[Genetic Markers for Personalized Therapy of Polygenic Diseases: Pharmacogenetics of Multiple Sclerosis].

Mol Biol (Mosk). 2019 Jul-Aug;53(4):574-599

Authors: Tsareva EY, Favorova OO, Boyko AN, Kulakova OG

Abstract
Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon β (IFN-β) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-β and GA in MS patients, including the author's original data.

PMID: 31397433 [PubMed - in process]

Concerns regarding use of patient-reported outcomes in biomarker studies of chemotherapy-induced peripheral neuropathy.

Pharmacogenomics J. 2019 Aug 09;:

Authors: Hertz DL

PMID: 31395959 [PubMed - as supplied by publisher]

Algorithm for predicting low maintenance doses of warfarin using age and polymorphisms in genes CYP2C9 and VKORC1 in Brazilian subjects.

Pharmacogenomics J. 2019 Aug 09;:

Authors: de Oliveira Magalhães Mourão A, Braga Gomes K, Afonso Reis E, Pedra de Souza R, de Freitas Campos EI, Dias Ribeiro D, da Costa Rocha MO, Parreiras Martins MA

Abstract
Warfarin exhibits a wide variation in dose requirements. We sought to evaluate the association of polymorphisms CYP2C9*2 (rs1799853), CYP2C9*3 (rs1075910), and VKORC1-G1639A (rs9923231) and nongenetic factors with maintenance doses of warfarin <17.5 mg/week and to create an algorithm to predict drug sensitivity. This is a retrospective cohort study including 312 patients assisted at an anticoagulation clinic in Brazil. The mean age of participants was 60.4 ± 13.5 years and 59.9% were female. The logistic regression model included: age [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06], genotype VKORC1 AA (OR 31.61, 95% CI 11.20-100.15) and genotype CYP2C9 2/2, 2/3 or 3/3 (OR 16.48, 95% CI 3.37-81.79). The creation of our algorithm involved warfarin-experienced patients on stable doses, identifying factors associated with drug sensitivity. The validation of this algorithm allows its use in future populations to determine the initial dose distinguishing patients with dose requirements <17.5 mg and reducing time to achieve stable doses.

PMID: 31395958 [PubMed - as supplied by publisher]

Pharmacogenomics.

Lancet. 2019 Aug 05;:

Authors: Roden DM, McLeod HL, Relling MV, Williams MS, Mensah GA, Peterson JF, Van Driest SL

Abstract
Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.

PMID: 31395440 [PubMed - as supplied by publisher]

Pharmacogenomic Testing: Clinical Evidence and Implementation Challenges.

J Pers Med. 2019 Aug 07;9(3):

Authors: Hippman C, Nislow C

Abstract
Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and lowering risk of serious adverse events. As of June 2019, there are 132 pharmacogenomic dosing guidelines for 99 drugs and pharmacogenomic information is included in 309 medication labels. Recently, the technology for identifying individual-specific genetic variants (genotyping) has become more accessible. Next generation sequencing (NGS) is a cost-effective option for genotyping patients at many pharmacogenomic loci simultaneously, and guidelines for implementation of these data are available from organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). NGS and related technologies are increasing knowledge in the research sphere, yet rates of genomic literacy remain low, resulting in a widening gap in knowledge translation to the patient. Multidisciplinary teams-including physicians, nurses, genetic counsellors, and pharmacists-will need to combine their expertise to deliver optimal pharmacogenomically-informed care.

PMID: 31394823 [PubMed]

Association study of the CTH 1364 G>T polymorphism with coronary artery disease in the Greek population.

