Number Of TA Repeats Research Articles

Взаимосвязь уровня неконьюгированного билирубина и спирометрических показателей у подростков с бронхиальной астмой

Either a high-to-normal or slightly elevated total bilirubin level may have external respiration protective effect in patients with bronchial asthma (BA). However, Authors have searched but not found any studies related to the connection between the unconjugated bilirubin level and spirometric parameters in adolescents. The purpose of this research was to study the connection between unconjugated bilirubin level and spirometric parameters in adolescents with BA. Materials and methods used: a single-center observational cross-sectional pilot study of 74 adolescents aged 10 to 17 y/o with BA was conducted. All participants had undergone measurements of anthropometric and spirometric parameters, hematological parameters, both total and unconjugated bilirubin level. Results: elevated total bilirubin (17.1 mmol/l and higher) occurred in 40.5% (30) being the highest in homozygous carriers of UGT1A1 gene polymorphisms with an increased number of TA repeats, the differences were statistically insignificant. The unconjugated bilirubin level and such spirometric indicators as z-ratio of forced expiratory volume in 1 s (FEV1)/forced vital capacity of the lungs (FVC) and z-criterion of the mean forced expiratory flow during the 25-75% of FVC (MEF25-75) had statistically significant direct correlation (R=0,42, p<0,001, R=0,37, p=0,001, respectively). Patients with obstructive lung ventilation disorders at the time of examination (zFEV1/FVC less than -1.645) had lower levels of both total and unconjugated bilirubin, the differences were statistically significant (p=0.002 and p=0.004, respectively). Conclusion: statistically significant correlations between unconjugated bilirubin level and such spirometric parameters as zFEV1/FVC and zMEF25-75 as well as unconjugated bilirubin low level identification in patients with spirometric indicators of bronchial obstruction suggest a protective effect of unconjugated bilirubin on the development of bronchial obstruction in adolescents with BA.

Molecular genetic aspects of Gilbert's syndrome, Crigler-Najjar syndromes types I and II

Variants of the UGT1A1 gene are associated with impaired bilirubin metabolism, which is clinically expressed in Gilbert's syndrome (GS), Crigler-Najjar syndrome types I and II, as well as increased toxicity intaking certain drugs (indinavir, irinotecan, atazanavir, sorafenib, tocilizumab, belinostat, and paracetamol). A common manifestation of these conditions is unconjugated hyperbilirubinemia. The most common variant in the UGT1A1 gene associated with GS (the most common pathology caused by UGT1A1 gene variants) is the UGT1A1*28 variant, which is an increased number of TA repeats in the promoter of the UGT1A1 gene up to 7. However, the UGT1A1*28 variant is not the only gene variant capable of causing unconjugated hyperbilirubinemia. It is known that the variants UGT1A*7, UGT1A*6, and UGT1A*27 were found in the Asian population, which also causes GS with a high frequency. For Caucasians, the UGT1A1*28 variant remains the only common variant that causes GS. At the same time, even the carriage of the UGT1A1*28 variant in the homozygous state does not always lead to the appearance of clinical symptoms. While in the heterozygous form of the UGT1A1*28 variant, high unconjugated hyperbilirubinemia can be observed. Thus, other molecular genetic markers probably explain the incomplete penetrance and variable expressivity of the clinical manifestations of the UGT1A1 gene variants

EP107: Accurate genotyping of UGT1A1 dinucleotide repeat polymorphism from targeted NGS data for the assessment of irinotecan chemotherapy adverse events

Colorectal cancer (CRC) is a leading cause of cancer-related death across the world. Irinotecan (IRI) is commonly used to treat metastatic CRC. The gene UGT1A1 encodes the enzyme responsible for the glucuronidation of SN-38, the active metabolite of IRI. Wild-type UGT1A1 contains six TA repeats [A(TA)6TAA] in its promoter region (also known as the *1 allele). Polymorphic UGT1A1 alleles with a higher number of TA repeats, such as UGT1A1 *28/(TA)7 and *37/(TA)8 alleles, cause decreased enzyme activity and are associated with severe toxicity in patients receiving IRI-based chemotherapy, for which dose reductions are recommended.

Dependence of blood biochemical parameters on various genotypes of the UGT1A1 gene associated with gilbert's syndrome.

