A pediatric perspective on genomics and prevention in the twenty-first century.

Pediatr Res. 2019 Oct 02;:

Authors: Chaudhari BP, Manickam K, McBride KL

Abstract
We present evidence from diverse disciplines and populations to identify the current and emerging role of genomics in prevention from both medical and public health perspectives as well as key challenges and potential untoward consequences of increasing the role of genomics in these endeavors. We begin by comparing screening in healthy populations (newborn screening), with testing in symptomatic populations, which may incidentally identify secondary findings and at-risk relatives. Emerging evidence suggests that variants in genes subject to the reporting of secondary findings are more common than expected in patients who otherwise would not meet the criteria for testing and population testing for variants in these genes may more precisely identify discrete populations to target for various prevention strategies starting in childhood. Conversely, despite its theoretical promise, recent studies attempting to demonstrate benefits of next-generation sequencing for newborn screening have instead demonstrated numerous barriers and pitfalls to this approach. We also examine the special cases of pharmacogenomics and polygenic risk scores as examples of ways genomics can contribute to prevention amongst a broader population than that affected by rare Mendelian disease. We conclude with unresolved questions which will benefit from future investigations of the role of genomics in disease prevention.

PMID: 31578042 [PubMed - as supplied by publisher]

Genetics and pharmacogenetics in the diagnosis and therapy of cardiovascular diseases.

Acta Biomed. 2019 Sep 30;90(10-S):7-19

Authors: Krasi G, Precone V, Paolacci S, Stuppia L, Nodari S, Romeo F, Perrone M, Bushati V, Dautaj A, Bertelli M

Abstract
Cardiovascular diseases are the main cause of death worldwide. The ability to accurately define individual susceptibility to these disorders is therefore of strategic importance. Linkage analysis and genome-wide association studies have been useful for the identification of genes related to cardiovascular diseases. The identification of variants predisposing to cardiovascular diseases contributes to the risk profile and the possibility of tailored preventive or therapeutic strategies. Molecular genetics and pharmacogenetics are playing an increasingly important role in the correct clinical management of patients. For instance, genetic testing can identify variants that influence how patients metabolize medications, making it possible to prescribe personalized, safer and more efficient treatments, reducing medical costs and improving clinical outcomes. In the near future we can expect a great increment in information and genetic testing, which should be acknowledged as a true branch of diagnostics in cardiology, like hemodynamics and electrophysiology. In this review we summarize the genetics and pharmacogenetics of the main cardiovascular diseases, showing the role played by genetic information in the identification of cardiovascular risk factors and in the diagnosis and therapy of these conditions.

PMID: 31577248 [PubMed - in process]

Antidiabetic Potential of Medicinal Plants and Their Active Components.

Biomolecules. 2019 Sep 30;9(10):

Authors: Salehi B, Ata A, V Anil Kumar N, Sharopov F, Ramírez-Alarcón K, Ruiz-Ortega A, Abdulmajid Ayatollahi S, Tsouh Fokou PV, Kobarfard F, Amiruddin Zakaria Z, Iriti M, Taheri Y, Martorell M, Sureda A, Setzer WN, Durazzo A, Lucarini M, Santini A, Capasso R, Ostrander EA, Atta-ur-Rahman, Choudhary MI, Cho WC, Sharifi-Rad J

Abstract
Diabetes mellitus is one of the major health problems in the world, the incidence and associated mortality are increasing. Inadequate regulation of the blood sugar imposes serious consequences for health. Conventional antidiabetic drugs are effective, however, also with unavoidable side effects. On the other hand, medicinal plants may act as an alternative source of antidiabetic agents. Examples of medicinal plants with antidiabetic potential are described, with focuses on preclinical and clinical studies. The beneficial potential of each plant matrix is given by the combined and concerted action of their profile of biologically active compounds.

PMID: 31575072 [PubMed - in process]

A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity.

