ABCG2 Single Nucleotide Polymorphisms Research Articles

Impact of ABCG2 Gene Polymorphism on the Predisposition to Psoriasis.

Psoriasis is a chronic inflammatory disease which is caused by the interaction between genetic and environmental factors. Evidence shows an association of psoriasis with co-morbidities including cardiovascular diseases, metabolic syndrome and hyperuricemia. Genome-wide association studies have revealed that the ABCG2 gene encoding ATP-binding cassette G2 protein was associated with inflammation and higher serum urate concentrations. In this study, we aimed to evaluate the role of ABCG2 gene polymorphisms on the susceptibility to psoriasis. The genotype distribution of two ABCG2 single nucleotide polymorphisms (SNPs), rs2231142 and rs2231137, was examined in 410 psoriasis patients and 1,089 gender-matched non-psoriasis controls. We found that heterozygotes (GT) for rs2231142 was associated with a decreased risk of psoriasis (p = 0.001; adjusted OR = 0.532; 95% CI, 0.370–0.765) after adjusting for age, as compared with homozygotes for the major allele (GG). Subjects who carried at least one polymorphic allele (homozygote or heterozygote for the minor allele) were less susceptible to psoriasis (p = 0.002; adjusted OR = 0.594; 95% CI, 0.249–0.823) and bearing higher serum urate levels (p = 0.026) than those homozygous for the major allele. Our results indicated that the ABCG2 gene polymorphism was associated with the risk of psoriasis.

ABCB1 and ABCG2 Together Limit the Distribution of ABCB1/ABCG2 Substrates to the Human Retina and the ABCG2 Single Nucleotide Polymorphism Q141K (c.421C> A) May Lead to Increased Drug Exposure.

The widely expressed and poly-specific ABC transporters breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) are co-localized at the blood-brain barrier (BBB) and have shown to limit the brain distribution of several clinically used ABCB1/ABCG2 substrate drugs. It is currently not known to which extent these transporters, which are also expressed at the blood-retinal barrier (BRB), may limit drug distribution to the human eye and whether the ABCG2 reduced-function single-nucleotide polymorphism (SNP) Q141K (c.421C > A) has an impact on retinal drug distribution. Ten healthy male volunteers (five subjects with the c.421CC and c.421CA genotype, respectively) underwent two consecutive positron emission tomography (PET) scans after intravenous injection of the model ABCB1/ABCG2 substrate [11C]tariquidar. The second PET scan was performed with concurrent intravenous infusion of unlabelled tariquidar to inhibit ABCB1 in order to specifically reveal ABCG2 function.In response to ABCB1 inhibition with unlabelled tariquidar, ABCG2 c.421C > A genotype carriers showed significant increases (as compared to the baseline scan) in retinal radiotracer influx K 1 (+62 ± 57%, p = 0.043) and volume of distribution V T (+86 ± 131%, p = 0.043), but no significant changes were observed in subjects with the c.421C > C genotype. Our results provide the first evidence that ABCB1 and ABCG2 may together limit the distribution of systemically administered ABCB1/ABCG2 substrate drugs to the human retina. Functional redundancy between ABCB1 and ABCG2 appears to be compromised in carriers of the c.421C > A SNP who may therefore be more susceptible to transporter-mediated drug-drug interactions at the BRB than non-carriers.

ABCG2 Single Nucleotide Polymorphism Affects Imatinib Pharmacokinetics in Lower Alpha-1-Acid Glycoprotein Levels in Humans.

