Genome-wide association study of platelet reactivity and cardiovascular response in patients treated with clopidogrel: a study by the International Clopidogrel Pharmacogenomics Consortium (ICPC).

Clin Pharmacol Ther. 2020 May 30;:

Authors: Verma SS, Bergmeijer TO, Gong L, Reny JL, Lewis JP, Mitchell BD, Alexopoulos D, Aradi D, Altman RB, Bliden K, Bradford Y, Campo G, Chang K, Cleator JH, Déry JP, Dridi NP, Fernandez-Cadenas I, Fontana P, Gawaz M, Geisler T, Gensini GF, Giusti B, Gurbel PA, Hochholzer W, Holmvang L, Kim EY, Kim HS, Marcucci R, Montaner J, Backman JD, Pakyz RE, Roden DM, Schaeffeler E, Schwab M, Shin JG, Siller-Matula JM, Ten Berg JM, Trenk D, Valgimigli M, Wallace J, Wen MS, Kubo M, Lee MTM, Whaley R, Winter S, Klein TE, Shuldiner AR, Ritchie MD, ICPC Investigators

Abstract
Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genome-wide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate (ADP) induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (p-value=1.67e-33). After correction for CYP2C19*2 no other SNP reached genome-wide significance. GWAS for a combined clinical endpoint of cardiovascular death, myocardial infarction, or stroke (5.0% event rate) or a combined endpoint of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA and CTRAC1 showed genome-wide significance (lowest p-values: 1.07e-09, 4.53e-08 and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

PMID: 32472697 [PubMed - as supplied by publisher]

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support.

Cancers (Basel). 2020 May 27;12(6):

Authors: Perera Y, Melão A, Ramón AC, Vázquez D, Ribeiro D, Perea SE, Barata JT

Abstract
Despite remarkable advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), relapsed cases are still a major challenge. Moreover, even successful cases often face long-term treatment-associated toxicities. Targeted therapeutics may overcome these limitations. We have previously demonstrated that casein kinase 2 (CK2)-mediated phosphatase and tensin homologue (PTEN) posttranslational inactivation, and consequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling hyperactivation, leads to increased T-ALL cell survival and proliferation. We also revealed the existence of a crosstalk between CK2 activity and the signaling mediated by interleukin 7 (IL-7), a critical leukemia-supportive cytokine. Here, we evaluated the impact of CIGB-300, a the clinical-grade peptide-based CK2 inhibitor CIGB-300 on T-ALL biology. We demonstrate that CIGB-300 decreases the viability and proliferation of T-ALL cell lines and diagnostic patient samples. Moreover, CIGB-300 overcomes IL-7-mediated T-ALL cell growth and viability, while preventing the positive effects of OP9-delta-like 1 (DL1) stromal support on leukemia cells. Signaling and pull-down experiments indicate that the CK2 substrate nucleophosmin 1 (B23/NPM1) and CK2 itself are the molecular targets for CIGB-300 in T-ALL cells. However, B23/NPM1 silencing only partially recapitulates the anti-leukemia effects of the peptide, suggesting that CIGB-300-mediated direct binding to CK2, and consequent CK2 inactivation, is the mechanism by which CIGB-300 downregulates PTEN S380 phosphorylation and inhibits PI3K/Akt signaling pathway. In the context of IL-7 stimulation, CIGB-300 blocks janus kinase / signal transducer and activator of transcription (JAK/STAT) signaling pathway in T-ALL cells. Altogether, our results strengthen the case for anti-CK2 therapeutic intervention in T-ALL, demonstrating that CIGB-300 (given its ability to circumvent the effects of pro-leukemic microenvironmental cues) may be a valid tool for clinical intervention in this aggressive malignancy.

PMID: 32471246 [PubMed - as supplied by publisher]

Arginase inhibitors: An alternative in treatment of obese asthma?

Allergy. 2020 Jun;75(6):1525-1526

Authors: Felix MMR, Kuschnir FC

PMID: 32470219 [PubMed - as supplied by publisher]

Clinical and genetic predictors of secondary sulfonylurea failure in type 2 diabetes patients: the SUCLINGEN study.