Genes (Basel). 2019 Sep 30;10(10):

Authors: Santos SM, Icyuz M, Pound I, William D, Guo J, McKinney BA, Niederweis M, Rodgers J, Iv JLH

Abstract
Knowledge about synthetic lethality can be applied to enhance the efficacy of anticancer therapies in individual patients harboring genetic alterations in their cancer that specifically render it vulnerable. We investigated the potential for high-resolution phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures yet distinct antitumor efficacy. Human deoxycytidine kinase (dCK) was conditionally expressed in the Saccharomyces cerevisiae genomic library of knockout and knockdown (YKO/KD) strains, to globally and quantitatively characterize differential drug-gene interaction for gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, histone modification, chromatin remodeling, and apoptosis-related processes influence gemcitabine specifically, while drug-gene interaction specific to cytarabine was less enriched in gene ontology. Processes having influence over both drugs were DNA repair and integrity checkpoints and vesicle transport and fusion. Non-gene ontology (GO)-enriched genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics data were integrated to identify yeast-human homologs with correlated differential gene expression and drug efficacy, thus providing a unique resource to predict whether differential gene expression observed in cancer genetic profiles are causal in tumor-specific responses to cytotoxic agents.

PMID: 31575041 [PubMed - in process]

The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)-Endoxifen in Breast Cancer.

Clin Transl Sci. 2019 Oct 01;:

Authors: Nardin JM, Schroth W, Almeida TA, Mürdter T, Picolotto S, Vendramini ECL, Hoppe R, Kogin JP, Miqueleto D, de Moraes SDR, Schwab M, Pecoits-Filho RF, Brauch H, Casali-da-Rocha JC

Abstract
Tamoxifen efficacy in breast cancer is suspected to depend on adherence and intact drug metabolism. We evaluated the role of adherence behavior and pharmacogenetics on the formation rate of (Z)-endoxifen. In 192 Brazilian patients we assessed plasma levels of tamoxifen and its metabolites at 3, 6, and 12 months of treatment (LC-MS/MS), adherence behavior (Morisky medication adherence scale), and CYP2D6 and other pharmacogene polymorphisms (MALDI-TOF mass spectrometry, real-time PCR). Adherence explained 47% of the variability of tamoxifen plasma concentrations (P<.001). While CYP2D6 alone explained 26.4%, the combination with adherence explained 40% of (Z)-endoxifen variability at 12 months (P<.001). The influence of low adherence to not achieving relevant (Z)-endoxifen levels was highest in patients with non-compromised CYP2D6 function (RR 3.65, 95% CI: 1.48-8.99). As a proof-of-concept we demonstrated that (Z)-endoxifen levels are influenced both by patient adherence to tamoxifen and CYP2D6 which is particularly relevant for patients with full CYP2D6 function.

PMID: 31573754 [PubMed - as supplied by publisher]

Editorial: Establishing Genetic Pleiotropy to Identify Common Pharmacological Agents for Common Diseases.

Front Pharmacol. 2019;10:1038

Authors: O'Mara TA, Batra J, Glubb D

PMID: 31572202 [PubMed]

Preliminary Clinical Investigation of Combinatorial Pharmacogenomic Testing for the Optimized Treatment of Depression: A Randomized Single-Blind Study.

Front Neurosci. 2019;13:960

Authors: Shan X, Zhao W, Qiu Y, Wu H, Chen J, Fang Y, Guo W, Li L

Abstract
This study aims to explore the potential benefits of antidepressant drugs related to metabolic enzyme and drug-targeted genes, identify the optimal treatment of major depression, and provide a reference for individualized medication selection. A prospective randomized single-blind investigation was conducted for 8 weeks. A pharmacogenomic-based interpretive report was provided to the treating physician in the guided group. Patients in this group were informed that their medication selection was directed by DNA testing. In the unguided group, treatment was provided based on the clinical experience of the physician without the guidance of pharmacogenomic testing. Pharmacogenomic-based interpretive report was not provided to these patients until treatment completion. The 17-item Hamilton depression scale (HAMD-17), Hamilton anxiety scale, and treatment emergent symptom scale were used to assess the clinical efficacy and side effects at baseline and after 2, 4, and 8 weeks of treatment. Among the 80 initially enrolled patients with depression, 71 participated in the full data analysis sets and were designated into guided (31) and unguided (40) groups, respectively. No significant difference (P > 0.05) in HAMD-17 total scores, response and remission rates was found between the guided and unguided groups at the end of the treatment. The incidence rate of adverse reaction was 55.56% in guided group and 57.89% in the unguided group. Our study suggested that pharmacogenomic testing might not considerably improve the clinical efficiency and safety for the guided group.

PMID: 31572113 [PubMed]

Association of IL-10-1082A/G polymorphism with cardiovascular disease risk: Evidence from a case-control study to an updated meta-analysis.

Mol Genet Genomic Med. 2019 Sep 30;:e888

Authors: Lu S, Zhong J, Huang K, Zhou H

Abstract
BACKGROUND: Previous studies have generated controversial results about the association of interleukin 10 (IL-10) gene polymorphisms (-1082G/A) in the progression of cardiovascular disease (CVD). Therefore, this study processed a systemic meta-analysis to verify this association.
METHODS: The publication studies on the IL-10 (-1082G/A) polymorphism and CVDs risk were obtained by searching PubMed and Embase databases. We analyzed the genotype data for meta-analysis. The results were evaluated by odds ratios (ORs) and 95% confidence intervals (CIs). Meanwhile, our meta-analysis was also performed sensitivity analyses, heterogeneity test, and identification of publication bias.
RESULTS: The present meta-analysis suggested that the risk with allele G is lower than with allele A for CVD. The G allele of IL-10 (-1082) could increase the risk of CVDs in the 31 case-control studies for all genetic models. (OR = 1.10, 95% CI: 1.04-1.15 for the allele model A vs. G; OR = 0.87, 95% CI: 0.72-1.04 for the dominant model GG+AG vs. AA; OR = 1.03, 95% CI: 1.02-1.05 for the recessive model GG vs. AG + AA; OR = 1.06, 95% CI = 1.03-1.10 for the homozygote comparison model GG vs. AA; and OR = 0.88, 95% CI = 0.73-1.06 for the heterozygote comparison model AG vs. AA).
CONCLUSIONS: In genetic models, the association between the IL-10 (-1082G/A) polymorphism and CVDs risk was significant. This meta-analysis proposes that the IL-10 (-1082G/A) polymorphism may serve as a risk factor for CVDs.

PMID: 31571432 [PubMed - as supplied by publisher]

Interaction Between Variations in Dopamine D2 and Serotonin 2A Receptor is Associated with Short-Term Response to Antipsychotics in Schizophrenia.

Neurosci Bull. 2019 Sep 30;:

Authors: Zhao L, Wang H, Zhang Y, Wei J, Ni P, Ren H, Li G, Wang Q, Reynolds GP, Yue W, Deng W, Yan H, Tan L, Chen Q, Yang G, Lu T, Wang L, Zhang F, Yang J, Li K, Lv L, Tan Q, Li Y, Yu H, Zhang H, Ma X, Yang F, Li L, Wang C, Wang H, Li X, Guo W, Hu X, Tian Y, Ma X, Coid J, Zhang D, Chen C, Li T, Chinese Antipsychotics Pharmacogenomics Consortium

PMID: 31571100 [PubMed - as supplied by publisher]

Age as a Predictor of Treatment Outcome in Metastatic Testicular Germ Cell Tumors.

Anticancer Res. 2019 Oct;39(10):5589-5596

Authors: Terbuch A, Posch F, Bauernhofer T, Pichler M, Peinsith H, Szkandera J, Riedl J, Hutterer GC, Pummer K, Partl R, Kapp KS, Stöger H, Stotz M, Gerger A

Abstract
BACKGROUND/AIM: To quantify the prognostic impact of age on relapse and mortality in patients with metastatic testicular germ cell tumors (TGCT).
PATIENTS AND METHODS: Electronical medical records of 1,225 TGCT patients who were treated at a single academic center between 1994 and 2015 were reviewed.
RESULTS: Higher age did not predict for worse progression-free survival (PFS) or for higher progression risk. The corresponding 5-year PFS estimates were 85% in patients younger than 40 years and 83% in the elderly population. Although not statistically significant, higher age was numerically associated with worse overall survival (OS) (univariate HR per five years increase in age=1.18, 95%CI=0.99-1.41). This was explained in regression analysis where age predicted for significantly higher risk of treatment-related death (p=0.022).
CONCLUSION: Elderly patients with metastatic TGCT can achieve high cure rates similar to younger patients if they tolerate risk-adapted chemotherapy.

PMID: 31570454 [PubMed - in process]

On the Marketing and Use of Pharmacogenetic Tests for Psychiatric Treatment.

JAMA Psychiatry. 2018 08 01;75(8):769-770

Authors: Zubenko GS, Sommer BR, Cohen BM

PMID: 29799933 [PubMed - indexed for MEDLINE]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/10/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/09/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Effect of Genetic and Non-genetic Factors on the Clinical Response to Mineralocorticoid Receptor Antagonist Therapy in Egyptians with Heart Failure.

