Identification of polymorphism in ABCG2 gene in Rathi cattle

Background:The level of uric acid is largely determined by the functions of urate transporters, which are located in the kidney and intestine. The ABCG2 protein is the major excretor of uric acid and its dysfunction may lead to the development of hyperuricemia and gout.Objectives:The aim of our study was to detect the occurrence and frequency of allelic variants in the ABCG2 gene that can lead to impaired function of the ABCG2 protein and to the development of hyperuricemia and gout.Methods:We examined allelic variants of ABCG2 using PCR amplification and Sanger sequencing of all coding regions and exon-intron boundaries in 359 patients with primary hyperuricemia and gout.Results:We found a rare in-frame deletion p.K360del and 15 missense variants, two of which were common (p.V12M, p.Q141K) and 13 were very rare (p.M71V, p.G74D, p.M131I, p.R147W, p.T153M, p.I242T, p.R236X, p.F373C, p.T421A, p.T434M, p.S476P, p.S572R, p.D620N). The p.R236X variant leads to a premature stop codon. The p.V12M variant probably has a protective effect against gout (minor allele frequency – MAF – in our cohort = 0,025 / MAF in the European population = 0,061), while the p.Q141K variant increases the risk of gout (MAF in our cohort = 0,213 / MAF in the European population = 0,094) (1). As for the rare variants, the p.R147W, p.T153M, p.F373C, p.T434M, p.S476P and p.S572R according to functional analyzes reduce the function of the ABCG2 protein (2). Based on in silico prediction, the impact on reduced function is expected for variants p.M71V, p.G74D, p.M131I, p.R147W, p.I242T, p.F373C, p.T434M, p.S476P and p.S572R.Conclusion:Our data suggest that the common variant p.Q141K and most of the rare variants in the ABCG2 gene affect the function of the ABCG2 urate transporter and are a genetic risk factor for hyperuricemia and gout.References:[1]Stiburkova B, et al. Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology (Oxford). 2017 Nov 1; 56(11):1982-1992.[2]Toyoda Y, et al. Functional characterization of clinically-relevant rare variants in ABCG2 identified in a gout and hyperuricemia cohort. Cells. 2019 Apr 18;8(4).Acknowledgements:This study was supported by the project for conceptual development of research organization 00023728 (Institute of Rheumatology) and RVO VFN64165.Disclosure of Interests:None declared

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Prognostic value of the multidrug resistance transporter ABCG2 gene polymorphisms in Chinese patients with de novo acute leukaemia

European Journal of Cancer ◽

10.1016/j.ejca.2011.03.032 ◽

2011 ◽

Vol 47 (13) ◽

pp. 1990-1999 ◽

Cited By ~ 15

Author(s):

Fang Wang ◽

Yong-ju Liang ◽

Xing-ping Wu ◽

Li-ming Chen ◽

Kenneth Kin Wah To ◽

...

Keyword(s):

Multidrug Resistance ◽

Acute Leukaemia ◽

Gene Polymorphisms ◽

Prognostic Value ◽

De Novo ◽

Chinese Patients ◽

Multidrug Resistance Transporter ◽

Abcg2 Gene

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Study of ABCG2 Gene polymorphism in Sahiwal and Hariana Cattle byPstI/PCR-RFLP Assay

Journal of Animal Research ◽

10.5958/2277-940x.2016.00049.8 ◽

2016 ◽

Vol 6 (3) ◽

pp. 475 ◽

Cited By ~ 1

Author(s):

Anita Sharma ◽

Madhu Tiwari ◽

Satyendra Pal Singh ◽

Deepak Sharma ◽

Sumit Kumar ◽

...

Keyword(s):

Gene Polymorphism ◽

Pcr Rflp ◽

Rflp Assay ◽

Abcg2 Gene

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Stroma-Induced Increase In ABCG2 Expression Is Involved In Resistance to Chemotherapy In Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v116.21.972.972 ◽

2010 ◽

Vol 116 (21) ◽

pp. 972-972

Author(s):

Rajesh Singh ◽

Kranthi Kunkalla ◽

Wesley Greaves ◽

Francisco Vega

Keyword(s):