Pharmacogenomics. 2020 May 29;:

Authors: Loganadan NK, Huri HZ, Vethakkan SR, Hussein Z

Abstract
Background: Due to several limitations in the study designs of sulfonylurea pharmacogenomics studies, we investigated the clinical and genetic predictors of secondary sulfonylurea failure in type 2 diabetes patients. Materials & methods: Patients receiving the maximum sulfonylurea and metformin doses for >1 year were enrolled. Secondary sulfonylurea failure was defined as HbA1c >7.0% (>53 mmol/mol) after a 12-month follow-up. Results: By multivariate analysis, increased insulin resistance (HOMA2-IR), baseline HbA1c >7.0%, residing in eastern Peninsular Malaysia, and the CC genotype of rs757110 ABCC8 gene polymorphism were independent predictors of secondary sulfonylurea failure (p < 0.05) while sulfonylurea-induced hypoglycemia was protective against such failure (p < 0.05). Conclusion: Sulfonylurea does not benefit patients with an increased risk of secondary sulfonylurea failure.

PMID: 32468916 [PubMed - as supplied by publisher]

The implementation of pharmacogenomics into UK general practice: a qualitative study exploring barriers, challenges and opportunities.

J Community Genet. 2020 May 28;:

Authors: Rafi I, Crinson I, Dawes M, Rafi D, Pirmohamed M, Walter FM

Abstract
Pharmacogenomics describes interpatient genetic variability in drug responses. Information based on whole genome sequencing will soon open up the field of pharmacogenomics and facilitate the use of genomic information relating to drug metabolism and drug responses. We undertook a qualitative study, aiming to explore the potential barriers, opportunities and challenges facing the implementation of pharmacogenomics into primary care. Semi-structured interviews were undertaken with 18 clinical participants (16 GPs and 2 other clinicians). All interviews were recorded and transcribed verbatim. Using a thematic analysis approach, data items were coded, ordered and themes constructed. Most participants were aged 55-60 years and worked as part-time clinical GPs with other clearly defined roles. The emerging themes covered several areas of concern, including the following: the utility of pharmacogenomics and the value of introducing such testing into primary care; how to educate the primary care workforce and 'mainstream' pharmacogenomics; the ethical, legal and social aspects of pharmacogenomics and its impact on patients; and potential impacts on the healthcare system particularly around economics and informatics. Most participants had concerns about pharmacogenomics and felt that there were a number of barriers and challenges to its implementation into routine primary care. Most striking were their concerns around the cost-effectiveness of using pharmacogenomics in primary care. At the same time most recognised the increasing availability of direct-to-consumer testing, and felt that this would drive the need to understand the ethical and social implications of using genomic information in primary care. This study has raised important issues that need to be considered when planning the implementation of pharmacogenomics into clinical practice. Prior to the implementation of genomic testing into day-to-day practice in UK primary care, it is important that considerations around education, cost-effectiveness and informatics are addressed, as well as the impact on patients.

PMID: 32468238 [PubMed - as supplied by publisher]

Comprehensive analysis of drugs to treat SARS‑CoV‑2 infection: Mechanistic insights into current COVID‑19 therapies (Review).

Int J Mol Med. 2020 May 18;:

Authors: Nitulescu GM, Paunescu H, Moschos SA, Petrakis D, Nitulescu G, Ion GND, Spandidos DA, Nikolouzakis TK, Drakoulis N, Tsatsakis A

Abstract
The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID‑19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID‑19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.

PMID: 32468014 [PubMed - as supplied by publisher]

Association of HLA-DRB1*04:05 allele with drug-induced interstitial lung disease in Japanese population.