Imatinib is transported extracellularly by ABCB1 and ABCG2 efflux transporters and bound to alpha-1-acid glycoprotein (AGP) in the bloodstream. However, the clinical and pharmacokinetic effects of ABCB1 and ABCG2 on imatinib were inconsistent in the previous literature and have not been confirmed. Therefore, in the present study, we explored the effects of the ABCG2 and ABCB1 genetic polymorphisms on imatinib pharmacokinetics in association with plasma AGP levels in healthy subjects. Twenty-seven healthy individuals were recruited, genotyped for ABCG2 and ABCB1, and given a single oral dose of 400 mg imatinib. Plasma imatinib concentrations were measured and its pharmacokinetics was assessed with respect to ABCG2 (c.421C>A and c.34G>A) and ABCB1 (c.1236C>T, c.2677C>T/A, and c.3435C>T) genotypes, and plasma AGP levels. AGP levels showed a strong positive correlation with imatinib pharmacokinetics. ABCG2 c.421C>A single nucleotide polymorphism showed a statistically significant effect on imatinib pharmacokinetics in low plasma AGP levels groups (<80 mg/dl); subjects with high plasma AGP levels (n = 5, ≥80 mg/dl) were excluded. The results indicate that plasma AGP levels and ABCG2 polymorphisms modulated imatinib pharmacokinetics; however, the effects of the ABCG2 transporter was masked at high plasma AGP levels.

Contribution of ABCG2 gene polymorphisms (G34A and C376T) in the prognosis of colorectal cancer

This study aims to assess the association of two single nucleotide polymorphisms (SNPs), G34A and C376T, in the ABCG2 gene with the risk of developing CRC. To the best of our knowledge, this is the first study that determined the role of genetic variations in the ABCG2 gene with the risk of CRC in Saudi Arabia. The gDNA was extracted from the blood of 58 CRC patients and 48 healthy subjects. The DNA sequencing was used to determine the distribution of genotypes. The results showed that CRC patients carried a heterozygous (GA) genotype for SNP G34A had a low risk of developing CRC (odds ratio=0.015, 95% CI [0.00–0.12]; risk ratio=0.35, 95% CI [0.25–0.12], P <0.0001). On the other hand, patients that carried a heterozygous (CT) genotype for SNP C376T had a high risk of developing CRC (odds ratio=13.83, 95% CI [4.31–44.38]; risk ratio=4.88, 95% CI [1.95–12.24], P <0.0001). In conclusion, the results indicated that a heterozygous (GA) genotype in SNP G34A may decrease the risk of CRC development, whereas, the heterozygous (CT) genotype in SNP C376T may increase the risk of CRC. The results may suggest a protective role of ABCG2 SNP G34A against CRC and a deleterious effect of ABCG2 SNP C376T for increasing the risk of CRC.

Fine mapping and identification of serum urate loci in American Indians: The Strong Heart Family Study

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) = 25–44%; P < 3 × 10−14) of solute carrier family 2, member 9 (SLC2A9) and rs41481455, rs2231142 and rs1481012 (MAF = 29%; p < 3 × 10−9) of ATP-binding cassette protein, subfamily G, member 2 (ABCG2). Carriers of G alleles of rs9998811, rs4148155 and rs1481012 and A alleles of rs4481233, rs7696092 and rs13145758 and rs2231142 had lower SU concentrations as compared to non-carriers. Genetic analysis of SU conditional on significant SLC2A9 and ABCG2 SNPs revealed new loci, nucleobindin 1 (NUCB1) and neuronal PAS domain protein 4 (NPAS4) (p <6× 10−6). To identify American Indian-specific SNPs, we conducted targeted sequencing of key regions of SLC2A9. A total of 233 SNPs were identified of which 89 were strongly associated with SU (p < 7.1 × 10−10) and 117 were American Indian specific. Analysis of key SNPs in cohorts of Mexican-mestizos, European, Indian and East Asian ancestries showed replication of common SNPs, including our lead SNPs. Our results demonstrate the association of SU with uric acid transporters in a minority population of American Indians and potential novel associations of SU with neuronal-related genes which warrant further investigation.