Diagnosis of Gilbert's syndrome is based on the detection of homozygous carriage of an additional TA-repeat in the promoter of the UGT1A1 gene, leading to a decrease in the activity of the UGT enzyme. No large studies have been done in the Russian Federation on the prevalence of carriage of Gilbert's syndrome, as well as the biochemical and molecular profile of such patients. The aim of the study is to evaluate biochemical and molecular genetic parameters in patients with Gilbert's syndrome in Russia. The study included 124 healthy volunteers (group 1) and 5650 patients with suspected Gilbert's syndrome (group 2). The number of TA-repeats of the promoter region of the UGT1A1 gene was determined by the method of fragment analysis for all participants. The following biochemical parameters were analyzed for 299 patients from group 2: the level of bilirubin and its fractions, AST, ALT, cholesterol and LDL. In group 1 the prevalence of genotype (TA)6/(TA)6 was 39,52%, (TA)6/(TA)7 - 53,23%, (TA)7/(TA)7 - 7,26%, no rare forms were found. In group 2 the prevalence of genotype (TA)6/(TA)6 was 6,04%, (TA)6/(TA)7 - 20,05%, (TA)7/(TA)7 - 73,7%, rare alleles - 0,2%. Rare alleles included (TA)5/(TA)6, (TA)5/(TA)7, (TA)6/(TA)8 and (TA)7/(TA)8, as well as a new genotype not described in the literature previously - (TA)7/(TA)9. When assessing the level of total bilirubin and its fractions, a difference was revealed between the genotype of Gilbert's syndrome (TA)7/(TA)7 and the reference genotype (TA)6/(TA)6, and between genotypes (TA)7/(TA)7 and (TA)6/(TA)7. A significant increase in total bilirubin was demonstrated in carriers of a larger number of TA-repeats. There was no significant difference in the concentration of ALT, AST, cholesterol or LDL between different genotypes.The number of TA-repeats of the UGT1A1 gene affects the increase of total bilirubin and its indirect fraction, including the cases of rare allelic variants (TA≤5, TA≥8), but not the activity of ALT and AST and the lipid profile.

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

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.

A Splice Variant of BrrWSD1 in Turnip (Brassica rapa var. rapa) and Its Possible Role in Wax Ester Synthesis under Drought Stress.

Cuticular wax accumulation in plants contributes to drought tolerance. Here, we compared the drought levels on two varieties with different genotypes in turnip (Brassica rapa var. rapa) and found that the drought tolerance was higher in the waxy KTRG-B48a than in the wax-free KTRG-B48b. A combination of PacBio and Illumina sequencing analyses revealed that differential transcripts were mainly enriched in the wax synthesis pathway, and a splice variant (BrrWSD1-X2) was identified in the waxy KTRG-B48a. BrrWSD1-X2 had a stronger ability to synthesize wax esters than BrrWSD1-X1 using heterologous expression in yeast (Saccharomyces cerevisiae) mutant H1246a. Then, we speculated that the T to C transversion of the third intron and the higher number of TA repeats in the third intron of BrrWSD1 DNA in the waxy KTRG-B48a may result in a lower efficiency of splicing recognition of the third intron, resulting in the emergence of BrrWSD1-X2 in waxy varieties.

Frequency of the UGT1A1*28 Polymorphism in a Romanian Cohort of Gilbert Syndrome Individuals.

Gilbert syndrome (GS) is characterized by unconjugated hyperbilirubinemia without liver disease or overt hemolysis and it is found in 3-10% of the general population. Inherited hyperbilirubinaemia is attributable to a reduced UGT1A1 activity. The UGT1A1 promoter (TA) repeats variants are documented of being involved in abnormally elevated bilirubin levels. The aim of the present study is to analyze the impact of UGT1A1 promoter variants on bilirubin levels in Romanian patients clinically supected with GS. The study group included 897 subjects: 292 GS patients and 605 healthy controls. Genomic DNA was extracted from the peripheral blood leukocytes. All individuals were screened for the presence of the (TA) insertion in the TATA box region of UGT1A1 gene by PCR amplification. This case-control study was conducted at the Department of Medical Genetics, Synevo, Romania. UGT1A1*28 (7TA) revealed the highest frequency (61.87%) of all individuals, while the UGT1A1*1 (6TA) allele was found in 36.79%. We identified two other variants of the UGT1A1 gene, depending on the number of TA repeats in the promoter: 5TA (0.61%) and 8TA (0.72%). The (TA)7/7 homozygous genotype was identified in 32.33% of all individuals, while the (TA)6/7 heterozygous genotype was the most prevalent (57.64%). The wild type (TA)6/6 was identified in 7.36% of the whole cohort. Because other polymorphisms have been associated with GS, the absence of the UGT1A1*28 allele does not rule out this condition. The results suggest that in the Romanian population there is a strong correlation between the UGT1A1*28 polymorphism and hyperbilirubinemia in patients with GS.

Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria

IntroductionGender dysphoria, a marked incongruence between one's experienced gender and biological sex, is commonly believed to arise from discrepant cerebral and genital sexual differentiation. With the discovery that estrogen receptor β is associated with female-to-male (FtM) but not with male-to-female (MtF) gender dysphoria, and given estrogen receptor α involvement in central nervous system masculinization, it was hypothesized that estrogen receptor α, encoded by the ESR1 gene, also might be implicated. AimTo investigate whether ESR1 polymorphisms (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 and their haplotypes are associated with gender dysphoria in adults. MethodsMolecular analysis was performed in peripheral blood samples from 183 FtM subjects, 184 MtF subjects, and 394 sex- and ethnically-matched controls. Main Outcome MeasuresGenotype and haplotype analyses of the (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 polymorphisms. ResultsAllele and genotype frequencies for the polymorphism XbaI were statistically significant only in FtM vs control XX subjects (P = .021 and P = .020). In XX individuals, the A/G genotype was associated with a low risk of gender dysphoria (odds ratio [OR] = 0.34; 95% CI = 0.16–0.74; P = .011); in XY individuals, the A/A genotype implied a low risk of gender dysphoria (OR = 0.39; 95% CI = 0.17–0.89; P = .008). Binary logistic regression showed partial effects for all three polymorphisms in FtM but not in MtF subjects. The three polymorphisms were in linkage disequilibrium: a small number of TA repeats was linked to the presence of PvuII and XbaI restriction sites (haplotype S-T-A), and a large number of TA repeats was linked to the absence of these restriction sites (haplotype L-C-G). In XX individuals, the presence of haplotype L-C-G carried a low risk of gender dysphoria (OR = 0.66; 95% CI = 0.44–0.99; P = .046), whereas the presence of haplotype L-C-A carried a high susceptibility to gender dysphoria (OR = 3.96; 95% CI = 1.04–15.02; P = .044). Global haplotype was associated with FtM gender dysphoria (P = .017) but not with MtF gender dysphoria. ConclusionsXbaI-rs9340799 is involved in FtM gender dysphoria in adults. Our findings suggest different genetic programs for gender dysphoria in men and women.Cortés-Cortés J, Fernández R, Teijeiro N, et al. Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria. J Sex Med 2017;14:464–472.

Genetic analysis of a Treponema phagedenis locus encoding antigenic lipoproteins with potential for antigenic variation

Digital dermatitis (DD) is a painful and debilitating claw disease in cattle. Spirochetes of the genus Treponema are found in high numbers in the lesions and are likely to be involved in the pathogenesis. The occurrence of Treponema phagedenis in DD lesions, especially near the interface of healthy and diseased tissue, suggests that this species contributes to the development and/or progression of the lesions. In this study we characterized a genetic locus in T. phagedenis that contains coding regions for three antigenic proteins, PrrA, VpsA, and VpsB. Comparative analysis of homologous loci from fifteen strains suggests that prrA may be transposed into or out of this locus. Alterations in the copy number of TA repeats within the putative promoter region may regulate VpsA/B expression. The vpsA and prrA genes occur in allelic variants in different T. phagedenis isolates and may provide one explanation for the antigenic variation observed in T. phagedenis DD isolates.