Drug Metab Pers Ther. 2019 03 12;34(1):

Authors: Giannakopoulou E, Konstantinou F, Ragia G, Gerontitis Z, Tavridou A, Papapetropoulos A, Mikroulis D, Manolopoulos VG

Abstract
Background Cystathionine γ-lyase enzyme, which is encoded by the CTH gene, is responsible for hydrogen sulfide (H2S) production in the endothelium. The CTH 1364 G>T polymorphism may alter the CTH expression and H2S bioavailability, thus leading to atherosclerosis and coronary artery disease (CAD). We examined the potential association of the CTH 1364 G>T polymorphism with CAD. Methods The CTH 1364 G>T polymorphism was determined in 178 coronary artery bypass grafting (CABG) patients and 156 non-atherosclerotic controls of Greek Caucasian origin using the PCR-RFLP method. Results No significant difference in the frequency of the CTH 1364 G>T genotypes (p = 0.281) and alleles (p = 0.265) was found between the CABG patients and controls. After conducting stratification according to sex, analysis showed a numerical difference in the CTH 1364 TT genotype frequency in female participants that did not reach statistical significance (16.3% and 8.5% in the CABG and controls, respectively, p = 0.26). The frequency of the CTH 1364 TT genotype between the male CABG patients and controls did not differ (p = 0.507). Conclusions The CTH 1364 G>T polymorphism was not associated with CAD in the studied population. However, interestingly, a higher - if not significantly so - CTH 1364 TT genotype frequency was present in female CABG patients compared with female controls. Larger studies are necessary to conclude on the potential overall or gender-driven association between CTH 1364 G>T gene polymorphism and CAD.

PMID: 30860977 [PubMed - indexed for MEDLINE]

[Pharmacogenetics of timolol].

Vestn Oftalmol. 2019;135(3):137-143

Authors: Moshetova LK, Soshina MM, Sychev DA, Turkina KI

Abstract
In recent years, β-adrenergic blockers have become the first choice drugs for glaucoma treatment. Timolol holds the main position among them, being a part of most combined antiglaucoma preparations. The use of timolol maleate in clinical practice may be accompanied by severe side effects affecting different organs and systems. The fact that cells with β-adrenergic receptors are widely common within the human body explains pharmacodynamic effects of timolol maleate. Because of these undesirable side effects, timolol maleate often evokes negative reaction from doctors and patients, which to certain extent limits its usage in ophthalmological practice. Obviously, efficacy and safety of timolol administration depends on individual characteristics making personalized approach necessary for every patient. Such particular approach, being the foundation of personalized medicine, increases efficacy and safety of timolol while reducing costs by using targeted doses.

PMID: 31393458 [PubMed - in process]

[Molecular and genetic aspects of age-related macular degeneration and glaucoma].

Vestn Oftalmol. 2019;135(3):121-127

Authors: Efendieva MH, Budzinskaya MV, Kadyshev VV, Zinchenko RA, Savochkina OA, Pupysheva AD

Abstract
In most cases, age-related macular degeneration (AMD) and glaucoma are considered multi-factor diseases that lead to irreversible blindness in senior population of developed countries. Among different types of these diseases, around 5% are monogenic. Studying their molecular and genetic aspects can lay the basis for improvement of diagnostic methods, prognosis of the risks of development, manner of progression and treatment outcomes, as well as creation of new therapy methods. The article reviews modern understanding of the etiopathogenesis of AMD and glaucoma and describes their interrelations.

PMID: 31393456 [PubMed - in process]

Mapping the knowledge structure and trends of epilepsy genetics over the past decade: A co-word analysis based on medical subject headings terms.