Single Nucleotide Polymorphisms (SNPs) of URAT1 (rs7932775) and ABCG2 (rs3825016) on Chronic Kidney Disease Patients with Hyperuricemia

Background: More and more chronic kidney disease (CKD) patients are accompanied with hyperuricaemia. As is known, hyperuricaemia is an independent hazard of both cardiovascular diseases (CVD) and chronic kidney diseases. We aim at identifying Single Nucleotide Polymorphism (SNP) difference of hURAT1 (rs7932775) and ABCG2 (rs3825016) on CKD patient with hyperuricemia and/or gout. Methods: All forty-two CKD patients were divided into two groups: hyperuricemia, and control group. 24 hours urine sample and serum were prepared for testing biochemistry parameters. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method is used to analyze hURAT1 and ABCG2 single nucleotide polymorphisms in different groups. Results: 17 patients have CT SNP of hURAT1 (rs7932775) and 13 patients have CT SNP of ABCG2 (rs3825016) in hyperuricemia group, while only 5 persons and 6 persons have the same mutations in control group respectively. 7 patients have CT SNP of both hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group, while only 2 persons have the same mutations in control group. CT mutation rates of hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group were 60.7% (17/28) and 50% (13/28) respectively, higher than that of control group (35.7% (5/14) and 42.8% (6/14)). What is more, Double SNP mutations in both hURAT1 (rs7932775) and ABCG2 (rs3825016) in hyperuricemia group were 25% (7/28), higher than that of control group (14.2%, 2/14). Conclusion: There are higher mutation rates of CT SNP in hURAT1 (rs7932775) and/or ABCG2 (rs3825016) in hyperuricemia group. We can conclude that hyperuricemia is a high risk factor in progress of CKD, which is necessary to take measures of decreasing serum uric acid to delay CKD progress.

907P - Impact of CYP3A4*22 on pazopanib pharmacokinetics in cancer patients

Background: Pazopanib is characterized by a large interpatient variability in systemic drug exposure. As pazopanib trough levels (>20.5 mg/L) are correlated with clinical outcome (Suttle et al, BJC 2014) in metastatic renal cell carcinoma (mRCC) patients, it is vital to identify factors that influence pazopanib pharmacokinetics (PK). The objective of the current analysis was to evaluate if single nucleotide polymorphisms (SNPs) in the metabolic pathway of pazopanib (i.e. CYP3A4, ABCB1 and ABCG2) affect systemic pazopanib concentrations. Methods: We analyzed 97 patients who participated in 3 pazopanib PK studies. Starting point of the current analysis was a population PK model for pazopanib (Yu et al, Clin Pharmacokinet 2017). Four SNPs located on 3 genes, that were associated with decrease of function were analyzed using real time PCR: CYP3A4 15389 C>T (*22), ABCB1 3435 C>T, and the ABCG2 SNPs 421 C>A, and 34G>A. The influence of these SNPs on pazopanib bioavailability and clearance (CL) was explored with NONMEM. Statistical significance was determined with the likelihood ratio test using the objective function value (OFV). Trough concentrations (Ctrough) at 6 weeks after start with doses of 400 to 800 mg once daily (OD), were simulated. A threshold Ctrough of 20.5 mg/L was used as reference. Results: From 3 patients, insufficient DNA was isolated to run a PCR analysis. All SNPs were in Hardy-Weinberg equilibrium. Eleven patients (12%) had a variant allele at CYP3A4*22, all of whom were heterozygous. Incorporation of CYP3A4*22 in the NONMEM model resulted in a 35% lower CL for the variant carriers (0.18 L/h vs 0.27 L/h; ΔOFV = -7.8; P < 0.01). Simulated median Ctrough of patients with CYP3A4*22 with 400 mg OD, 600 mg OD or 800 mg OD were 16 mg/L, 25 mg/L and 33 mg/L, respectively. Simulated Ctrough for the population excluding the CYP3A4*22 heterozygotes after 800 mg OD was 21 mg/L. No effect of the ABCB1 or ABCG2 SNPs on systemic concentrations were found. Conclusions: Our analysis shows that CYP3A4*22 carriers have a clinically relevant lower pazopanib CL. Prospective analysis should point out whether CYP3A4*22 carriers are at risk for more toxicity and require a lower pazopanib starting dose. Legal entity responsible for the study: Erasmus MC, Rotterdam, The Netherlands Funding: None Disclosure: All authors have declared no conflicts of interest.