Stromal Cells ◽

Cell Lymphoma ◽

Drug Transporters ◽

B Cell Lymphoma ◽

Drug Transporter ◽

Expression Levels ◽

Large B Cell Lymphoma ◽

Hh Signaling ◽

Abcg2 Gene ◽

Large B Cell

Abstract Abstract 972 Successful treatment of diffuse large B-cell lymphoma (DLBCL) is frequently hindered by development of resistance to conventional chemotherapy resulting in disease relapse and high mortality. High expression of anti-apoptotic and/or drug transporter proteins induced by oncogenic signaling pathways has been implicated in the development of chemoresistance in cancer. However, the cellular mechanisms responsible for drug resistance and treatment failure in DLBCL are poorly understood and their elucidation could lead to development of new therapeutic approaches. Activated Hedgehog (HH) signaling was identified in our laboratory to contribute to DLBCL cell survival and proliferation. We also found that inhibiting HH signaling resulted in decrease of BCL-2 protein and mRNA levels in ABC DLBCL cells but not in GC DLBCL cells, and that the resistance to apoptosis to HH inhibition observed in GC DLBCL cells can be overcome using the BCL2 inhibitor YC137. (Leukemia 2010;24:1025). We also found that the drug transporter protein ABCG2 is a potential prognostic factor in DLBCL given that its expression (as detected by immunohistochemistry) inversely correlated with overall survival and failure-free survival (Mod Pathol 2009;22:1312). Here, we investigate potential mechanistic connections between HH signaling and chemoresistance in DLBCL. Using chromatin immunoprecipitation (ChIP), site directed mutagenesis and luciferase reporter based assays, we confirmed the presence of a GLI-1 transcription factor-binding site in the ABCG2 gene promoter and we established ABCG2 gene as a direct downstream target of HH signaling. We also characterized the baseline expression and functionality of ABCG2 in DLBCL cell lines and explored the role of stroma in modulating its expression levels as well as the expression of other drug transporters (MDR1 and ABCC1) and the levels of the anti-apoptotic proteins, BCL-2, BCL2A1 and BCL-xL. Co-culturing DLBCL cell lines (BJAB and DOHH2) with human bone marrow stromal cells (HS5) resulted in decreased chemosensitivity to doxorubicin and methotrexate that was associated to marked increased expression levels of the drug transporters ABCG2, MDR1 and ABCC1 as well as of the expression levels of BCL2, BCL2A1 and BCL-xL. Our results also showed that pharmacologic inhibition of the activity of ABCG2, using fumitremorgin C and glefanine, significantly increased the chemosensitivity of BJAB and DOHH2 cells in the presence of stromal cells. However, this effect was not seen in the absence of stromal cells. Collectively, our data confirm that the stromal cells plays a role in inducing chemoresistance in DLBCL and that this effect is in part mediated by inducing high expression of drug protein transporters and antiapoptotic proteins. Inhibition of HH signaling as well as inhibition of drug transporters abrogates the stroma-induced chemoresistance suggesting that targeting these molecules may have a therapeutic value for the treatment of DLBCL. Disclosures: No relevant conflicts of interest to declare.

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ABCG2 Polymorphism Is Associated with Lower Major Molecular Response Rates in CML Patients Treated with 400 Mg Imatinib but Not in Patients Treated with 600 Mg Imatinib.

Blood ◽

10.1182/blood.v120.21.2465.2465 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2465-2465

Author(s):

Marc Delord ◽

Philippe Rousselot ◽

Jean-Michel Cayuela ◽

Pascale Loiseau ◽

Odile Maarek ◽

...

Keyword(s):

