Genetic variation in Kruppel like factor 15 is associated with left ventricular hypertrophy in patients with type 2 diabetes: Discovery and replication cohorts.

EBioMedicine. 2017 Mar 30;:

Authors: Patel SK, Wai B, Lang CC, Levin D, Palmer CN, Parry HM, Velkoska E, Harrap SB, Srivastava PM, Burrell LM

Abstract
Left ventricular (LV) hypertrophy (LVH) is a heritable trait that is common in type 2 diabetes and is associated with the development of heart failure. The transcriptional factor Kruppel like factor 15 (KLF15) is expressed in the heart and acts as a repressor of cardiac hypertrophy in experimental models. This study investigated if KLF15 gene variants were associated with LVH in type 2 diabetes. In stage 1 of a 2-stage approach, patients with type 2 diabetes and no known cardiac disease were prospectively recruited for a transthoracic echocardiographic assessment (Melbourne Diabetes Heart Cohort) (n=318) and genotyping of two KLF15 single nucleotide polymorphisms (SNPs) (rs9838915, rs6796325). In stage 2, the association of KLF15 SNPs with LVH was investigated in the Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) type 2 diabetes cohort (n=5631). The KLF15 SNP rs9838915 A allele was associated in a dominant manner with LV mass before (P=0.003) and after (P=0.001) adjustment for age, gender, body mass index (BMI) and hypertension, and with adjusted septal (P<0.0001) and posterior (P=0.004) wall thickness. LVH was present in 35% of patients. Over a median follow up of 5.6years, there were 22 (7%) first heart failure hospitalizations. The adjusted risk of heart failure hospitalization was 5.5-fold greater in those with LVH and the rs9838915 A allele compared to those without LVH and the GG genotype (hazard ratio (HR) 5.5 (1.6-18.6), P=0.006). The association of rs9838915 A allele with LVH was replicated in the Go-DARTS cohort. We have identified the KLF15 SNP rs9838915 A allele as a marker of LVH in patients with type 2 diabetes, and replicated these findings in a large independent cohort. Studies are needed to characterize the functional importance of these results, and to determine if the SNP rs9838915 A allele is associated with LVH in other high risk patient cohorts.

PMID: 28400202 [PubMed - as supplied by publisher]

Pharmacogenetic Tests in Psychiatry: From Fear to Failure to Hype.

J Clin Psychopharmacol. 2016 Aug;36(4):299-304

Authors: de Leon J

PMID: 27269957 [PubMed - indexed for MEDLINE]

Genes affecting warfarin response-interactive or additive?

J Clin Pharmacol. 2015 03;55(3):258-60

Authors: Cavallari LH, Duarte JD

Abstract
Genotypes for cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) contribute significantly to the inter-patient variability in warfarin dose requirements. These genotypes in addition to clinical factors explain approximately 50% of the dose variability in Europeans, but less in other populations. Thus, a large portion of the variability remains unexplained and has been the focus of on-going research. Trials evaluating the clinical utility of genotype-guided warfarin dosing have shown a benefit in Europeans, but not in an ethnically diverse cohort. Identifying and accounting for variants important in non-European populations will likely be necessary before a benefit with genotype-guided dosing will be realized in these populations.

PMID: 25385663 [PubMed - indexed for MEDLINE]

Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing.

Clin Pharmacol Ther. 2017 Apr 11;:

Authors: O'Donnell PH, Wadhwa N, Danahey K, Borden BA, Lee SM, Hall JP, Klammer C, Hussain S, Siegler M, Sorrentino MJ, Davis AM, Sacro YA, Nanda R, Polonsky TS, Koyner JL, Burnet DL, Lipstreuer K, Rubin DT, Mulcahy C, Strek ME, Harper W, Cifu AS, Polite B, Patrick-Miller L, Yeo KJ, Leung EK, Volchenboum SL, Altman RB, Olopade OI, Stadler WM, Meltzer DO, Ratain MJ

Abstract
Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green/genomically favorable, yellow/genomic caution, red/high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. 2279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio [OR]=26.2 [9.0-75.3], p<0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR=2.4 [1.7-3.5], p<0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine. This article is protected by copyright. All rights reserved.

PMID: 28398598 [PubMed - as supplied by publisher]

SNP-based HLA allele tagging, imputation and association with antiepileptic drug-induced cutaneous reactions in Hong Kong Han Chinese.

Pharmacogenomics J. 2017 Apr 11;:

Authors: Gui H, Kwok M, Baum L, Sham PC, Kwan P, Cherny SS

Abstract
Human leukocyte antigen (HLA) genes control the regulation of the human immune system and are involved in immune-related diseases. Population surveys on relationships between single nucleotide polymorphisms (SNP) and HLA alleles are essential to conduct genetic association between HLA variants and diseases. Samples were obtained from our in-house database for epilepsy genetics and pharmacogenetics research. Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation. The performance of our new panel was compared to a recent Han Chinese panel. Finally, genetic associations of HLA variants with mild skin rash were performed on the combined sample of 408 patients. Common SNPs rs2571375 and rs144295468 were found to successfully tag HLA risk alleles A*31:01 and B*13:01, respectively. HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity. The imputation reference panel for the Hong Kong population had comparable performance to the Han Chinese panel due to the large sample size for common HLA alleles, though it retained discordance for imputing rare alleles. No significant genetic associations were found between HLA genetic variants and mild skin rash induced by aromatic antiepileptic drugs. This study provides new information on the genetic structure of HLA regions in the Hong Kong population by identifying tagging SNPs and serving as a reference panel. Moreover, our comprehensive genetic analyses revealed no significant association between HLA alleles and mild skin rash in Hong Kong Han Chinese.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.11.

PMID: 28398356 [PubMed - as supplied by publisher]

Prognostic impact of FOXF1 polymorphisms in gastric cancer patients.

Pharmacogenomics J. 2017 Apr 11;:

Authors: Matsusaka S, Wu AH, Cao S, Hanna DL, Chin K, Yang D, Zhang W, Ning Y, Stintzing S, Sebio A, Sunakawa Y, Stremitzer S, Yamauchi S, Okazaki S, Berger MD, Parekh A, Miyamoto Y, Mizunuma N, Lenz HJ

Abstract
A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P=0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P=0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P=0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.9.

PMID: 28398355 [PubMed - as supplied by publisher]

Global genetic variation of select opiate metabolism genes in self-reported healthy individuals.

Pharmacogenomics J. 2017 Apr 11;:

Authors: Wendt FR, Pathak G, Sajantila A, Chakraborty R, Budowle B

Abstract
CYP2D6 is a key pharmacogene encoding an enzyme impacting poor, intermediate, extensive and ultrarapid phase I metabolism of many marketed drugs. The pharmacogenetics of opiate drug metabolism is particularly interesting due to the relatively high incidence of addiction and overdose. Recently, trans-acting opiate metabolism and analgesic response enzymes (UGT2B7, ABCB1, OPRM1 and COMT) have been incorporated into pharmacogenetic studies to generate more comprehensive metabolic profiles of patients. With use of massively parallel sequencing, it is possible to identify additional polymorphisms that fine tune, or redefine, previous pharmacogenetic findings, which typically rely on targeted approaches. The 1000 Genomes Project data were analyzed to describe population genetic variation and statistics for these five genes in self-reported healthy individuals in five global super- and 26 sub-populations. Findings on the variation of these genes in various populations expand baseline understanding of pharmacogenetically relevant polymorphisms for future studies of affected cohorts.The Pharmacogenomics Journal advance online publication, 11 April 2017; doi:10.1038/tpj.2017.13.

PMID: 28398354 [PubMed - as supplied by publisher]

The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

Transl Psychiatry. 2017 Apr 11;7(4):e1086

Authors: Soeiro-de-Souza MG, Lafer B, Moreno RA, Nery FG, Chile T, Chaim K, da Costa Leite C, Machado-Vieira R, Otaduy MC, Vallada H

Abstract
Calcium channels control the inflow of calcium ions into cells and are involved in diverse cellular functions. The CACNA1C gene polymorphism rs1006737 A allele has been strongly associated with increased risk for bipolar disorder (BD) and with modulation of brain morphology. The medial prefrontal cortex (mPFC) has been widely associated with mood regulation in BD, but the role of this CACNA1C polymorphism in mPFC morphology and brain aging has yet to be elucidated. One hundred seventeen euthymic BD type I subjects were genotyped for CACNA1C rs1006737 and underwent 3 T three-dimensional structural magnetic resonance imaging scans to determine cortical thickness of mPFC components (superior frontal cortex (sFC), medial orbitofrontal cortex (mOFC), caudal anterior cingulate cortex (cACC) and rostral anterior cingulate cortex (rACC)). Carriers of the CACNA1C allele A exhibited greater left mOFC thickness compared to non-carriers. Moreover, CACNA1C A carriers showed age-related cortical thinning of the left cACC, whereas among A non-carriers there was not an effect of age on left cACC cortical thinning. In the sFC, mOFC and rACC (left or right), a negative correlation was observed between age and cortical thickness, regardless of CACNA1C rs1006737 A status. Further studies investigating the direct link between cortical thickness, calcium channel function, apoptosis mechanism and their underlying relationship with aging-associated cognitive decline in BD are warranted.

PMID: 28398341 [PubMed - in process]

Testing Na(+) in blood.

Clin Kidney J. 2017 Apr;10(2):147-148

Authors: Lava SA, Bianchetti MG, Milani GP

Abstract
Both direct potentiometry and indirect potentiometry are currently used for Na(+) testing in blood. These measurement techniques show good agreement as long as protein and lipid concentrations in blood remain normal. In severely ill patients, indirect potentiometry commonly leads to relevant errors in Na(+) estimation: 25% of specimens show a disagreement between direct and indirect potentiometry, which is ≥4 mmol/L (mostly spuriously elevated Na(+) level due to low circulating albumin concentration). There is a need for increased awareness of the poor performance of indirect potentiometry in some clinical settings.

PMID: 28396732 [PubMed - in process]

What's new about oral treatments in Multiple Sclerosis? Immunogenetics still under question.

Pharmacol Res. 2017 Apr 07;:

Authors: Pistono C, Osera C, Boiocchi C, Mallucci G, Cuccia M, Bergamaschi R, Pascale A

Abstract
Multiple Sclerosis (MS) is a chronic pathology affecting the Central Nervous System characterized by inflammatory processes that lead to demyelination and neurodegeneration. In MS treatment, disease modifying therapies (DMTs) are essential to reduce disease progression by suppressing the inflammatory response responsible for promoting lesion formation. Recently, in addition to the classical injectable DMTs like Interferons and Glatiramer acetate, new orally administered drugs have been approved for MS therapy: dimethyl fumarate, teriflunomide and fingolimod. These drugs act with different mechanisms on the immune system, in order to suppress the harmful inflammatory process. An additional layer of complexity is introduced by the influence of polymorphic gene variants in the Human Leukocyte Antigen region on the risk of developing MS and its progression. To date, pharmacogenomic studies have mainly focused on the patient's response following admission of injectable drugs. Therefore, greater consideration must be made to pharmacogenomics with a view to developing more effective and personalized therapies. This review aims to shed light on the mechanism of action of the new oral drugs dimethyl fumarate, teriflunomide and fingolimod, taking into account both the importance of immunogenetics in drug response and pharmacogenomic studies.

PMID: 28396093 [PubMed - as supplied by publisher]

A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification.

Semin Oncol. 2017 Feb;44(1):24-33

Authors: Boisdron-Celle M, Metges JP, Capitain O, Adenis A, Raoul JL, Lecomte T, Lam YH, Faroux R, Masliah C, Poirier AL, Berger V, Morel A, Gamelin E

Abstract
We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FU(ODPM Tox)) followed by PK-guided dose optimization (5-FU(ODPM Protocol)). An advanced cetuximab PK/pharmacodynamics (PD) study was performed but dosage remained unchanged. Eighty-five patients receiving second-line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247 ± 50, 210 ± 53 and 140 ± 21 mg/m(2) for those with 6/6 (33), 6/7 (26), and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency, but mean 5-FU dose at 3 months was 2,412 ± 364 mg/m(2) (1,615-3,170 mg/m(2)). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9%, and 0% of patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes. The objective response rate was 25.8% among the 85 patients, 57.3% in patients with tumors wild type (WT) for KRAS, and 25% in those whose tumor harbored a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median progression-free survival (PFS) for all 85 patients was 181 days and 200, 132, and 121 days for patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes, respectively; these differences were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy. We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification.

PMID: 28395759 [PubMed - in process]

Genetic study of neuregulin 1 and receptor tyrosine-protein kinase erbB-4 in tardive dyskinesia.

World J Biol Psychiatry. 2017 Apr 10;:1-5

Authors: Zai CC, Tiwari AK, Chowdhury NI, Yilmaz Z, de Luca V, Müller DJ, Potkin SG, Lieberman JA, Meltzer HY, Voineskos AN, Remington G, Kennedy JL

Abstract
OBJECTIVES: Tardive dyskinesia (TD) is a movement disorder that may develop as a side effect of antipsychotic medication. The aetiology underlying TD is unclear, but a number of mechanisms have been proposed.
METHODS: We investigated single-nucleotide polymorphisms (SNPs) in the genes coding for neuregulin-1 and erbB-4 receptor in our sample of 153 European schizophrenia patients for possible association with TD.
RESULTS: We found the ERBB4 rs839523 CC genotype to be associated with risk for TD occurrence and increased severity as measured by the Abnormal Involuntary Movement Scale (AIMS) (P = .003).
CONCLUSIONS: This study supports a role for the neuregulin signalling pathway in TD, although independent replications are warranted.

PMID: 28394697 [PubMed - as supplied by publisher]

Determination of irinotecan, SN-38 and SN-38 glucuronide using HPLC/MS/MS: Application in a clinical pharmacokinetic and personalized medicine in colorectal cancer patients.

J Clin Lab Anal. 2017 Apr 10;:

Authors: Atasilp C, Chansriwong P, Sirachainan E, Reungwetwattana T, Puangpetch A, Prommas S, Sirilerttrakul S, Rerkarmnuaychoke B, Wongwaisayawan S, Sukasem C

Abstract
BACKGROUND: Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G.
METHODS: A 100 μL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G.
RESULTS: In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G.
CONCLUSION: This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study.

PMID: 28393405 [PubMed - as supplied by publisher]

Interaction between COX-1 and COX-2 Variants Associated with Aspirin Resistance in Chinese Stroke Patients.

J Stroke Cerebrovasc Dis. 2016 Sep;25(9):2136-44

Authors: Yi X, Cheng W, Lin J, Zhou Q, Wang C

Abstract
BACKGROUND: There have been conflicting results for the association between cyclooxygenase (COX) genetic variants and aspirin resistance (AR). The aim of this study was to investigate the association of the COX genetic variants and interaction among these variants with AR in patients with acute ischemic stroke (IS).
METHODS: We consecutively enrolled 850 acute IS patients. Platelet aggregation activity was measured before and after a 7- to 10-day aspirin treatment. The four variants from COX genes were examined using mass spectrometry. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods.
RESULTS: Among the 850 acute IS patients, 175 (20.6%) patients had AR, 45 (5.3%) patients had aspirin semiresistance (ASR), and 630 (74.1%) patients had aspirin sensitivity (AS). The genotype distributions of the 4 variants did not differ significantly between the ASR + AR group and the AS group using the single-locus analytical approach. However, the GMDR analysis showed a significant gene-gene interaction between COX-1 (rs3842787) and COX-2 (rs20417), and scored 10/10 for cross-validation consistency and 9 for the sign test (P = .0127). Individual patients with the combination of rs3842787CT and rs20417CC or rs3842787CT and rs20417GC had a significantly higher risk of ASR + AR than those with rs3842787CC and rs20417GG. The high-risk interactions between rs3842787 and rs20417 were independent predictors of ASR + AR, and were associated with lower reduction of platelet aggregation activity.
CONCLUSIONS: The interactions of rs3842787 and rs20417 were associated with AR. The combinational analysis used in this study may provide further insight into the complex genetic risk of AR.

PMID: 27318652 [PubMed - indexed for MEDLINE]

Precision Medicine, Cardiovascular Disease and Hunting Elephants.

Prog Cardiovasc Dis. 2016 May-Jun;58(6):651-60

Authors: Joyner MJ

Abstract
Precision medicine postulates improved prediction, prevention, diagnosis and treatment of disease based on patient specific factors especially DNA sequence (i.e., gene) variants. Ideas related to precision medicine stem from the much anticipated "genetic revolution in medicine" arising seamlessly from the human genome project (HGP). In this essay I deconstruct the concept of precision medicine and raise questions about the validity of the paradigm in general and its application to cardiovascular disease. Thus far precision medicine has underperformed based on the vision promulgated by enthusiasts. While niche successes for precision medicine are likely, the promises of broad based transformation should be viewed with skepticism. Open discussion and debate related to precision medicine are urgently needed to avoid misapplication of resources, hype, iatrogenic interventions, and distraction from established approaches with ongoing utility. Failure to engage in such debate will lead to negative unintended consequences from a revolution that might never come.

PMID: 26902518 [PubMed - indexed for MEDLINE]

Influence of genetic and non-genetic factors on phenytoin-induced severe cutaneous adverse drug reactions.

Eur J Clin Pharmacol. 2017 Apr 08;:

Authors: Yampayon K, Sukasem C, Limwongse C, Chinvarun Y, Tempark T, Rerkpattanapipat T, Kijsanayotin P

Abstract
PURPOSE: The purpose of this study was to investigate the association of genetic factors including variants in HLA-B and CYP2C genes and non-genetic factors with phenotype-specific phenytoin (PHT)-induced severe cutaneous adverse reactions (SCARs) in Thai patients.
METHODS: Thirty-six PHT-induced SCAR cases (15 Stevens-Johnson syndrome (SJS) and 21 drug rash with eosinophilia and systemic symptoms (DRESS)/drug hypersensitivity syndrome (DHS)) and 100 PHT-tolerant controls were studied. Variants in HLA-B, CYP2C9, and CYP2C19 genes were genotyped. Fisher's exact test and multiple logistic regression analysis were performed to test the association of genetic and non-genetic factors with specific type of SCARs.
RESULTS: Multiple logistic regression models showed that genetic and non-genetic factors associated with PHT-induced SCARs were specified to its phenotype. HLA-B*13:01, HLA-B*56:02/04, CYP2C19*3, and omeprazole co-medication were strong risk factors of DRESS/DHS (adjusted OR = 13.29, p = 0.0001; adjusted OR = 56.23, p = 0.0007; adjusted OR = 6.75, p = 0.0414; and adjusted OR = 9.21, p = 0.0020, respectively). While CYP2C9*3 and having Chinese ancestry were significant risk factors of SJS (adjusted OR = 10.41, p = 0.0042 and adjusted OR = 5.40, p = 0.0097, respectively). Combined genetic and non-genetic risk factors optimized sensitivity and increased specificity for predicting PHT-induced SCARs.
CONCLUSION: This study showed that distinct genetic markers were associated with phenotype-specific PHT-induced SCARs. Non-genetic factor, omeprazole co-medication, was strongly associated with PHT-induced DRESS/DHS in addition to variants in HLA-B and CYP2C genes. Combined markers may be better predictors for PHT-induced SCARs.