A comprehensive analysis of the association of common variants of ABCG2 with gout

The objective of the present study was to determine whether there was an association between single nucleotide polymorphisms (SNPs) in ABCG2 and gout. We recruited 333 participants including 210 patients with gout and 123 controls and genotyped 45 SNPs in both cohorts. We found that 24 SNPs in ABCG2 are susceptibility loci associated with gout. Haplotype analysis revealed five blocks across the ABCG2 locus were associated with an increased risk of gout with odds ratios (ORs) from 2.59–3.17 (all P < 0.0001). A novel finding in the present study was the identification of rs3114018 in block 3 and its association with increased gout risk. We found that the rs2231142T allele in block 2 and the rs3114018C-rs3109823T (C-T) risk haplotype in block 3 conferred the greatest evidence of association to gout risk (P = 1.19 × 10−12 and P = 9.20 × 10−11, respectively). Our study provides an improved understanding of ABCG2 variations in patients with gout and, as shown by haplotype analysis, that ABCG2 may have a role in gout susceptibility.

Population-specific association between ABCG2 variants and tophaceous disease in people with gout

BackgroundTophi contribute to musculoskeletal disability, joint damage and poor health-related quality of life in people with gout. The aim of this study was to examine the role of SLC2A9 and ABCG2 variants in tophaceous disease in people with gout.MethodsParticipants (n = 1778) with gout fulfilling the 1977 American Rheumatism Association (ARA) classification criteria, who were recruited from primary and secondary care, attended a detailed study visit. The presence of palpable tophi was recorded. SLC2A9 rs11942223, ABCG2 rs2231142 and ABCG2 rs10011796 were genotyped. Data were analysed according to tophus status.ResultsCompared to participants without tophi, those with tophi were older, had longer disease duration and higher serum creatinine, and were more likely to be of Māori or Pacific (Polynesian) ancestry. SLC2A9 rs11942223 was not associated with tophi. However, the risk alleles for both ABCG2 single nucleotide polymorphisms (SNPs) were present more frequently in those with tophi (OR (95% CI) 1.24 (1.02–1.51) for rs2231142 and 1.33 (1.01–1.74) for rs10011796, p < 0.05 for both). The effect of rs2231142 was limited to participants of Māori or Pacific ancestry (OR 1.50 (1.14–1.99), p = 0.004), with a significant effect observed in those of Western Polynesian ancestry only (OR 1.71 (1.07–2.72), p = 0.017). The rs10011796 risk allele was strongly associated with tophi in the Western Polynesian group (OR 3.76 (1.61–8.77), p = 0.002), but not in the Eastern Polynesian group (OR 0.87 (0.52–1.46), p = 0.60) nor in the non-Polynesian group (OR 1.16 (0.81–1.66), p = 0.32). The ABCG2 associations persisted in the Western Polynesian group after adjusting for serum urate, creatinine, and disease duration, and when including both ABCG2 variants in the regression models.ConclusionsVariation in ABCG2 function may play a role in the development of tophaceous disease in some populations with high prevalence of severe gout.

Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

ABCB1 and ABCG2 work together at the blood–brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([11C]elacridar and [11C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single‐nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high‐dose tariquidar. In contrast to the ABCB1‐selective substrate (R)‐[11C]verapamil, [11C]elacridar and [11C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [11C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling.