Medicine (Baltimore). 2019 Aug;98(32):e16782

Authors: Gan J, Cai Q, Galer P, Ma D, Chen X, Huang J, Bao S, Luo R

Abstract
INTRODUCTION: Over the past 10 years, epilepsy genetics has made dramatic progress. This study aimed to analyze the knowledge structure and the advancement of epilepsy genetics over the past decade based on co-word analysis of medical subject headings (MeSH) terms.
METHODS: Scientific publications focusing on epilepsy genetics from the PubMed database (January 2009-December 2018) were retrieved. Bibliometric information was analyzed quantitatively using Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) software. A knowledge social network analysis and publication trend based on the high-frequency MeSH terms was built using VOSviewer.
RESULTS: According to the search strategy, a total of 5185 papers were included. Among all the extracted MeSH terms, 86 high-frequency MeSH terms were identified. Hot spots were clustered into 5 categories including: "ion channel diseases," "beyond ion channel diseases," "experimental research & epigenetics," "single nucleotide polymorphism & pharmacogenetics," and "genetic techniques". "Epilepsy," "mutation," and "seizures," were located at the center of the knowledge network. "Ion channel diseases" are typically in the most prominent position of epilepsy genetics research. "Beyond ion channel diseases" and "genetic techniques," however, have gradually grown into research cores and trends, such as "intellectual disability," "infantile spasms," "phenotype," "exome," " deoxyribonucleic acid (DNA) copy number variations," and "application of next-generation sequencing." While ion channel genes such as "SCN1A," "KCNQ2," "SCN2A," "SCN8A" accounted for nearly half of epilepsy genes in MeSH terms, a number of additional beyond ion channel genes like "CDKL5," "STXBP1," "PCDH19," "PRRT2," "LGI1," "ALDH7A1," "MECP2," "EPM2A," "ARX," "SLC2A1," and more were becoming increasingly popular. In contrast, gene therapies, treatment outcome, and genotype-phenotype correlations were still in their early stages of research.
CONCLUSION: This co-word analysis provides an overview of epilepsy genetics research over the past decade. The 5 research categories display publication hot spots and trends in epilepsy genetics research which could consequently supply some direction for geneticists and epileptologists when launching new projects.

PMID: 31393404 [PubMed - in process]

Computational and Pharmacogenomics Insights on Hypertension Treatment: Rational Drug Design and Optimization Strategies.

Curr Drug Targets. 2019 Aug 07;:

Authors: Loganathan L, Gopinath K, Sankaranarayanan VM, Kukreti R, Rajendran K, Lee JK, Muthusamy K

Abstract
Alzheimer's disease (AD) is one of the most common forms of dementia and has been a global concern for several years. Due to the multi-factorial nature of the disease, AD has become irreversible, fatal and imposes a tremendous socio-economic burden. Even though experimental medicines suggested moderate benefits, AD still lacks an effective treatment strategy for the management of symptoms or cure. Among various hypothesises that describe the development and progression of AD, the amyloid hypothesis has been a long-term adherent to the AD due to the involvement of various forms of amyloid beta (Aβ) peptides in the impairment of neuronal and cognitive functions. Hence, majority of the drug discovery approaches in the past have focused on preventing the accumulation of Aβ peptides. Currently, there are several agents in the phase III clinical trials that target Aβ or the various macromolecules triggering Aβ deposition. In this review, we present the state of the art knowledge on the functional aspects of the key players involved in the amyloid hypothesis. Furthermore, we also discuss anti-amyloid agents present in the Phase III clinical trials.

PMID: 31393243 [PubMed - as supplied by publisher]

Genomic variants in members of the Krüppel-like factor gene family are associated with disease severity and hydroxyurea treatment efficacy in β-hemoglobinopathies patients.

Pharmacogenomics. 2019 Aug 08;:

Authors: Stratopoulos A, Kolliopoulou A, Karamperis K, John A, Kydonopoulou K, Esftathiou G, Sgourou A, Kourakli A, Vlachaki E, Chalkia P, Theodoridou S, Papadakis MN, Gerou S, Symeonidis A, Katsila T, Ali BR, Papachatzopoulou A, Patrinos GP

Abstract
Aim: β-Type hemoglobinopathies are characterized by vast phenotypic diversity as far as disease severity is concerned, while differences have also been observed in hydroxyurea (HU) treatment efficacy. These differences are partly attributed to the residual expression of fetal hemoglobin (HbF) in adulthood. The Krüppel-like family of transcription factors (KLFs) are a set of zinc finger DNA-binding proteins which play a major role in HbF regulation. Here, we explored the possible association of variants in KLF gene family members with response to HU treatment efficacy and disease severity in β-hemoglobinopathies patients. Materials & methods: Six tag single nucleotide polymorphisms, located in four KLF genes, namely KLF3, KLF4, KLF9 and KLF10, were analyzed in 110 β-thalassemia major patients (TDT), 18 nontransfusion dependent β-thalassemia patients (NTDT), 82 sickle cell disease/β-thalassemia compound heterozygous patients and 85 healthy individuals as controls. Results: Our findings show that a KLF4 genomic variant (rs2236599) is associated with HU treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients and two KLF10 genomic variants (rs980112, rs3191333) are associated with persistent HbF levels in NTDT patients. Conclusion: Our findings provide evidence that genomic variants located in KLF10 gene may be considered as potential prognostic biomarkers of β-thalassemia clinical severity and an additional variant in KLF4 gene as a pharmacogenomic biomarker, predicting response to HU treatment.

PMID: 31393228 [PubMed - as supplied by publisher]

Early adoption of pharmacogenetic testing for veterans prescribed psychotropic medications.

Pharmacogenomics. 2019 Aug 08;:

Authors: Hull LE, Chanfreau-Coffinier C, Tuteja S, Berlowitz D, Lehmann LS, Oslin DW, Pyne JM, DuVall SL, Lynch JA

Abstract
Aim: Describe the characteristics of providers ordering, patients receiving, and clinical impact of a psychotropic pharmacogenetic test on veteran care. Patients & methods: Observational cohort study linking veterans' laboratory results to electronic health record data. Changes in psychotropic medication prescribing were measured as a function of test results. Results: A total of 38 providers tested 181 veterans between 10/6/2014 and 2/1/2018. Prescriptions for medications with severe gene-drug interactions decreased; however, 11 such medications were used after testing. For 43 patients, documentation of the results was missing. Conclusion: Most prescribing decisions were congruent with test results, but in a nontrivial number of cases, prescribers appeared not to act on the results. Poor result documentation impeded the potential of results to inform clinical care.

PMID: 31393222 [PubMed - as supplied by publisher]

Role of Four ABC Transporter Genes in Pharmacogenetic Susceptibility to Breast Cancer in Jordanian Patients.

J Oncol. 2019;2019:6425708

Authors: Al-Eitan LN, Rababa'h DM, Alghamdi MA, Khasawneh RH

Abstract
Breast cancer pharmacogenetics is increasingly being explored due to chemotherapy resistance among certain classes of patients. The ATP binding cassette (ABC) transporter genes have been previously implicated in breast cancer progression and drug response. In the present study, single nucleotide polymorphisms (SNPs) from the ABCC1, ABCC2, ABCB1, and ABCG2 genes were screened in breast cancer patients and healthy volunteers from the Jordanian-Arab population. Only the ABCB1 SNPs showed a significant association with BC in Jordanian-Arab patients, and the ABCB1 SNP rs2032582 exhibited a strong genotypic association with BC. With regard to the clinical characteristics of BC, the ABCC2 SNPs rs2273697 and rs717620 were found to be significantly associated with age at breast cancer diagnosis and breastfeeding status, while the ABCB1 SNP rs1045642 was significantly associated with age at breast cancer diagnosis. In terms of pathological characteristics, the ABCC1 SNP rs35628 and the ABCB1 SNP rs2032582 were significantly associated with tumor size, the ABCC2 SNP rs2273697 was significantly associated with estrogen receptor status, and the ABCG2 SNP rs2231142 was significantly associated with axillary lymph node status. In this current study, we assume that significant genetic variants within the ABC superfamily may increase the risk of breast cancer among Jordanian women. Furthermore, these variants might be responsible for worse BC prognosis.

PMID: 31391850 [PubMed]

Impact of gene expression associated with glucocorticoid-induced transcript 1 (GLCCI1) on severe asthma and future exacerbation.

