with the calcaneus stiffness index as measured by quantitative ultrasound (QUS-SI) in adolescents. We recruited 1,143 adolescents with a mean age of 14.8±1.8 years (501 boys and 642 girls). The subjects calcaneus QUS-SI was measured using an ultrasound bone densitometer. We also measured the subjects height, weight, and grip strength. Data on prenatal and postnatal factors were obtained from maternal and child health handbooks. A self-reporting questionnaire was used to obtain information on subjects secondary sexual characteristics and lifestyle factors. We found that maternal weight gain during pregnancy was independently associated with calcaneus QUS-SI in girls, and that grip strength was also significantly associated with calcaneus QUS-SI in both sexes. The present findings suggest that excessive restriction of maternal weight gain would have a negative effect on the calcaneus QUS-SI of girls, and that exercise and strength-building activities are likely to result in a higher calcaneus QUS-SI in both sexes of adolescents.
UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil  [cached]
Yan Wang,Lin Shen,Nong Xu,Jin-Wan Wang
World Journal of Gastroenterology , 2012, DOI: 10.3748/wjg.v18.i45.6635
Abstract: AIM: To evaluate effects of UDP-glucuronosyltransferase1A1 (UGT1A1) and thymidylate synthetase (TS) gene polymorphisms on irinotecan in metastatic colorectal cancer (mCRC). METHODS: 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. RESULTS: 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 wi
Targeted quantitative mass spectrometric immunoassay for human protein variants
Olgica Trenchevska, Dobrin Nedelkov
Proteome Science , 2011, DOI: 10.1186/1477-5956-9-19
Abstract: Presented here is a mass spectrometric immunoassay method for targeted quantitative proteomics analysis of protein modifications. Cystatin C, a cysteine proteinase inhibitor and a potential marker for several pathological processes, was used as a target analyte. An internal reference standard was incorporated into the assay, serving as a normalization point for cystatin C quantification. The precision, linearity, and recovery characteristics of the assay were established. The new assay was also benchmarked against existing cystatin C ELISA. In application, the assay was utilized to determine the individual concentration of several cystatin C variants across a cohort of samples, demonstrating the ability to fully quantify individual forms of post-translationally modified proteins.The mass spectrometric immunoassays can find use in quantifying specific protein modifications, either as a part of a specific protein biomarker discovery/rediscovery effort to delineate the role of these variants in the onset of the disease, progression, and response to therapy, or in a more systematic study to delineate and understand human protein diversity.Protein modifications play important roles in biological process, and can serve as diagnostic indicators of pathological events [1]. However, their detection and quantification is not straightforward because oftentimes these modified forms are only slightly chemically different from their wild-type proteins. Powerful separation methods are thus needed to differentiate protein variants in preparation for subsequent detection. Alternatively, mass spectrometry can detect all protein variants in a single analysis; a MALDI mass spectrum can contain signals from multiple protein variants, as long as the variants (along with the targeted native protein) are not hindered by other overabundant proteins which can dynamically suppress their signals. In that case, some sort of fractionation is still needed, especially when analyzing complex sample
The Effect of UGT1A1 Promoter Polymorphism in the Development of Hyperbilirubinemia and Cholelithiasis in Hemoglobinopathy Patients  [PDF]
Suad AlFadhli, Hassan Al-Jafer, Mays Hadi, Mashael Al-Mutairi, Rasheeba Nizam
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077681
Abstract: Present study was aimed to explore the effect of (TA)n UGT1A1 gene promoter polymorphism on bilirubin metabolism, bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in Sickle-Cell Anemia (SCA) and beta-Thalasemia major (bTH) in Kuwaiti subjects compared to other population. This polymorphism was analyzed and correlated to total bilirubin and cholelithiasis in 270 age, gender, ethnically matched subjects (92 bTH, 116 SCA and 62 Controls) using PCR, dHPLC, fragment analysis and direct sequencing. Four genotypes of UGT1A1 were detected in this study (TA6/6, TA6/7, TA6/8 and TA7/7). (TA)6/8 was found only in four individuals; hence it was not included in the analysis. There was a statistically significant association of genotypes with serum total bilirubin levels in both bTH and SCA groups (p<0.001). Subjects with (TA)7/7 had the highest total serum bilirubin level (178.7±3.5 μmole/l). A significant association was observed between allele (TA)7 and cholelithiasis development (p = 0.0001). The 40%, 67.5% and 100% of SCA with (TA)6/6, (TA)6/7 and (TA)7/7 respectively developed cholelithiasis and were subsequently cholecystectomized. Our results confirm UGT1A1 (TA)7 allele as one of the factors accounting for the hyperbilirubinemia and cholelithiasis observed in SCA and bTH.
Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference
Patrick F McArdle, Brian W Whitcomb, Keith Tanner, Braxton D Mitchell, Alan R Shuldiner, Afshin Parsa
BMC Cardiovascular Disorders , 2012, DOI: 10.1186/1471-2261-12-16
Abstract: Study subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels.Serum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01).Our findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity.Bilirubin is a metabolic byproduct of the breakdown of hemoglobin degradation which itself must be metabolized for appropriate excretion. High levels of bilirubin are associated with decreased risk of coronary heart disease (CHD) and cardiovascular disease (CVD) [1]. While the full spectrum by which bilirubin acts to protect against CVD is not fully understood, there has been evidence of protecting against oxidative stress by reducing reactive oxygen species and possibly having additional anti-atherogenetic properties [2,3]. Previous studies have reported associations of serum bilirubin levels to cardiovascular disease risk factors, including total cholesterol and blood pressure [4-6]. Serum bilirubin levels have also been associated with socioeconomic and behavioral CVD risk factors such as smoking and alcohol intake [7,8]. However, the nature of these associations is unclear, including the potential for residual confounding among serum bilirubin levels and the associated CVD risk factors due to factors measured poorly or not measured
Combined effect of regulatory polymorphisms on transcription of UGT1A1 as a cause of Gilbert syndrome
Katsuyuki Matsui, Yoshihiro Maruo, Hiroshi Sato, Yoshihiro Takeuchi
BMC Gastroenterology , 2010, DOI: 10.1186/1471-230x-10-57
Abstract: In an analysis of 15 patients and 60 normal subjects, we detected 14 polymorphisms and nine haplotypes in the regulatory region. We classified the 4-kbp regulatory region of the patients into: the TATA box including A(TA)7TAA; a phenobarbital responsive enhancer module including c.-3275T>G; and a region including other ten linked polymorphisms. The effect on transcription of these polymorphisms was studied.All haplotypes with A(TA)7TAA had c.-3275T>G and additional polymorphisms. In an in-vitro expression study of the 4-kbp regulatory region, A(TA)7TAA alone did not significantly reduce transcription. In contrast, c.-3275T>G reduced transcription to 69% of that of wild type, and the linked polymorphisms reduced transcription to 88% of wild type. Transcription of the typical regulatory region of the patients was 56% of wild type. Co-expression of constitutive androstane receptor (CAR) increased the transcription of wild type by a factor of 4.3. Each polymorphism by itself did not reduce transcription to the level of the patients, however, even in the presence of CAR.These results imply that co-operation of A(TA)7TAA, c.-3275T>G and the linked polymorphisms is necessary in causing Gilbert syndrome.The elimination pathway of bilirubin in humans is catalyzed exclusively by bilirubin UDP-glucuronosyltransferase (UGT1A1) [1]. Gilbert syndrome is a mild hereditary unconjugated hyperbilirubinemia without liver dysfunction or hemolytic anemia. It is caused by defects of UGT1A1 and is one of the most prevalent congenital metabolic disorders; Gilbert syndrome is found clinically in 3-10% of the population [2-5].The UGT1A1 gene (UGT1A1) has the TATA box and a phenobarbital responsive enhancer module (gtPBREM) in its regulatory region [6,7]. The wild type of TATA box has six repeats of TA, and is conventionally written as A(TA)6TAA [6]. The gtPBREM is an important enhancer module of UGT1A1, comprising a region of 290-bp. It is located approximately 3.5 kbp upstream from the codi
CCRaVAT and QuTie - enabling analysis of rare variants in large-scale case control and quantitative trait association studies
Robert Lawrence, Aaron G Day-Williams, Katherine S Elliott, Andrew P Morris, Eleftheria Zeggini
BMC Bioinformatics , 2010, DOI: 10.1186/1471-2105-11-527
Abstract: We have developed two software tools, CCRaVAT (Case-Control Rare Variant Analysis Tool) and QuTie (Quantitative Trait), which enable efficient large-scale analysis of low frequency and rare variants. Both programs implement a collapsing method examining the accumulation of low frequency and rare variants across a locus of interest that has more power than single variant analysis. CCRaVAT carries out case-control analyses whereas QuTie has been developed for continuous trait analysis.CCRaVAT and QuTie are easy to use software tools that allow users to perform genome-wide association analysis on low frequency and rare variants for both binary and quantitative traits. The software is freely available and provides the genetics community with a resource to perform association analysis on rarer genetic variants.Recent advances in high-throughput genotyping have made large-scale genetic association studies possible. Genome-wide association studies (GWAS) for complex disease have met with unprecedented success in identifying common susceptibility variants. However, the discovered common-frequency single nucleotide polymorphism (SNP) associations do not account for a large proportion of the genetic component of disease. The field is now focusing on the analysis of low frequency and rare variants (i.e. minor allele frequency (MAF) ≤0.05) to investigate if they will help explain the missing heritability in complex trait etiology [1,2]. While the sample sizes currently investigated are large enough for a well-powered GWAS of common variants, they are not large enough to provide sufficient power for the single-point analysis of low frequency/rare variants with small to moderate effect sizes [3]. We have developed association analysis software, CCRaVAT (Case-Control Rare Variant Analysis Tool) and QuTie (Quantitative Trait), which allow the large-scale analysis of low frequency/rare polymorphisms. The software increases power over single marker analysis of these variants by pooli
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