BackgroundIn the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29–44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury.MethodsData from the Chronic Renal Insufficiency Cohort (CRIC; n = 3598) were used to study associations between serum uric acid and single nucleotide polymorphisms (SNPs) on the following uric acid transporters: ABCG2 (BRCP), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC17A1-A3 (NPTs), SLC2A9 (GLUT9), ABCC2 (MRP2) and ABCC4 (MRP4). Regression models, controlling for principal components age, gender and renal function, were run separately for those of European (EA) and African ancestry (AA), and P-values corrected for multiple comparisons. A twin cohort with participants of EA and normal renal function was used for comparison.ResultsAmong those of EA in CRIC, statistically significant signals were observed for SNPs in ABCG2 (rs4148157; beta-coefficient = 0.68; P = 4.78E-13) and SNPs in SLC2A9 (rs13125646; beta-coefficient = −0.30; P = 1.06E-5). Among those of AA, the strongest (but not statistically significant) signals were observed for SNPs in SLC2A9, followed by SNPs in ABCG2. In the twin study (normal renal function), only SNPs in SLC2A9 were significant (rs4481233; beta-coefficient=−0.45; P = 7.0E-6). In CRIC, weaker associations were also found for SLC17A3 (NPT4) and gender-specific associations found for SLC22A8 (OAT3), SLC22A11 (OAT4), and ABCC4 (MRP4).ConclusionsIn patients of EA with CKD (CRIC cohort), we found striking associations between uric acid and SNPs on ABCG2, a key transporter of uric acid by intestine. Compared with ABCG2, SLC2A9 played a much less significant role in this subset of patients with CKD. SNPs in other SLC (e.g. SLC22A8 or OAT3) and ABC (e.g. ABCC4 or MRP4) genes appear to make a weak gender-dependent contribution to uric acid homeostasis in CKD. As renal urate transport is affected in the setting of declining kidney function, extra-renal ABCG2 appears to play a compensatory role—a notion consistent with animal studies and the Remote Sensing and Signaling Hypothesis. Overall, the data indicate how different urate transporters become more or less important depending on renal function, ethnicity and gender. Therapies focused on enhancing ABCG2 urate handling may be helpful in the setting of CKD and hyperuricemia.

ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl-1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl-1 on allopurinol ⩽300 mgd-1 and poor response as SU⩾6 mgdl-1 despite allopurinol >300 mgd-1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70-4.48), P=6.0 × 10-5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl-1 despite allopurinol >300 mgd-1.

Association of ABCG2 rs2231142-A allele and serum uric acid levels in male and obese individuals in a Han Taiwanese population

Recent studies suggest that hyperuricemia is a potential risk factor for cardiovascular disease (CVD). Hyperuricemia is highly heritable and is associated with sex and body weight. Previous genome-wide association studies have found that the ABCG2 single nucleotide polymorphism (SNP) rs2231142 is an important genetic factor for increased uric acid (UA) levels, and the degree of association between rs2231142 and hyperuricemia is affected by both sex and ethnicity. This investigation aimed to analyze the association between ABCG2 polymorphisms and UA levels, as well as their interactions with sex and obesity in Taiwanese. Two genetic polymorphisms around the ABCG2 gene were genotyped in 459 patients. After adjusting for clinical covariates, the rs2231142 SNP was found significantly associated with UA levels using a dominant inheritance model. Patients carrying the rs2231142-A allele had a higher frequency of hyperuricemia than those with the rs2231142-CC allele. Subgroup analysis revealed an association of rs2231142 with UA levels in male or obese patients, and there was no association in nonobese female patients. The rs2231142 SNP is associated with serum UA levels and hyperuricemia in Taiwanese patients and it occurs predominantly in male or obese patients. Hyperuricemia might be controlled differently by sex and obesity.

Association of ABCB1 and ABCG2 single nucleotide polymorphisms with clinical findings and response to chemotherapy treatments in Kurdish patients with breast cancer.

The possible interaction between gene polymorphisms and risk of cancer progression is very interesting. Polymorphisms in multi-drug resistance genes have an important role in response to anti-cancer drugs. The present study was aimed to evaluate the possible effects of ABCB1 C3435T and ABCG2 C421A single nucleotide polymorphisms on clinical and pathological outcomes of Kurdish patients with breast cancer. One hundred breast cancer patients and 200 healthy controls were enrolled in this case-control study. Clinical and pathological findings of all individuals were reported, and immunohistochemistry staining was used to assess the tissue expression of specific breast cancer proteins. The ABCB1 C3435T and ABCG2 C421 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). The distribution of different genotypes between patient and control groups was only significant for ABCG2 C421A. A allele of ABCG2 C421A polymorphisms were significantly higher in patients than in controls. Patients with AA genotype of ABCG2 C421A were at higher risk of progressing breast cancer. Patients with A allele of ABCG2 had complete response to chemotherapeutic agents. There was no statistically significant association between ABCB1 C3435T and ABCG2 C421A polymorphisms and tissue expression of ER, PR, Her2/neu, and Ki67. The ABCB1 C3435T has no correlation with clinical findings and treatment with chemotherapy drugs. The A allele of ABCG2 C421A may be a risk factor for progression of breast cancer in Kurdish patients. In addition, breast cancer patients with C allele of this polymorphism have weaker response to treatments with anthracyclines and Paclitaxol.