Biol Pharm Bull. 2019 Aug 06;:

Authors: Hirai K, Shirai T, Rachi Y, Uehara S, Ueda M, Nakatani E, Itoh K

Abstract
Genetic variations in glucocorticoid-induced transcript 1 (GLCCI1) have been associated with the response to corticosteroid treatment. However, the associations of GLCCI1 polymorphisms or gene expression with the prognosis of asthma and pathophysiological factors related to steroid insensitivity remain unclear. We sought to investigate the associations of GLCCI1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and histone deacetylase 2 (HDAC2) mRNA expression levels and the GLCCI1 rs37973 polymorphism with asthma severity and future exacerbation in patients with asthma. Subjects included 25 patients with severe asthma and 127 patients with nonsevere asthma. mRNA expression levels in peripheral blood mononuclear cells were measured and evaluated as predictors of severe asthma using receiver operating characteristic (ROC) analysis. The hazard ratios of the mRNA expression levels for time to first exacerbation in the 1-year follow-up period were calculated. GLCCI1, Nrf2, and HDAC2 mRNA expression levels were significantly lower in patients with severe asthma than in patients with nonsevere asthma and could predict severe asthma with an area under the ROC curve of 0.68, 0.71, and 0.65, respectively. In contrast, no relationship was found between the GLCCI1 rs37973 polymorphism and severe asthma. The hazard ratios for asthma exacerbation in patients with low GLCCI1, Nrf2, and HDAC2 mRNA expression levels were 3.24 (95% confidence interval, 1.42-7.40), 3.13 (1.37-7.16), and 2.98 (1.22-7.25), respectively. Patients with severe asthma could be distinguished by lower GLCCI1, Nrf2, and HDAC2 mRNA levels in peripheral blood cells, and all of these gene signatures could predict future asthma exacerbations.

PMID: 31391381 [PubMed - as supplied by publisher]

A non-intrusive evaluation method for tumor-targeting characteristics of nanomedicines based on in vivo near-infrared fluorescence imaging.

J Mater Chem B. 2019 Aug 07;7(31):4751-4757

Authors: Liu H, Marquez RT, Wu X, Li K, Vadlamani S, Li S, Wang Y, Xu L, Wu D

Abstract
We developed a novel evaluation method for tumor-targeting characteristics of nanomedicines, average tumor-targeting index (average TTI) and "area under the tumor-targeting index-time curve" (AUTC) were established as the indicators for tumor targeting of nanomedicines based on NIR fluorescence imaging, which helps real-time monitoring of targeting ability and tumor changes in vivo without culling animals.

PMID: 31389969 [PubMed - in process]

Results and challenges of Cytochrome P450 2D6 (CYP2D6) testing in an ethnically diverse South Florida population.

Mol Genet Genomic Med. 2019 Aug 07;:e922

Authors: Salyakina D, Roy S, Wang W, Oliva M, Akhouri R, Sotto I, Mulas N, Solano R, Fernández JR, Sanchez S, Shamshad U, Perlyn C, McCafferty-Fernandez J

Abstract
BACKGROUND: This study focuses on the implementation of CYP2D6 genetic test profiling and the challenges associated with using standard pharmacogenetics panels in a diverse South Florida population.
METHODS: A total of 413 participants were recruited to participate in this study through Nicklaus Children's Hospital. Buccal swabs were collected and tested using an extended CYP2D6 panel including 22 alleles. Phenotype, genotype, and allelic frequencies were compared among different racial and ethnic groups.
RESULTS: The majority of participants (75.0%) self-identified as Hispanics. Four alleles, CYP2D6*4, *17, *41, and *2A, showed a statistically significant difference between White Hispanics and Black Non-Hispanics. Aggregate frequency of all alleles with decreased function varied between 2.8% and 50.0% in different racial and ethnic groups. Additionally, rare allele combinations were observed in this South Florida cohort.
CONCLUSIONS: The heterogeneity among Hispanic groups demonstrated in previous literature and by this study reflects the complexity of ethnicity and suggests that a more granular categorization is needed, one based on ancestry and migration history rather than primary language. Overall, we have determined that there are statistically significant differences in CYP2D6 allele frequencies in the distinct racial and ethnic populations of South Florida, demonstrating a unique genetic makeup within South Florida. However, overall, the frequencies of Poor Metabolizer, Normal Metabolizer, Intermediate Metabolizer, and Ultrarapid Metabolizer did not differ between racial and ethnic groups at a statistically significant level.