Distinct Associations Between UGT1A1 Gene Promoter Polymorphism and Hyperbilirubinemia in Korean CML Patients Treated with Nilotinib and Radotinib

Background: Second-generation BCR-ABL tyrosine kinase inhibitors (2nd generation TKIs) including nilotinib (NIL) and radotinib (RAD) are approved for the treatment of newly diagnosed and other TKI failed chronic myeloid leukemia (CML). Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphism, distinct number of TA repeats in promoter, has been reported for an association with hyperbilirubinemia on nilotinib therapy (Singer et al. Leukemia (2007) 21, 2311–2315). However, the distribution of UGT1A1 (TA)7 repeat polymorphism differs greatly between Caucasians and Japanese, namely, the frequency of UGT1A1(TA)7 repeat polymorphism is high in Caucasians, whereas it is low in Asians (Beutler et al. Proc. Natl. Acad. Sci. USA 95 (1998) 95, 8170–8174 ).Aims: The aim of this study was to investigate the association between UGT1A1 gene promoter polymorphism and hyperbilirubinemia in Korean CML patients treated with NIL and RAD as a frontline therapy.Methods: A total of 88 newly diagnosed chronic phase CML patients who treated with frontline NIL (n=39) and RAD (n=49) was screened for UGT1A1 promoter polymorphism genotype analysis. We used the High Pure PCR Template Preparation Kit (Roche, Germany) to prepare genomic DNA from whole blood and genotyped by direct sequencing of the 253- to 255-bp fragments produced by PCR.Results: The (TA)6/(TA)6 homozygote and (TA)6/(TA)7 heterozygote were seen in all genotyped population and frequency of (TA)6/(TA)6 homozygote was 79.5% (70/88) in our patients. (TA)6/(TA)6 homozygote predominated with 81.6% of the alleles in the RAD group and 76.9% in the NIL group. Relative riskfor each genotype presented in Table 1, with hyperbilirubinemia defined as CTCAE grade 2 or greater observed at any post-baseline point. The relative risks for 6/6 genotype versus 6/7 genotype was 3.5 with 95% CIs of (0.6, 18.9) in the RAD group compared with 8.1 (1.5, 43.8) in the NIL group and NIL group showed significantly high association with UGT1A1 gene promoter polymorphism (P<0.05).Conclusions: This finding suggests that UGT1A1 gene promoter polymorphism may be an important determinant of hyperbilirubinemia in CML patients with NIL therapy, but not in RAD. However other mechanisms should be explored in patients who have significant hyperbilirubinemia with RAD therapy. Updated data with longer follow-up duration will be presented in the meeting.Table 1Relative risk calculations for prevalence of hyperbilirubinemiaRadotinibNilotinibMax grade=,<1Max grade>,=2TotalMax grade=,<1Max grade>,=2Total(TA)6/(TA)6202040(TA)6/(TA)62643050.00%50.00%65.00%10.00%(TA)6/(TA)7279(TA)6/(TA)745922.22%77.78%44.44%55.56%Total222749Total30939Relative risk=3.5, 95% CI of (0.6, 18.9)Relative risk=8.1, 95% CI of (1.5, 43.8)Abbreviation: CI, confidence interval. DisclosuresNo relevant conflicts of interest to declare.

UGT1A1 promoter polymorphism associated with serum bilirubin level in Saudi patients with sickle cell disease

BACKGROUND AND OBJECTIVESPolymorphism in (TA)n of the UGT1A1 promoter influences bilirubin level and risk of gallstones in patients with sickle cell disease (SCD) of African descent. Modifiers of bilirubin level and gallstones in Saudi patients with SCD are not known.DESIGN AND SETTINGSPatients with SCD presenting to participating institutions between July 2009 and July 2012 were enrolled in our study.METHODSA total of 223 SCD patients were enrolled. Laboratory workup at steady state included complete blood count, reticulocytes, serum bilirubin, lactate dehydrogenase (LDH), G6PD level, and hemoglobin (Hb) electrophoresis. The (TA)n UGT1A1 promoter polymorphism and presence of α-thalassemia were also determined.RESULTSTA6/6 in the UGT1A1 promoter was identified in 189 patients (84.7%), TA7/7 in 26 (11.7%), TA5/5 in 6 (2.7%), and TA5/6 in 2 (0.9%). Increased (TA)n of the UGT1A1 promoter (P<.0001), male gender (P=.02), higher LDH (P=.001), and lower Hb level (P=.009) were associated with higher bilirubin level, while the co-inheritance of α-thalassemia (P=.003) was linked with lower bilirubin level. UGT1A1 (TA)n (P<.0001) and Hb level (P=.005) remained significant on multivariate analysis. Gallstones were more frequent in patients with TA7/7 (72%) compared to patients with TA6/6 (57%) and TA5/5 or 5/6 (37%); however, this difference was not statistically significance (P=.18). Older age (P=.0001) and absence of α-thalassemia (P=.03) were associated with higher risk of gallstones.CONCLUSION(TA)n in the UGT1A1 promoter and intensity of hemolysis modify steady-state serum bilirubin level in SCD. Co-inheritance of α-thalassemia reduces the risk of gallstones in Saudi patients with SCD.