Impact of Drug Transporters ABCB1 and ABCG2 and Regulators of Xenobiotic Transport and Metabolism Pxr and CAR Gene Polymorphisms on Clinical Efficacy of Imatinib in Chronic Myeloid Leukemia (CML)

Background: Inherited background in mechanisms regulating cellular uptake, elimination and metabolism of imatinib and other BCR-ABL tyrosine kinase inhibitors may influence treatment outcome in chronic myeloid leukemia (CML). Despite good efficacy of imatinib in CML therapy, a proportion of patients show suboptimal responses or even primary resistance. Imatinib is a well-established substrate of ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). However, the results of published studies regarding impact of ABCB1 and ABCG2 single nucleotide polymorphisms (SNPs) on imatinib treatment outcome have shown discrepant results. Moreover, little is known on the potential role of polymorphisms of regulators of xenobiotic transport and metabolism, pregnane X receptor (PXR, NR1|2) and constitutive androstane receptor (CAR, NR1|3) in imatinib efficacy.Aim: In this study we verified whether 61 tagging SNPs in drug transporters genes (ABCB1 and ABCG2) and regulators of xenobiotic transport and metabolism gene (PXR and CAR) genes affect imatinib therapy outcomes in CML.Methods: Genotyping was performed in 256 patients of Polish Caucasian origin (141 men and 117 women) treated with imatinib as first line treatment (229; 89.5%) or after second-line after interferon therapy (27; 10.5%). Tagging SNP approach was used to select the genetic variants and resulted in a selection of 61 tagging SNPs including 26 SNPs for ABCB1, 17 SNPs for ABCG2, 11 SNPs for PXR and 7 SNPs for CAR gene. Complete clinical data on imatinib treatment outcome were assessable for analyses of associations with tested SNPs. The influence of SNPs on imatinib outcomes including achievement of complete cytogenetic response (CCyR) at 12 months, achievement of major molecular response (MMR) at 18 months, progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. Three inheritance models (co-dominant, dominant and recessive) were tested for all allelic variants.Results: In this study we found that carriers of minor allele of CAR rs4073054A>C SNP significantly associated with shorter TTF on imatinib therapy (OR=2.42, 95%CI 1.41 - 4.17; p=0.0014; Bonferroni corrected p=0.048). In contrast, no impact of other tested allelic variants in ABCB1, ABCG2, PXR and CAR genes on proportion of patients who achieved CCyR at 12 months, MMR at 18 months as well as on probability of PFS, TTF and OS was observed.Conclusion: Our data suggest that inherited variants in the regulator of xenobiotic transport and metabolism CAR gene may modify results of imatinib therapy in CML patients. In contrast, the results of this relatively large study indicate that polymorphic variants in ABCB1, ABCG2 and PXR genes do not seem to play major role as determinants of response to imatinib in CML. DisclosuresRobak:MorphoSys AG: Research Funding.