Pharmacogenomics J. 2020 May 28;:

Authors: Imatoh T, Ushiki A, Ota M, Ito M, Sekine A, Yamashita T, Mashimo Y, Nakamura R, Saito K, Saito Y, Hanaoka M

Abstract
Drug-induced interstitial lung disease (DILD) is a life-threatening adverse reaction. The Japanese population is more susceptible to DILD as compared with other populations, suggesting its pathogenesis could vary depending on ethnic genetic background. We conducted case-control studies to elucidate the association between DILD and HLA alleles in the Japanese. The 177 clinically diagnosed DILD patients and 3002 healthy controls for exploration and 55 DILD patients and 201 healthy controls for validation were genotyped for four HLA genes. HLA-DRB1*04:05 was significantly associated with DILD (corrected p = 0.014); this was also validated in the other set of patients/controls. Chemical drugs other than protein therapeutics showed this association (p = 1.7 × 10-4) . The Japanese population showed a higher HLA-DRB1*04:05 frequency than most other populations. In conclusion, HLA-DRB1*04:05 could be associated with DILD susceptibility in Japanese individuals, and its high general frequency may explain the high reported incidence of DILD in Japanese.

PMID: 32467566 [PubMed - as supplied by publisher]

Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal Cancer.

Int J Mol Sci. 2020 May 26;21(11):

Authors: Papachristos A, Karatza E, Kalofonos H, Sivolapenko G

Abstract
Vascular endothelial growth factor A (VEGF-A) and intercellular adhesion molecule 1 (ICAM-1) are significant regulators of angiogenesis, an important biological process involved in carcinogenesis. Bevacizumab, an anti-VEGF monoclonal antibody (MAB), is approved for the treatment of metastatic Colorectal cancer (mCRC), however clinical outcomes are highly variable. In the present study, we developed a pharmacokinetic (PK), a simplified quasi-steady state (QSS) and a pharmacokinetic/pharmacodynamic (PK/PD) model to identify potential sources of variability. A total of 46 mCRC patients, who received bevacizumab in combination with chemotherapy were studied. VEGF-A (rs2010963, rs1570360, rs699947) and ICAM-1 (rs5498, rs1799969) genes' polymorphisms, age, gender, weight, and dosing scheme were investigated as possible co-variates of the model's parameters. Polymorphisms, trough, and peak levels of bevacizumab, and free VEGF-A were determined in whole blood and serum. Data were analyzed using nonlinear mixed-effects modeling. The two-compartment PK model showed that clearance (CL) was significantly lower in patients with mutant ICAM-1 rs1799969 (p < 0.0001), inter-compartmental clearance (Q) was significantly higher with mutant VEGF-A rs1570360 (p < 0.0001), and lower in patients with mutant VEGF-A rs699947 (p < 0.0001). The binding QSS model also showed that mutant ICAM-1 rs1799969 was associated with a lower CL (p = 0.0177). Mutant VEGF-A rs699947 was associated with a lower free VEGF-A levels, prior to the next dose (p = 0.000445). The above results were confirmed by the PK/PD model. Findings of the present study indicated that variants of the genes regulating angiogenesis might affect PK and PD characteristics of bevacizumab, possibly influencing the clinical outcomes.

PMID: 32466535 [PubMed - in process]

Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-inflammatory Potential.

Antioxidants (Basel). 2020 May 25;9(5):

Authors: Dobiasová S, Řehořová K, Kučerová D, Biedermann D, Káňová K, Petrásková L, Koucká K, Václavíková R, Valentová K, Ruml T, Macek T, Křen V, Viktorová J

Abstract
Silybin is considered to be the main biologically active component of silymarin. Its oxidized derivative 2,3-dehydrosilybin typically occurs in silymarin in small, but non-negligible amounts (up to 3%). Here, we investigated in detail complex biological activities of silybin and 2,3-dehydrosilybin optical isomers. Antioxidant activities of pure stereomers A and B of silybin and 2,3-dehydrosilybin, as well as their racemic mixtures, were investigated by using oxygen radical absorption capacity (ORAC) and cellular antioxidant activity (CAA) assay. All substances efficiently reduced nitric oxide production and cytokines (TNF-α, IL-6) release in a dose-dependent manner. Multidrug resistance (MDR) modulating potential was evaluated as inhibition of P-glycoprotein (P-gp) ATPase activity and regulation of ATP-binding cassette (ABC) protein expression. All the tested compounds showed strong dose-dependent inhibition of P-gp pump. Moreover, 2,3-dehydrosilybin A (30 µM) displayed the strongest sensitization of doxorubicin-resistant ovarian carcinoma. Despite these significant effects, silybin B was the only compound acting directly upon P-gp in vitro and also downregulating the expression of respective MDR genes. This compound altered the expression of P-glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). 2,3-Dehydrosilybin AB exhibited the most effective inhibition of acetylcholinesterase activity. We can clearly postulate that silybin derivatives could serve well as modulators of a cancer drug-resistant phenotype.

PMID: 32466263 [PubMed]

Association between hTERT Polymorphisms and Female Papillary Thyroid Carcinoma.

Recent Pat Anticancer Drug Discov. 2019;14(3):268-279

Authors: Liu Y, Li Z, Tang X, Li M, Shi F

Abstract
BACKGROUND: A previous genome-wide association study showed that hTERT rs10069690 and rs2736100 polymorphisms were associated with thyroid cancer risk.
OBJECTIVE: This study further investigated the association between increased risk and clinicopathologic characteristics for Papillary Thyroid Carcinoma (PTC) and hTERT polymorphisms rs10069690 or rs2736100 in a Chinese female population.
METHODS: The hTERT genotypes of 276 PTC patients and 345 healthy subjects were determined with regard to SNPs rs10069690 and rs2736100. The association between these SNPs and the risk of PTC and clinicopathologic characteristics was investigated by logistic regression.
RESULTS: We found a significant difference between PTC and rs10069690 (Odds Ratio (OR) = 1.515; P = 0.005), but not between PTC and rs2736100. When the analysis was limited to females, rs10069690 and rs2736100 were both associated with increased risk for PTC in female individuals (OR = 1.647, P = 0.007; OR = 1.339, P = 0.041, respectively). Further haplotype analysis revealed a stimulative effect of haplotypes TC and CA of TERT rs10069690-rs2736100, which increased risk for PTC in female individuals (OR = 1.579, P = 0.014; OR = 0.726, P = 0.025, respectively). Furthermore, the heterozygote A/C of rs2736100 showed significant difference for age (OR = 0.514, P = 0.047).
CONCLUSION: Our finding suggests that hTERT polymorphisms rs10069690 and rs2736100 are associated with increased risk for PTC in Chinese female population and rs2736100 may be related to age. Consistent with US20170360914 and US20170232075, they are expected to be a potential molecular target for anti-cancer therapy.

PMID: 31538903 [PubMed - indexed for MEDLINE]

Introducing the Canadian Women's Heart Health Alliance ATLAS on the Epidemiology, Diagnosis, and Management of Cardiovascular Diseases in Women.

CJC Open. 2020 May;2(3):145-150

Authors: Norris CM, Yip CYY, Nerenberg KA, Jaffer S, Grewal J, Levinsson ALE, Mulvagh SL

Abstract
Despite a global understanding that indicators and outcomes of cardiovascular disease (CVD) are known to differ between men and women, uptake of the recognition of sex and gender influences on the clinical care of women has been slow or absent. The Canadian Women's Heart Health Alliance (CWHHA) was established as a network of experts and advocates to develop and disseminate evidence-informed strategies to transform clinical practice and augment collaborative action on women's cardiovascular health in Canada. As an initial project, the CWHHA membership undertook an environmental scan of CVD in women in Canada from which a scientific statement could be developed to summarize critical sex- and gender-specific issues in CVD. This comprehensive review of the evidence focused on the sex- and gender-specific differences in comorbidity, risk factors, disease awareness, presentation, diagnosis, and treatment across the entire spectrum of CVD. In the process of creating the review, it was recognized that the team of CWHHA experts had also assembled an expansive collection of original research articles that were synthesized into detailed chapters reporting on the present state of the evidence unique to each cardiovascular condition in women. This work comprises an "ATLAS" on the epidemiology, diagnosis, and management of CVD in women. The overall goal of the ATLAS is to create a living document that will help clinicians and the public recognize the unique aspects of women's heart health care and provide policy makers with information they need to ensure equitable care for women with CVD.