Estrogen receptor 1 promoter polymorphism and digit ratio in men

The 2D:4D digit ratio, the relative lengths of the index and ring fingers in humans, is a widely used proxy measure for prenatal testosterone exposure. Varying distributions of androgen and estrogen receptors on the second and fourth digits, both of which regulate digit development, appears to be the basis for this effect. Polymorphism in a tandem repeat in the gene coding for the estrogen receptor α (ESR1) in zebra finches (Taeniopygia guttata) not only explains a significant amount of variation in digit ratio but also seems to explain the significant correlation between digit ratio and sexual behavior in these birds. Here, we investigate the effect of TA polymorphism in ESR1 on 2D:4D and aggressive behavior in men. We genotyped ESR1 polymorphism in samples collected for a previous study in which we had demonstrated an association between androgen receptor polymorphism and aggression, but not 2D:4D. We found a significant effect of ESR1 TA repeat number on left hand 2D:4D ratio. More TA repeats were associated with higher, more feminized, digit ratios. We found no effect on right hand 2D:4D. We also found an effect of ESR1 polymorphism on aggressive behavior. Greater heterozygosity in TA(n) was associated with lower physical aggression. Our results suggest that a significant amount of left hand 2D:4D variation and aggressive behavior is due to this variation in ESR1, and that some of the correlation between digit ratio and social behavior is due to pleiotropic effects of ESR1 variation on the two traits.

Analysis of allelic polymorphism in the ESR1 gene in the Ukraine’s population

In this study analysis of single nucleotide polymorhisms A351G, 397 and number of TA-repeats in ESR1 gene among 199 healthy volunteers from Ukraine was performed. Data concerning genotypes and particular alleles of polymorphic variants distribution were obtained. Possible mechanisms of these polymorphic variants role in ESR1 gene transcription and estrogen receptor expression changes are being discussed.

Abstract 4120: UDP-Glucuronosyltransferase 1 (UGT1A1) down-regulation correlates to menopausal status and stage of disease in human breast cancer tissues

Abstract Estrogen metabolism, catalyzed by UGTs, is a major drug-metabolic pathway that results in the complete inactivation of estrogens and their hydroxylated metabolites. Alterations in UGTs, resulting in decreased UGT expression and glucuronidation activity towards estrogens and their metabolites, has been suggested to play a potential role in breast cancer risk. The purpose of this study was to: 1) compare the mRNA expression levels of UGTs responsible for conjugating estrogens in human breast cancers and normal breast tissues from women; 2) compare UGT1A1 mRNA expression to tumor stage, ER status, ethnicity, and menopausal status in a group of human breast tumors and normal breast tissues, and 3) investigate the association between variations in the number of TA repeats in the promoter region of UGT1A1 to gene expression. Quantification of UGT mRNA in breast tissues revealed that UGT1A4, UGT1A9, UGT1A10, and UGT2B7 mRNA levels were decreased in breast cancers as compared to normal breast tissues. UGT1A1 mRNA levels were also significantly decreased in breast cancers (N = 17) as compared to normal breast tissues (N = 30) (p = 0.02). UGT1A1 down-regulation strongly correlated with menopausal status (premenopausal vs. postmenopausal; p = 0.04) and stage of breast disease (p = 0.01). This may account for variations in response to chemotherapy used for the treatment of more aggressive breast cancers. UGT1A1 mRNA was also decreased in breast tumors as compared to normal breast tissues from both African American and European American women. We postulated that the decreased levels of UGT1A1 mRNA in breast cancers may be due to a genetic variant in the promoter of UGT1A1. In all UGT1A1 genotypes observed in our study, the mean UGT1A1 mRNA expression levels was significantly decreased among breast cancer cases as compared to controls (p = 0.04). Our research findings suggest that further investigations are necessary to determine the role of UGT1A1 in breast carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4120. doi:1538-7445.AM2012-4120

Promoter length polymorphism in UGT1A1 and the risk of sporadic colorectal cancer

Uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) is the key hepatic detoxification enzyme involved in the biotransformation of many carcinogens implicated in the development of colon, breast, and prostate cancers in humans. A polymorphism in the UGT1A1 promoter containing a TA-repeat element [(TA)5-8TAA] is involved in the modulation of UGT1A1 transcriptional activity. The wild-type activity is associated with the (TA)6TAA allele (UGT1A1*1), whereas UGT1A1 expression decreases with the increase of the TA-repeat number. We hypothesize that the low-activity allele UGT1A1*28 with seven TA repeats is associated with a higher risk for colorectal cancer. Our study involved 168 patients with histopathologically confirmed sporadic colorectal cancer and a control group of 96 individuals with no personal history of colorectal cancer. We detected a higher frequency of UGT1A1*28 than the wild-type UGT1A1*1 allele in colorectal cancer patients as compared with that of controls (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.07-2.26, P = 0.021). The frequency of genotypes containing the UGT1A1*28 allele in the homozygous or heterozygous state was significantly higher than the frequency of the wild-type UGT1A1*1/*1 genotype in colorectal cancer patients as compared with controls (OR = 2.0, 95% CI = 1.19-3.34, P = 0.007). Our results indicate that the UGT1A1*28 allele is a risk factor for colorectal cancer in the Macedonian male population, whereas no significant risk was detected among women.

Characterization of UDP-glucuronosyltransferase (UGT1A1) Promoter Polymorphisms and Gene Expression on Ethnicity, Stage of Disease, and Menopausal Status in Breast Cancer.

Estrogen metabolism, catalyzed by UGTs, is a major drug-metabolic pathway that results in inactivation of estrogens and their metabolites. Alterations in UGTs involved in estrogen metabolism, has been suggested to play a role in breast cancer risk. The purpose of this study was to: 1) compare the mRNA expression levels of UGTs involved in estrogen metabolism in human breast tissues from women; 2) compare UGT1A1 mRNA expression to tumor stage, ethnicity, and menopausal status in a group of human breast tumors and normal breast tissues, and 3) investigate the association between variations in the number of TA repeats in the promoter region of UGT1A1 to gene expression. Quantification of UGT mRNA in breast tissues revealed that UGT1A4, UGT1A10, and UGT2B7 mRNA levels were decreased in breast cancers as compared to normal breast tissues. UGT1A1 mRNA levels were also significantly decreased in breast cancers as compared to normal breast tissues (Tumor: 0.5 ± 0.2; Normal: 4.1 ± 1.3, p = 0.0006). UGT1A1 mRNA down-regulation was strongly correlated with postmenopausal status in breast cancer versus controls (p = 0.04). In all the UGT1A1 genotypes observed in our study, the mean mRNA levels was significantly decreased among breast cancer cases as compared to controls for UGT1A1*1/*1 (p = 0.004), UGT1A1*28/*28 (p = 0.03) and UGT1A1*28/*37 (p = 0.06). Our findings demonstrate that further investigations are necessary to determine the role of UGT1A1 in breast carcinogenesis.

ESR1 promoter polymorphism is not associated with nonsyndromic cryptorchidism

The ESR1 promoter microsatellite (TA)n was reported as a potential functional polymorphism. In a case-control study, we were unable to demonstrate any association between (TA)n and nonsyndromic cryptorchidism in Italian and Spanish study populations.