P1-26-1 - Association of Abc Polymorphism with Antiemetic Efficacy in Cancer Patients Treated with Highly Emetogenic Chemotherapy

Background: Chemotherapy-induced nausea and vomiting (CINV) are one of the most unpleasant non-haematological adverse effects that affect the well-being of cancer patients. The aim of this study was to evaluate the association between the antiemetic efficacy and the ABC genetic polymorphisms and clarify the risk of CINV.Methods: Patients receiving highly emetogenic chemotherapy were examined for antiemetic responses to aprepitant in combination with granisetron and dexamethasone. The efficacy endpoint of this study was complete response (no vomiting and no use of rescue medications). Patient DNA samples were genotyped for ABCB1 and ABCG2 single nucleotide polymorphism. In this study, the impact on complete response of treatment and a number of prespecified risk factors, including gender, age, performance status (PS) and alcohol use was assessed. Complete response and the associations with patients factor including genetic polymorphisms were evaluated in acute and in delayed phases using univariate and multivariate analyses.Results: Sixty-eight patients receiving doxorubicin plus cyclophosphamide chemotherapy and 30 patients receiving cisplatin containing chemotherapy were evaluated. The multivariate logistic regression analyses showed that female gender (odds ratio [OR], 7.17; 95% confidence interval [CI] 1.43-35.82), age <50 years (OR 4.02; 95%CI 1.42-11.36), ABCB1 1236 TT (OR 3.27; 95%CI 1.18-9.07), and ABCG2 421 AA (OR 0.09; 95%CI 0.01-0.93) were associated with antiemetic treatment failure in the acute phase. In contrast, only female gender (OR 14.30; 95%CI 4.38-46.71) was associated in the delayed phase.Conclusions: In addition to gender and age known to be risk factors for CINV, ABC transporter polymorphisms may influence the extent of acute CINV control in aprepitant, granisetron and dexamethasone-treated patients. ABC genotypes might be a predictor of antiemetic response in acute phase.

Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia

Imatinib mesylate (IM) has become a standard of care in chronic myeloid leukemia (CML) therapy. Single nucleotide polymorphisms (SNPs) and altered expression in drug transporter genes may influence IM response. In order to investigate whether mRNA expression and SNPs in drug transporters are associated with IM resistance, we studied 118 chronic-phase CML patients receiving the standard dose of IM (400 mg/day). They were assigned as responders and non-responders according to European LeukemiaNet criteria (2009). mRNA expression in samples at diagnosis (without IM therapy) and outcomes after IM failure were also evaluated in subgroups of patients. Major molecular response (MMR), complete molecular response and primary and secondary resistance were all assessed. BCR-ABL1, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression and SNPs in ABCG2 and SLC22A1 genes were analyzed. ABCG2 mRNA expression in the non-responders was higher before and during IM therapy. Furthermore, ABCG2 was overexpressed in those who did not achieve MMR (P=0.027). In a subgroup of patients who switched to second-generation tyrosine kinase inhibitors, high mRNA expression of ABCG2 was associated with a risk of 24 times that of not achieving complete cytogenetic response (OR 24.00, 95% CI 1.74-330.80; P=0.018). In the responder group, patients who achieved MMR (P=0.009) presented higher mRNA levels of SLC22A1. The SNPs were not associated with mRNA expression of ABCG2 and SLC22A1. Our data suggest that elevated ABCG2 expression (an efflux transporter) could be associated with IM resistance and could impact on second-generation TKI response, whereas high SLC22A1 expression (an influx transporter) may be associated with a successful IM therapy in CML patients.

The ABCG2 Polymorphism rs2725220 Is Associated with Hyperuricemia in the Korean Population.

Elevated serum uric acid levels are associated with a variety of adverse health outcomes, including gout, hypertension, diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Several genome-wide association studies on uric acid levels have implicated the ATP-binding cassette, subfamily G, member 2 (ABCG2) gene as being possibly causal. We investigated an association between the single-nucleotide polymorphism (SNP) rs2725220 in the ABCG2 gene and uric acid levels in the Korean population. A total of 991 subjects in Seoul City were used for a replication study with ABCG2 SNP rs2725220. The rs2725220 SNP in the ABCG2 gene was associated with mean uric acid levels (effect per allele 0.25 mg/dL, p < 0.0001). Subjects with the GC/CC genotype had a 1.78-fold (range, 1.22- to 2.62-fold) higher risk of having abnormal uric acid levels (≥7.0 mg/dL) than subjects with the GG genotype. When analyzed by gender, the association with ABCG2 was stronger in men than in women. The association with ABCG2 was much stronger in male subjects with body mass index (BMI) ≥ 26.4 (odds ratio, 5.09; 95% confidence interval, 2.41 to 10.8) than in male subjects with BMI < 26.4. This study clearly demonstrates that genetic variations in ABCG2 influence uric acid levels in Korean adults.