PMID: 31389673 [PubMed - as supplied by publisher]

Regulatory and other responses to the pharmaceutical opioid problem.

Med J Aust. 2019 Aug 06;:

Authors: Polasek T, Caramins M, Suthers G

PMID: 31389024 [PubMed - as supplied by publisher]

Regulatory and other responses to the pharmaceutical opioid problem.

Med J Aust. 2019 Aug 06;:

Authors: Campbell G, Larance B, Lintzeris N

PMID: 31389014 [PubMed - as supplied by publisher]

Racial association and pharmacotherapy in neonatal opioid withdrawal syndrome.

J Perinatol. 2019 Aug 06;:

Authors: Parikh A, Gopalakrishnan M, Azeem A, Booth A, El-Metwally D

Abstract
OBJECTIVE: To determine if racial differences are associated with Neonatal Opioid Withdrawal Syndrome (NOWS) severity.
STUDY DESIGN: A 10-year (2008-2017) retrospective cohort of infants ≥35 weeks gestation with prenatal exposure to opioids was included. The primary measure was the need for pharmacotherapy. Multivariable logistic regression and propensity score analysis were performed.
RESULTS: Among 345 infants with NOWS, 111 (32%) were black infants with 70% of them requiring pharmacotherapy as compared with 84% of white infants. Upon adjusting for significant covariates (methadone, benzodiazepine use, and gestational age), black infants were 57% less likely than whites to require pharmacotherapy (Odds ratio: 0.43, 95%CI: 0.22-0.80, p = 0.009). Similar results were observed with propensity score analysis.
CONCLUSIONS: Significant racial disparity observed may be secondary to genetic variations in opioid pharmacogenomics and/or extrinsic factors. Large-scale studies are warranted to include race in predictive models for early pharmacological intervention.

PMID: 31388115 [PubMed - as supplied by publisher]

Prediction of Acquired Taxane Resistance Using a Personalized Pathway-Based Machine Learning Method.

Cancer Res Treat. 2019 Apr;51(2):672-684

Authors: Kim YR, Kim D, Kim SY

Abstract
PURPOSE: This study was conducted to develop and validate an individualized prediction model for automated detection of acquired taxane resistance (ATR).
Materials and Methods: Penalized regression, combinedwith an individualized pathway score algorithm,was applied to construct a predictive model using publically available genomic cohorts of ATR and intrinsic taxane resistance (ITR). To develop a model with enhanced generalizability, we merged multiple ATR studies then updated the learning parameter via robust cross-study validation.
RESULTS: For internal cross-study validation, the ATR model produced a perfect performance with an overall area under the receiver operating curve (AUROC) of 1.000 with an area under the precision-recall curve (AUPRC) of 1.000, a Brier score of 0.007, a sensitivity and a specificity of 100%. The model showed an excellent performance on two independent blind ATR cohorts (overall AUROC of 0.940, AUPRC of 0.940, a Brier score of 0.127). When we applied our algorithm to two large-scale pharmacogenomic resources for ITR, the Cancer Genome Project (CGP) and the Cancer Cell Line Encyclopedia (CCLE), an overall ITR cross-study AUROC was 0.70, which is a far better accuracy than an almost random level reported by previous studies. Furthermore, this model had a high transferability on blind ATR cohorts with an AUROC of 0.69, suggesting that general predictive features may be at work across both ITR and ATR.
CONCLUSION: We successfully constructed a multi-study-derived personalized prediction model for ATR with excellent accuracy, generalizability, and transferability.

PMID: 30092623 [PubMed - indexed for MEDLINE]