PMID: 28391407 [PubMed - as supplied by publisher]

The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment.

Genomics Proteomics Bioinformatics. 2017 Apr 05;:

Authors: Rudin S, Marable M, Stephanie Huang R

Abstract
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and potentially inosine triphosphatase (ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) and dihydrofolate reductase (DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1) and thymidylate synthetase (TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

PMID: 28391009 [PubMed - as supplied by publisher]

Electronic medical record-integrated pharmacogenomics and related clinical decision support concepts.

Clin Pharmacol Ther. 2017 Apr 08;:

Authors: Caraballo PJ, Bielinski SJ, St Sauver JL, Weinshilboum RM

PMID: 28390138 [PubMed - as supplied by publisher]

Exploring functions of long noncoding RNAs across multiple cancers through co-expression network.

Sci Rep. 2017 Apr 07;7(1):754

Authors: Li S, Li B, Zheng Y, Li M, Shi L, Pu X

Abstract
In contrast to protein-coding genes, long-noncoding RNAs (lncRNAs) are much less well understood, despite increasing evidence indicating a wide range of their biological functions, and possible roles in various cancers. Based on public RNA-seq datasets of four solid cancer types, we here utilize Weighted Correlation Network Analysis (WGCNA) to propose a strategy for exploring the functions of lncRNAs altered in more than two cancer types, which we call onco-lncRNAs. Results indicate that cancer-expressed lncRNAs show high tissue specificity and are weakly expressed, more so than protein-coding genes. Most of the 236 onco-lncRNAs we identified have not been reported to have associations with cancers before. Our analysis exploits co-expression network to reveal that onco-lncRNAs likely play key roles in the multistep development of human cancers, covering a wide range of functions in genome stability maintenance, signaling, cell adhesion and motility, morphogenesis, cell cycle, immune and inflammatory response. These observations contribute to a more comprehensive understanding of cancer-associated lncRNAs, while demonstrating a novel and efficient strategy for subsequent functional studies of lncRNAs.

PMID: 28389669 [PubMed - in process]

Identification of IGF-1-enhanced cytokine expressions targeted by miR-181d in glioblastomas via an integrative miRNA/mRNA regulatory network analysis.

Sci Rep. 2017 Apr 07;7(1):732

Authors: Ho KH, Chen PH, Hsi E, Shih CM, Chang WC, Cheng CH, Lin CW, Chen KC

Abstract
The insulin-like growth factor (IGF)-1 signaling is relevant in regulating cell growth and cytokine secretions by glioblastomas. MicroRNAs determine the cell fate in glioblastomas. However, relationships between IGF-1 signaling and miRNAs in glioblastoma pathogenesis are still unclear. Our aim was to validate the IGF-1-mediated mRNA/miRNA regulatory network in glioblastomas. Using in silico analyses of mRNA array and RNA sequencing data from The Cancer Genome Atlas (TCGA), we identified 32 core enrichment genes that were highly associated with IGF-1-promoted cytokine-cytokine receptor interactions. To investigate the IGF-1-downregulated miRNA signature, microarray-based approaches with IGF-1-treated U87-MG cells and array data in TCGA were used. Four miRNAs, including microRNA (miR)-9-5p, miR-9-3p, miR-181d, and miR-130b, exhibited an inverse correlation with IGF-1 levels. The miR-181d, that targeted the most IGF-1-related cytokine genes, was significantly reduced in IGF-1-treated glioma cells. Statistical models incorporating both high-IGF-1 and low-miR-181d statuses better predicted poor patient survival, and can be used as an independent prognostic factor in glioblastomas. The C-C chemokine receptor type 1 (CCR1) and interleukin (IL)-1b demonstrated inverse correlations with miR-181d levels and associations with patient survival. miR-181d significantly attenuated IGF-1-upregulated CCR1 and IL-1b gene expressions. These findings demonstrate a distinct role for IGF-1 signaling in glioma progression via miR-181d/cytokine networks.

PMID: 28389653 [PubMed - in process]