PMID: 32462128 [PubMed]

Persistent Hypersomnolence Following Clobazam in a Child With Epilepsy and Undiagnosed CYP2C19 Polymorphism.

J Pediatr Pharmacol Ther. 2020;25(4):320-327

Authors: Hamilton KE, Shelton CM, Wheless J, Phelps SJ

Abstract
We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 week of modest doses of clobazam (CLB). In reviewing the above case, we considered that the hypersomnolence could be related to a pharmacodynamic, pharmacokinetic, or pharmacogenomic issue associated with CLB or to a combination of these factors. Although serum concentrations of CLB and its active metabolite are sensitive to factors that affect cytochrome-dependent metabolism, drug-drug interactions were omitted as a cause of the hypersomnolence. Subsequent DNA analysis of the cytochrome P450 2C19 gene revealed the patient as *2/*2 genotype with poor metabolizer enzyme activity. Because genetic testing of all patients treated with CLB is currently not practical, CLB dose/concentration ratios and pharmacokinetic drug-drug interaction impact models may be indicated. Genetic testing should be considered when an adverse effect suggests the possibility of a polymorphism important to drug metabolism.

PMID: 32461746 [PubMed]

Generating a Cost-Effective, Weekend-Free Chemically Defined Human Induced Pluripotent Stem Cell (hiPSC) Culture Medium.

Curr Protoc Stem Cell Biol. 2020 Jun;53(1):e110

Authors: Fonoudi H, Lyra-Leite DM, Javed HA, Burridge PW

Abstract
We have previously developed a cost-effective chemically defined medium formula for weekend-free culture of human induced pluripotent stem cells (hiPSCs), costing ∼3% of the price of commercial medium. This medium, which we termed B8, is specifically optimized for robust and fast growth of hiPSCs and for a weekend-free medium change regimen. We demonstrated that this medium is suitable for reprogramming of somatic cells into hiPSCs and for differentiation into a variety of lineages. Here, we provide a protocol for simple generation of the most cost-effective variant of this medium, along with a protocol for making Matrigel-coated plates and culturing, passaging, cryopreserving, and thawing hiPSCs. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Preparation of a highly optimized, robust, and cost-effective human induced pluripotent stem cell culture medium Basic Protocol 2: Weekend-free maintenance and passaging of human induced pluripotent stem cells in B8 medium.

PMID: 32463953 [PubMed - as supplied by publisher]

Robot technology identifies a Parkinsonian therapeutics repurpose to target stem cells of glioblastoma.

CNS Oncol. 2020 May 28;:

Authors: Vargas-Toscano A, Khan D, Nickel AC, Hewera M, Kamp MA, Fischer I, Steiger HJ, Zhang W, Muhammad S, Hänggi D, Kahlert UD

Abstract
Aim: Glioblastoma is a heterogeneous lethal disease, regulated by a stem-cell hierarchy and the neurotransmitter microenvironment. The identification of chemotherapies targeting individual cancer stem cells is a clinical need. Methodology: A robotic workstation was programmed to perform a drug concentration to cell-growth analysis on an in vitro model of glioblastoma stem cells (GSCs). Mode-of-action analysis of the selected top substance was performed with manual repetition assays and acquisition of further parameters. Results: We identified 22 therapeutic potential substances. Three suggested a repurpose potential of neurotransmitter signal-modulating agents to target GSCs, out of which the Parkinson's therapeutic trihexyphenidyl was most effective. Manual repetition assays and initial mode of action characterization revealed suppression of cell proliferation, cell cycle and survival. Conclusion: Anti-neurotransmitter signaling directed therapy has potential to target GSCs. We established a drug testing facility that is able to define a mid-scale chemo responsome of in vitro cancer models, possibly also suitable for other cell systems.

PMID: 32462934 [PubMed - as supplied by publisher]

Association study between HTR2A rs6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients.

Drug Dev Res. 2020 May 27;:

Authors: Maffioletti E, Valsecchi P, Minelli A, Magri C, Bonvicini C, Barlati S, Sacchetti E, Vita A, Gennarelli M

Abstract
Antipsychotic drugs are the preferred choice for schizophrenia treatment; however, response is highly variable. In the context of the search for predictors of antipsychotic treatment effectiveness, the evaluation of response within 2 weeks has been indicated to predict long-term outcome. Moreover, a focus on symptomatological domains could be helpful to better characterize antipsychotic response, identifying more specific predictors. Pharmacogenetic studies have indicated a role for rs6313 in the serotonin receptor gene HTR2A in affecting response to antipsychotics, with heterogeneous results. With the aim to test for the first time the application of a dimensional approach for the evaluation of early response, we carried out a genetic association study between rs6313 and antipsychotic response in two groups of schizophrenia patients in monotherapy with risperidone (n = 121) and olanzapine (n = 100). Patients were evaluated at the baseline and after 1 and 2 weeks of treatment. When comparing early responders versus early nonresponders, no association was detected for the two drugs separately, whereas by taking into consideration the two drugs together it was observed that carriers of the T allele had a higher response probability compared to noncarriers. Considering 2-week improvements, changes in PANSS total scores, subscores and in PANSS Emsley's symptomatological dimensions were associated with rs6313 for both risperidone and olanzapine. Moreover, the repeated measures analysis indicated an association of rs6313 with the disorganized thought dimension for risperidone, and with the depressive and anxiety dimensions for olanzapine. These data add support to the hypothesis that the HTR2A gene is involved in antipsychotic treatment outcome.

PMID: 32462699 [PubMed - as supplied by publisher]

Oral absorption of voriconazole is affected by SLCO2B1 c.*396T>C genetic polymorphism in CYP2C19 poor metabolizers.

Pharmacogenomics J. 2020 May 27;:

Authors: Lee SW, Oh J, Kim AH, Ji SC, Park SI, Yoon SH, Chung JY, Yu KS, Jang IJ, Lee S

Abstract
High pharmacokinetic variability of voriconazole is mainly explained by CYP2C19 phenotype, but there are still unknown factors affecting the variability. In this study, the effect of solute carrier organic anion transporter family member 2B1 (SLCO2B1) genotype on the pharmacokinetics (PKs) of voriconazole was evaluated in 12 healthy CYP2C19 poor metabolizers after a single administration of voriconazole 200 mg intravenously and orally. In addition, the influence of CYP3A4 enzyme activity was also explored. The oral absorption of voriconazole was decreased and delayed in the subjects with the SLCO2B1 c.*396T>C variant compared to the subjects with wild type. However, the CYP3A activity markers measured in this study did not show significant association with metabolism of voriconazole. The results suggest that the SLCO2B1 c.*396T>C may be associated with the decreased function of intestinal OATP2B1, and it could contribute to interindividual PK variability of voriconazole.

PMID: 32461666 [PubMed - as supplied by publisher]

Predictive value of genetic variants XRCC1 rs1799782, APEX1 rs1760944, and MUTYH rs3219489 for adjuvant concurrent chemoradiotherapy outcomes in oral squamous cell carcinoma patients.

Pharmacogenomics J. 2020 May 27;:

Authors: Senghore T, Chien HT, Wang WC, Chen YX, Young CK, Huang SF, Yeh CC

Abstract
Genetic variations in DNA base excision repair (BER) genes may affect tumor sensitivity to chemotherapy and radiotherapy. Thus, we investigated the effects of single-nucleotide polymorphisms (SNPs) in key BER pathway genes on clinical outcomes in male patients who received concurrent chemoradiotherapy (CCRT). Seven SNPs from XRCC1, OGG1, APEX1, and MUTYH were genotyped using the Sequenom iPLEX MassARRAY system in samples from 319 men with advanced oral squamous cell carcinoma. The disease-free survival (DFS) rates of the MUTYH rs3219489 genotypes and those of the other genotypes differed significantly (log-rank test p = 0.027). Multivariate Cox proportional hazard analysis showed that the MUTYH rs3219489 GG genotype was associated with poor DFS (recessive model: hazard ratio [HR] = 2.01, 95% confidence interval [CI] = 1.31-3.10; p = 0.002). The CT + TT genotypes of XRCC1 rs1799782 (dominant model: HR = 0.65, 95% CI = 0.43-0.99; p = 0.044) and GG genotype of APEX1 rs1760944 (recessive model: HR = 1.64, 95% CI = 1.00-2.70; p = 0.050) were associated with overall survival (OS). Carrying the two risk genotypes, CC and GG of XRCC1 rs1799782 and APEX1 rs1760944, respectively, (HR = 2.95, 95% CI = 1.47-5.88; p = 0.002) increased mortality risk. Our findings showed that carrying the two risk genotypes of XRCC1 rs1799782 and APEX1 rs1760944 was associated with poor OS, while the GG genotype of MUTYH rs3219489 was associated with poor DFS. Patients carrying the risk genotypes may not benefit from CCRT; therefore, they will need alternative treatments.

PMID: 32461665 [PubMed - as supplied by publisher]

Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.

J Crohns Colitis. 2019 Dec 10;13(12):1578-1582

Authors: Green HD, Beaumont RN, Thomas A, Hamilton B, Wood AR, Sharp S, Jones SE, Tyrrell J, Walker G, Goodhand J, Kennedy NA, Ahmad T, Weedon MN

Abstract
BACKGROUND AND AIMS: The causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank.
METHODS: In total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores.
RESULTS: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis.
CONCLUSIONS: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.

PMID: 31125052 [PubMed - indexed for MEDLINE]

Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.

Front Pharmacol. 2020;11:555

Authors: Calderon-Ospina CA, Galvez JM, López-Cabra C, Morales N, Restrepo CM, Rodríguez J, Aristizábal-Gutiérrez FA, Velez-van-Meerbeke A, Laissue P, Fonseca-Mendoza DJ

Abstract
Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality.
Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy.
Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology).
Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients.
Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study.

PMID: 32457604 [PubMed]

How to Transition from Single Gene Pharmacogenetic Testing to Preemptive Panel-Based Testing: A Tutorial.

Clin Pharmacol Ther. 2020 May 27;:

Authors: Marrero RJ, Cicali EJ, Arwood MJ, Eddy E, DeRemer D, Ramnaraign BH, Daily KC, Jones D, Cook KJ, Cavallari LH, Weitzel KW, Langaee T, Newsom KJ, Starostik P, Clare-Salzer MJ, Johnson JA, George TJ, Cooper-DeHoff RM

Abstract
There have been significant advancements in precision medicine and approaches to medication selection based on pharmacogenetic results. With the availability of direct-to-consumer genetic testing and growing awareness of genetic inter-individual variability, patient demand for more precise, individually tailored drug regimens is increasing. The University of Florida (UF) Health Precision Medicine Program (PMP) was established in 2011 to improve integration of genomic data into clinical practice. In the ensuing years, the UF Health PMP has successfully implemented several single-gene tests to optimize the precision of medication prescribing across a variety of clinical settings. Most recently, the UF Health PMP launched a custom-designed pharmacogenetic panel including pharmacogenes relevant to supportive care medications commonly prescribed to patients undergoing chemotherapy treatment, referred to as "GatorPGx". This tutorial provides guidance and information to institutions on how to transition from the implementation of single-gene pharmacogenetic testing to a preemptive panel-based testing approach. Here, we demonstrate application of the preemptive panel in the setting of an adult solid tumor oncology clinic. Importantly, the information included herein can be applied to other clinical practice settings.

PMID: 32460360 [PubMed - as supplied by publisher]