Interindividual differences in drug response are a frequent clinical challenge partly due to variation in pharmacokinetics. ATP-binding cassette (ABC) transporters are crucial determinants of drug ...

ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding?

Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP. A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed. Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients. Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

/pdf/association-of-genetic-polymorphisms-in-genes-involved-in-20v9idwbb8.pdf

Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML)

Resistant disease is still a main obstacle in acute myeloid leukemia (AML) treatment Therefore, individual genetic variations affecting therapy response are gaining increasing importance Both SNPs and ABC transporter genes could already be associated with drug resistance Here, we report allelic variants of MRP1 (ABCC1) SNPs rs129081, rs212090, and rs212091 with significant influences on survival in AML patients DNA was extracted from bone marrow samples (n = 160) at diagnosis Genotyping 48 SNPs within seven different ABC transporter genes using real-time PCR revealed rs129081 GG variant with a significant higher OS (p = 0035) and DFS (p = 001) Comparing TT and AA rs212090 variants showed significant influences on DFS (p = 0021) SNP rs212091 GG expression was associated with worse OS (p = 0006) and a significant difference in DFS between alleles GG and AA (p = 0018) The multivariable models confirmed a significant influence on OS for rs212091 (AA HR = 0296, 95% CI 0113–0774, p = 0013 and GG p = 0044) Rs129081 variant CG, TT of rs212090, AA, and AG of rs212091 demonstrated significant impact on DFS (p = 0024, p = 0029, p = 0017, and p = 0042, respectively) This analysis demonstrates a significant influence of MRP1 SNPs on survival in AML As they were not associated to prognostic characteristics, we suggest these SNPs to be independent prognostic markers for AML

/pdf/multidrug-related-protein-1-mrp1-polymorphisms-rs129081-8c8s89fqbd.pdf

Multidrug-related protein 1 (MRP1) polymorphisms rs129081, rs212090, and rs212091 predict survival in normal karyotype acute myeloid leukemia

Microbes are closely related to human health and diseases. Identification of disease-related microbes is of great significance for revealing the pathological mechanism of human diseases and understanding the interaction mechanisms between microbes and humans, which is also useful for the prevention, diagnosis and treatment of human diseases. Considering the known disease-related microbes are still insufficient, it is necessary to develop effective computational methods and reduce the time and cost of biological experiments. In this work, we developed a novel computational method called MDAKRLS to discover potential microbe-disease associations (MDAs) based on the Kronecker regularized least squares. Specifically, we introduced the Hamming interaction profile similarity to measure the similarities of microbes and diseases besides Gaussian interaction profile kernel similarity. In addition, we introduced the Kronecker product to construct two kinds of Kronecker similarities between microbe-disease pairs. Then, we designed the Kronecker regularized least squares with different Kronecker similarities to obtain prediction scores, respectively, and calculated the final prediction scores by integrating the contributions of different similarities. The AUCs value of global leave-one-out cross-validation and 5-fold cross-validation achieved by MDAKRLS were 0.9327 and 0.9023 ± 0.0015, which were significantly higher than five state-of-the-art methods used for comparison. Comparison results demonstrate that MDAKRLS has faster computing speed under two kinds of frameworks. In addition, case studies of inflammatory bowel disease (IBD) and asthma further showed 19 (IBD), 19 (asthma) of the top 20 prediction disease-related microbes could be verified by previously published biological or medical literature. All the evaluation results adequately demonstrated that MDAKRLS has an effective and reliable prediction performance. It may be a useful tool to seek disease-related new microbes and help biomedical researchers to carry out follow-up studies.

/pdf/mdakrls-predicting-human-microbe-disease-association-based-58plryobam.pdf

MDAKRLS: Predicting human microbe-disease association based on Kronecker regularized least squares and similarities.

Background Intensified treatment of head and neck cancers (HNC): by radiotherapy (RTH) commonly combined with cytotoxic drugs is associated with oral mucositis (OM). Changes in the functioning of nucleotide synthesis pathway (RNR1, coded by RRM1 gene) can modulate the efficiency of cellular DNA repair mechanisms and influence the risk of occurrence and severity of OM in HNC patients after RTH. Objective The objective of this study was to evaluate the correlation between expression of RRM1 gene measured in free circulating RNA (cfRNA) and the risk of more severe OM and disease-free survival (DFS) and overall survival (OS) in patients undergoing RTH for HNC. Methods The study included 60 patients treated with RTH for HNC. RRM1 gene expression was examined in circulating RNA isolated from peripheral blood plasma (before treatment). Results High RRM1 gene expression was significantly associated with higher risk of grade 3 OM after 5 (OR = 4.97), 6 (OR = 4.33) and 7 (OR = 3.50) weeks of RTH. Expression of RRM1 gene was not significantly related with risk of DFS and OS shortening (however well separated Kaplan-Meier curves might suggest its potential prognostic impact). Conclusions The evaluation of RRM1 gene expression in cfRNA allows for estimation of the risk of severe OM in patients subjected to RTH.

RRM1 gene expression evaluated in the liquid biopsy (blood cfRNA) as a non-invasive, predictive factor for radiotherapy-induced oral mucositis and potential prognostic biomarker in head and neck cancer patients.

Gene polymorphisms at microRNA-binding sites (poly-miRTS) may affect gene transcription and expression through miRNA regulation, which is associated with cancer susceptibility, sensitivity to chemotherapy and prognosis. This study investigated the association between poly-miRTS of Ara-C/anthracycline metabolic pathways genes and the outcome of acute myeloid leukemia (AML) in Chinese patients after Ara-C-based chemotherapy. A total of 17 poly-miRTS were selected from the SNPinfo Web Server and genotyped in 206 Chinese Han non-FAB-M3 AML patients using the SEQUENOM Mass-ARRAY system. Among these 17 poly-miRTS, five Ara-C metabolic gene single nucleotide polymorphisms (SNPs, NT5C2 rs10786736 and rs8139, SLC29A1 rs3734703, DCTD rs7278, and RRM1 rs1042919) were identified to significantly associate with complete AML remission and/or overall and relapse-free survival (OS and RFS, respectively), and four anthracycline-metabolic gene SNPs (ABCC1 rs3743527, rs212091, and rs212090 and CBR1 rs9024) were significantly associated with chemotherapy-related toxicities. Moreover, SLC29A1 rs3734703 was shown to associate with both chemotherapy response and survival (adjusted OR 2.561 in the overdominant model; adjusted HR 2.876 for OS and 2.357 for RFS in the dominant model). The data from the current study demonstrated that the poly-miRTS of Ara-C/anthracyclines metabolic genes predicted the sensitivity and side effects of AML to Ara-C-based chemotherapy and patient survival. Further study will confirm them as biomarkers for AML patients after Ara-C-based chemotherapy.

/pdf/polymorphisms-at-microrna-binding-sites-of-ara-c-and-o9yuep0msi.pdf

Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients

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Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients