Impact of Solute Carrier Family 29 Member 1 (SLC29A1) Single Nucleotide Polymorphisms on mRNA Expression in Peripheral Blood Mononuclear Cells

Suzuki, Yoshiharu; Homma, Masato; Abei, Masato; Hyodo, Ichinosuke; Kohda, Yukinao

doi:10.1248/bpb.b12-00809

Cited by 12 publications

(9 citation statements)

References 14 publications

(19 reference statements)

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“…The exact impacts of this SNP on treatment responses remain to be determined in future studies. 34,35 The CC variant of ITPA rs1127354 can predict the severity of RBV-induced anemia, as was previously reported. 13,14 Moreover, the severity of RBV-related anemia was inversely correlated with PLT reduction in an East Asian population.…”

Section: Discussionsupporting

confidence: 67%

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Sustained viral response and treatment‐induced cytopenia correlate with SLCs and KLF12 genotypes in interferon/ribavirin‐treated Chinese chronic hepatitis C patients

Mei

Chi

et al. 2016

J of Gastro and Hepatol

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Background and aim: Genetic variations in solute carrier (SLC) genes are associated with liver diseases, and Kruppel-like factor 12 (KLF12) affects the b chain of hemoglobin. We investigated possible correlations of SLC and KLF12 polymorphisms with viral clearance (spontaneous and treatment-induced) and adverse effects in Chinese chronic hepatitis C (CHC) patients. Methods: We genotyped the single nucleotide polymorphisms in 525 CHC patients, 137 patients with spontaneous clearance, and 207 healthy controls. Three hundred fifty-seven CHC patients received recombinant interferon-alpha2b/ribavirin (IFN-α2b/RBV) treatment, and 175 patients were chosen for analysis of drug-induced cytopenia. All raw P-values were corrected by the Bonferroni method. Results: A higher rate of sustained viral response was detected in patients with SLC4A11 rs3810560 CC variant versus TT/TC variant (76.9% vs 59.2%; OR, 2.42; 95% CI, 1.06-5.56, P = 0.037 after adjustment), but there was no significant difference among different hepatitis C virus genotypes. RBV-induced anemia was independently correlated with SLC29A1 rs760370 AA genotype (OR, 2.90; 95% CI, 1.29-6.54, P = 0.010), and the severity of IFN-induced thrombocytopenia was related to GG genotype (OR, 4.98; 95% CI, 1.27-19.61; P = 0.021); the detected effects held true for HCV-2a patients but weakened in HCV-1b patients. A reactive increase in platelet count was closely associated with KLF12 rs9543524 TT variant. Conclusion: SLC4A11 rs3810560 polymorphism independently affected the sustained viral response rates in CHC patients, whereas SLC29A1 rs760370 and KLF12 rs9543524 single nucleotide polymorphisms correlated with treatment-induced adverse events. Clearly, the predictive power varied with HCV genotypes and the reason for genotype-dependent discrepancy was not fully understood.

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Section: Discussionsupporting

confidence: 67%

“…It was also noted that inclusion of telaprevir into dual therapy increased the frequency and/or severity of anemia, augmenting RBV‐related anemia. The exact impacts of this SNP on treatment responses remain to be determined in future studies …”

Section: Discussionmentioning

confidence: 99%

Sustained viral response and treatment‐induced cytopenia correlate with SLCs and KLF12 genotypes in interferon/ribavirin‐treated Chinese chronic hepatitis C patients

Mei

Chi

et al. 2016

J of Gastro and Hepatol

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“…The DCTD rs9990999 AA genotype was associated with a longer duration of neutropenia than the AA or CC genotype. The SLC29A1 rs693955 AA genotype was associated with a longer duration of both neutropenia and thrombocytopenia than the AA or CC genotype mRNA expression [24,25]. However, hENT1 is a limiting determinant of Ara-C efficacy, and the simple diffusion rate of Ara-C exceeds its pump-mediated transport in high plasma concentrations of Ara-C [26].…”

Section: Discussionmentioning

confidence: 99%

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

et al. 2015

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Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

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“…19) Currently, we found differences in SLC29A1 mRNA expression in PBMCs between subjects with wild-type and mutant carriers on rs6932345 (1.20 vs. 0.70). 30) We, therefore, used a cutoff value of 0.7 to discriminate between high and low mRNA expression in the present study's subjects. Since individuals with wild-type rs6932345 provide higher SLC29A1 mRNA expression in PBMCs (0.75-2.77), intestinal RBV absorption might be enhanced in such individuals.…”

Section: Discussionmentioning

confidence: 99%

Effects of Dipyridamole Coadministration on the Pharmacokinetics of Ribavirin in Healthy Volunteers

Suzuki

Homma

Abei

et al. 2013

Drug Metabolism and Pharmacokinetics

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Ribavirin (RBV), a guanosine analog for treatment of hepatitis C, is a substrate of a nucleoside transporter, solute carrier family 29 member 1 (SLC29A1). To clarify the impact of SLC29A1 on the pharmacokinetics of RBV, an open-label, crossover study of single-dose RBV (200 mg, p.o.) with and without coadministration of dipyridamole (DP), an inhibitor of SLC29A1, was performed. Plasma and erythrocyte concentrations of RBV in the control phase and DP phase (25 mg, 3 times daily for 4 days) were compared in 10 healthy volunteers. SLC29A1 mRNA expression in peripheral blood mononuclear cells was also determined. In the DP phase, area under the concentration-time curves (AUC) of RBV in plasma and erythrocytes showed reductions of 23% and 17%, respectively (p < 0.05), with increases in apparent oral clearance of 18% and 25%, respectively (p < 0.05). The reduction rate of the AUC of erythrocyte RBV in the DP phase was associated with SLC29A1 mRNA expression: higher mRNA expression showed greater AUC reduction. The elimination half-life of both plasma and erythrocyte RBV did not differ between the 2 phases. These results suggest that RBV/DP coadministration reduces the concentration of RBV in blood by inhibiting an important role of SLC29A1 in gastrointestinal absorption of RBV.

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Impact of Solute Carrier Family 29 Member 1 (SLC29A1) Single Nucleotide Polymorphisms on mRNA Expression in Peripheral Blood Mononuclear Cells

Cited by 12 publications

References 14 publications

Sustained viral response and treatment‐induced cytopenia correlate with SLCs and KLF12 genotypes in interferon/ribavirin‐treated Chinese chronic hepatitis C patients

Sustained viral response and treatment‐induced cytopenia correlate with SLCs and KLF12 genotypes in interferon/ribavirin‐treated Chinese chronic hepatitis C patients

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

Effects of Dipyridamole Coadministration on the Pharmacokinetics of Ribavirin in Healthy Volunteers

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