Cumulative Incidence ◽

Spline Interpolation ◽

Cox Model ◽

Chronic Phase ◽

Lower Probability ◽

Molecular Response ◽

Major Molecular Response ◽

Validation Set ◽

Sokal Score ◽

Abcg2 Gene

Abstract Abstract 2465 Background This study was designed to identify single nucleotide polymorphisms (SNPs) associated with probability of achieving a major molecular response (MMR) in chronic phase CML patients (pts) treated with imatinib. We used a non-commercial, pharmacogenetics-dedicated DNA chip containing 16561 SNPs covering 1916 candidate genes. We tested an exploratory cohort of pts treated with imatinib first line or after interferon therapy and then extended our finding in a validation set of pts included in the French SPIRIT trial (C Preudhomme, NEJM 2011) and randomized to the 400 mg or the 600 mg imatinib arm. Patients and methods Constitutive DNA samples from 312 pts were analyzed: samples from 91 pts in the exploratory set and 221 pts in the validation set (SPIRIT trial: 120 pts within the 400 mg imatinib arm and 101 pts within the 600 mg imatinib arm). We analyzed the expression of BCR-ABL/ABL standardized ratio as a function of the time elapsed since imatinib initiation for each patient using nonlinear (spline) interpolation and then derived the delay to achieve MMR or time of follow-up. With this method, we obtained a cumulative incidence curve of MMR in both groups. Relevant SNPs were identified using a COX model adjusted for covariates (sex, two first principal components and Sokal score when available). SNP with FDR (False Discovery Rate) below 30% in the exploratory cohort where subsequently investigate in the SPIRIT trial groups. Results Patient characteristics such as age, sex, Sokal score were homogeneous between exploratory and validations sets as well as within both arms of the SPIRIT trial. We confirmed the prognostic value of the Sokal score in term of cumulative incidence of MMR (CI-MMR) in both sets of pts (CI-MMR was 83%, 67% and 56% for low, intermediate and hight Sokal risk groups respectively, additive log rank, p < 0.001), as well as the significant improvement of CI-MMR within the SPIRIT trial for pts assigned to the 600 mg daily imatinib arm as compared to the 400 mg daily arm (CI-MMR was 80% in the 600 mg imatinib arm compared to 61% in 400 mg/day arm, log rank, p = 0.008). CI-MMR was similar between exploratory set and the 400 mg/day arm of the SPIRIT trial (63% vs 61%, log rank, p = 0.56) and higher in the 600 mg arm of the SPIRIT trial compared to the exploratory set: 80% vs 63% (log rank, p < 0.001), consistent with dose received in the exploratory set (imatinib 400 mg/d). Association study shows that 10 SNPs identified pts with significantly different probability to achieve MMR within the two first year of therapy (FDR less than 30% p < 0,01) in the exploratory cohort three of which belong to ABCG2 gene. In the SPIRIT trial (n=221), only two SNPs from ABCG2 locus were significantly associated with a higher probability of achieving MMR. We then analyzed separately both arms of the SPIRIT trial. All tree ABCG2-SNPs identified in the exploratory set of pts were significantly associated with CI-MMR in the 400 arm at the 5% level. In contrast, none of them were confirmed in the 600 mg arm. In order generalize our results and to get closer to the underling molecular structure of genotypes markers we performed haplotyping at locus of ABCG2 gene. Multivariate analysis distinguished two minor haplotypes (haplotype 1 and 3) linked to MMR achievement in pts receiving 400 mg/day of imatinib (from exploratory set and SPIRIT, n=211). Haplotypes 1 had G-C-G and haplotype 2 had G-T-G at rs12505410, rs13120400 and rs2725252 respectively and their frequencies were 26 and 6% respectively. Collapsing these haplotypes yielded a surrogate dominant marker highly associated to CI-MMR in this group (p < 0.001, figure 1A) whereas in the SPIRIT 600 mg arm, this phenomenon did not hold anymore (p=0.25, figure 1B). Interestingly, CI-MMR in the 400 mg/day harboring a copy of minor haplotypes (1 or 3) was comparable to the CI-MMR observed in pts receiving 600 mg/d imatinib lacking of at least one copy of the two minor haplotypes (75% vs 70% respectively, p=0.99) or whatever haplotype they had (75% vs 80%, p=0.37). Conclusion The ABCG2 gene product is a well-known protein involved in drug absorption in the bowel. Polymorphism of the ABCG2 gene has been implicated in drugs absorption including imatinib. We here confirm that ABCG2 haplotypes could distinguish patients at a lower probability to achieve MMR. We report for the first time that this unfavorable pharmacologic effect can be overcome in vivo by increasing imatinib daily dose from 400 mg to 600 mg. Disclosures: Rousselot: BMS, Novartis: Research Funding. Guilhot:ARIAD: Honoraria.

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Genotype and allele frequencies of polymorphisms in ABCG2, PPARGC1A and OLR1 genes in indigenous cattle breeds in Turkey

Acta veterinaria ◽

10.2478/acve-2014-0008 ◽

2014 ◽

Vol 64 (1) ◽

pp. 73-80 ◽

Cited By ~ 3

Author(s):

Atila Ateş ◽

Gülhan Türkay Hoştürk ◽

Iraz Akiş ◽

Feraye Esen Gürsel ◽

Hasret Yardibi ◽

...

Keyword(s):

Milk Fat ◽

Autosomal Gene ◽

Zebu Cattle ◽

Peroxisome Proliferator ◽

Nucleotide Polymorphisms ◽

Fat Percentage ◽

Indigenous Cattle ◽

Allele Distribution ◽

Cattle Breeds ◽

Abcg2 Gene

Abstract This study was carried out to determine polymorphisms of four genes in South Anatolian Red (SAR) and East Anatolian Red (EAR) indigenous cattle breeds in Turkey. Single nucleotide polymorphisms (SNPs) monitored in this study are Y581S in ATP binding cassette sub family G member 2 (ABCG2) gene, c.1892T>C and c.3359A>C in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene and g.8232C>A in oxidized low-density lipoprotein receptor 1 (OLR1) gene. The frequency of the ancestral allele A of the ABCG2 gene Y581S polymorphism was found to be very high (SAR: 0.63; EAR: 0.64) in both cattle breeds. The CC genotypes of PPARGC1A gene c.1892T>C (SAR: 0.65; EAR: 0.80) and OLR1 gene g.8232C>A polymorphisms (SAR: 0.82; EAR: 0.86), which are associated with high milk fat percentage, had higher frequencies than those of the other genotypes. In conclusion, we might suggest that the allele distribution of the ABCG2 gene Y581S polymorphism can be the evidence indicating autosomal gene flow from zebu cattle to SAR and EAR cattle breeds.

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