Genotypes and Haplotypes of the Estrogen Receptor Genes, but Not the Retinoblastoma-interacting Zinc Finger Protein 1 Gene, Are Associated with Osteoporosis

Osteoporosis is a common age-related disease with a strong genetic influence. Polymorphisms of ESR1 have consistently been shown to be associated with bone mineral density (BMD) and fracture; however, in regulating bone metabolism, ESR1 interacts with both ESR2 and RIZ1. We therefore examined the effects of polymorphisms in the ESR1, ESR2, and RIZ1 genes and their haplotypes on vertebral fractures and BMD in a case-control study comprising 462 osteoporotic patients and 336 controls. In ESR1, we found the variant C allele of the XbaI polymorphism to be associated with decreased risk of vertebral fractures in women (P < 0.01), whereas in men, the T allele seemed protective (P = 0.05). The variant G allele of the PvuII polymorphism decreased the risk of vertebral fractures independently of lumbar spine BMD in women (P = 0.04) but had no effect in men. Haplotype X-P-H (XbaI:C, PvuII:G, and a high number of TA repeats) was associated with decreased risk of vertebral fractures in women (P = 0.04) but not men. In ESR2, the G allele of the AluI polymorphism was associated with increased fracture risk (P = 0.04), and the haplotype that comprises rs1256031:T and AluI:A increased lumbar spine BMD by 0.04 +/- 0.02 g/cm(2) (P < 0.05) and decreased the risk of vertebral fractures (P = 0.04). There was no effect of the RIZ1 polymorphism on BMD or fracture risk and no evidence of interaction between the polymorphisms and haplotypes thereof. We confirm that genetic variants in ESR1 and ESR2, but not RIZ1, are important in osteoporosis. We found no evidence of interaction between polymorphisms, but we found that the effects of genetic variants in ESR1 might be sex dependent.

The &lt;I&gt;UGT1A1*28&lt;/I&gt; Genotype and the Toxicity of Low-Dose Irinotecan in Patients With Advanced Lung Cancer

The association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan has been controversial, and few studies have examined this association in patients with lung cancer. The aim of this study was to assess the association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan in Japanese patients with lung cancer. From December 2005 through July 2008, 53 Japanese patients with advanced lung cancer who underwent chemotherapy that included low-dose irinotecan (50 or 60 mg/m2) as a single agent or in combination chemotherapy were retrospectively analyzed. Genomic DNA was extracted from peripheral blood. Genotypes for the UGT1A1*28 were denoted as wild-type for 6/6, heterozygous for 6/7, or homozygous for 7/7 depending on the number of TA repeats found in each allele. Of the 53 patients, 42 (79.2%) were wild-type, 9 (17.0%) were heterozygous, and 2 (3.7%) were homozygous for the UGT1A1*28 genotype. The UGT1A1*28 genotype was not associated with grade 3 or 4 neutropenia, thrombocytopia, diarrhea, or febrile neutropenia. The frequency of dose reduction of irinotecan did not differ between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In addition, there were no significant differences in response rates and survival between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In conclusion, the UGT1A1*28 genotype did not predict the severe toxicity of low-dose irinotecan in patients with lung cancer. Therefore, low-dose irinotecan could be administered without reducing starting dose in patients with UGT1A1*28 genotype.

Significant Correlation between Polymorphisms of UGT1A1 Gene and Low Irinotecan Toxicity in Colorectal Cancer Patients with FOLFIRI

Aim: To investigate the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity in Taiwanese patients with metastatic colorectal cancer (mCRC) receiving irinotecan chemotherapy. Methods: We genotyped the UGT1A1 gene by direct sequencing. All the patients were evaluated to see whether the variant UGT1A1 genotype would correlate to severe toxicity of irinotecan consisting of grade III-IV neutropenia, diarrhea and nausea/vomiting. Genomic DNA was genotyped for UGT1A1, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the promoter region. Results: The results showed that the genotype distribution of UGT1A1 in Taiwanese subjects differed significantly from that in Caucasians. Furthermore, patients with 6/7 or 7/7 genotype were associated with a higher incidence of grade III-IV neutropenia or diarrhea or nausea/vomiting (all p < 0.0001). The less frequencies of 6/7 and 7/7 genotypes may be responsible for the considerably lower occurrence of grade III-IV neutropenia and diarrhea in Taiwanese patients. Indeed, the UGT1A1 genotype was closely related to clinical response (p = 0.018). Conclusion: UGT1A1 genotyping is a potential predictor of severe toxicity for Taiwanese mCRC patients treated with irinotecan chemotherapy, and may be useful to identify patients at-risk of toxicity, and thus could be used as a screening tool prior to therapy.