Urate transporters in the genomic era

Recent advances in genome technology have provided us with a list of molecules affecting urate handling in humans, many of which are unlikely to be identified through traditional physiological approach alone. Although this article is focused on urate, this can be viewed as a successful model of genomics-physiology collaboration. URATv1/GLUT9 (SLC2A9) is shown to play a critical role in urate reabsorption at the proximal tubule, probably more prominent than its partner URAT1 (SLC22A12). The major site of action of ABCG2 (ABCG2), an influential urate secretion transporter, has been shown to be the intestine rather than the kidney proximal tubule. Accordingly, hypofunction of ABCG2 leads to increased fractional excretion of urate, a finding traditionally interpreted as overproduction hyperuricemia. Some SLC17 family members secrete urate in the kidney or intestine. OAT2 (SLC22A7) may take up urate from blood to the proximal tubular cell. In addition, how a common single-nucleotide polymorphisms in ABCG2 affects its function has been elucidated. A finer grained picture of urate handling in the human body is now emerging, which will help choosing novel targets for urate-lowering therapy.

640 - The Predictive Role of MTHFR and ABCG2 Single Nucleotide Polymorphisms on the Outcome of Advanced Colorectal Cancer Treated with First-Line Chemotherapy

ABSTRACT Objective Chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI) has become the mainstay of treatment for advanced colorectal cancer. Since not all patients would benefit from the chemotherapy they received, exploring factors that would predict better effectiveness remains meaningful for understanding the concept of individual treatment. The purpose of this study is to confirm the predictive role of a serial of SNPs, MTHFR C677T, A1298C, ABCG2 G34A and C421A, as well as the clinical features for the efficacy of first-line chemotherapy in advanced colorectal cancer. Methods Patients with advanced colorectal cancer and treated with first-line standard FOLFOX/XELOX or FOLFIRI regimens between January 2009 and May 2011 at Fudan University Shanghai Cancer Center were retrospectively studied. Gene polymorphisms of MTHFR and ABCG2 were detected using gene sequencing method, after DNA extraction from peripheral blood karyocytes and PCR amplification. Results Of all 154 patients, patients with 3 ∼ 4 of the favorable genotypes (MTHFR 677C/C, MTHFR 1298 A/A, ABCG2 G/A or A/A， and ABCG2 421C/A or A/A) had a longer PFS than those with 0 ∼ 2 above genotypes (9.8m vs. 7.5m, P = 0.013; HR = 0.627, 95%CI: 0.427 ∼ 0.920, P = 0.017) The radical resection of primary lesion was also found as an independent factor for both PFS (HR = 0.524, 95%CI: 0.320 ∼ 0.859, P = 0.010) and OS (HR = 0.291, 95%CI: 0.147 ∼ 0.575, P = 0.000). Interestingly, stratified univariate analysis revealed that patients with 2 ∼ 4 genotypes of MTHFR 677C/C、MTHFR 1298 A/C or C/C、ABCG2 34G/G and ABCG2 421C/A or A/A would benefit more from FOLFOX/XELOX than FOLFIRI as first-line chemotherapy (FOLFIRI: HR = 1.722, 95%CI: 1.026 ∼ 2.892, P = 0.040, compared with FOLFOX/XELOX). In contrast, patients with 0 or 1 above-mentioned genotype would have better outcomes if receiving FOLFIRI (FOLFIRI: HR = 0.422, 95%CI: 0.205 ∼ 0.870, P = 0.019, compared with FOLFOX/XELOX). Conclusions SNPs detection may play a predictive role in selecting first-line chemotherapy for advanced colorectal cancer patients. Radical resection of primary lesion is an independent factor for both PFS and OS. Disclosure All authors have declared no conflicts of interest.