Clin Transl Sci. 2019 Sep 27;:

Authors: Sarhan NM, Shahin MH, El Rouby NM, El-Wakeel LM, Solayman MH, Langaee T, Khorshid H, Schaalan MF, Sabri NA, Cavallari LH

Abstract
This prospective cohort study evaluated the association between renin-angiotensin-aldosterone-system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction (HFrEF). Genotype frequencies for AGT rs699 were: CC=16%, CT=48%, and TT=36%. Frequencies for CYP11B2 rs1799998 were: TT=33%, TC=50%, and CC=17%. After six months of spironolactone treatment, change in left ventricular ejection fraction (LVEF) differed by both AGT rs699 (CC, 14.6%; TC, 7.9%; TT, 2.7%; p=2.1E-26) and CYP11B2 rs1799998 (TT, 9.1%; TC, 8.7%; CC, 1.4%; p=0.0006) genotypes. Multivariate linear regression showed that the AGT rs699 and CYP11B2 rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in LVEF improvement (p=0.001), 63% of variability in serum potassium increase (p=2.25E-08), and 39% of the variability in improvement in quality of life (p=2.3E-04) with spironolactone therapy. These data suggest that AGT and CYP11B2 genotypes as well as baseline serum K are predictors of spironolactone response in HFrEF.

PMID: 31560448 [PubMed - as supplied by publisher]

APOE polymorphism is associated with blood lipid and serum uric acid metabolism in hypertension or coronary heart disease in a Chinese population.

Pharmacogenomics. 2019 Sep;20(14):1021-1031

Authors: Wang C, Yan W, Wang H, Zhu J, Chen H

Abstract
Aim: To explore the association of APOE polymorphism (rs7412:526C>T and rs429358:388T>C) with glucose, lipid and serum uric acid (UA) metabolism in patients with hypertension or coronary heart disease (CHD). Methods: A total of 544 patients with hypertension or CHD were selected for this study from March 2017 to January 2018. According to the APOE genotypes (excluding the E2/E4 genotype), the subjects were divided into three groups (E2/E2+E2/E3 genotypes, E3/E3 genotype [the wild-type] and E3/E4+E4/E4 genotypes) and the difference of metabolism among the three groups was compared. Results: There were significant differences in total cholesterol (TC), triglycerides, low-density lipoprotein (LDL), high-density lipoprotein and serum UA levels among the three groups. Compared with APOE E3 homozygote, APOE E4 carriers possessed higher TC, triglycerides and LDL levels, whereas APOE E2 carriers had higher high-density lipoprotein level, lower TC and LDL levels. Furthermore, multivariate logistic regression analysis found that setting E3/E3 genotype as the reference group, the carriers of APOE E4 allele (E3/E4+E4/E4 genotypes) were significantly related to hypertriglyceridemia, and APOE E2 allele (E2/E2+E2/E3 genotypes) was significantly correlated with hyperuricemia. Conclusion: APOE polymorphism was associated with blood lipid and serum UA metabolism in patients with hypertension or CHD. Compared with APOE E3 homozygote, APOE E4 allele was related to elevated triglycerides, and APOE E2 allele was correlated with increased serum UA level.

PMID: 31559922 [PubMed - in process]

Nanopore sequencing of the pharmacogene CYP2D6 allows simultaneous haplotyping and detection of duplications.

Pharmacogenomics. 2019 Sep;20(14):1033-1047

Authors: Liau Y, Maggo S, Miller AL, Pearson JF, Kennedy MA, Cree SL

Abstract
Aim: Long read sequencing offers the promise of overcoming some of the challenges in accurate genotyping of complex genes, along with the advantage of straightforward variant phasing. We have established methods for sequencing and haplotyping of the whole CYP2D6 gene using nanopore sequencing. Materials and methods: 32 samples covering various haplotypes including gene duplication were sequenced on the GridION platform. Results: Haplotypes of 52 alleles matched accurately to known star (*) allele subvariants, with the remaining 12 being assigned as new alleles, or new subvariants of known alleles. Duplicated alleles could be detected by analyzing the allelic balance. Conclusion: Nanopore sequencing of CYP2D6 offers a high throughput method for accurate haplotyping, detection of new variants and determination of duplicated alleles.

PMID: 31559921 [PubMed - in process]

Integration of machine learning and pharmacogenomic biomarkers for predicting response to antidepressant treatment: can computational intelligence be used to augment clinical assessments?

Pharmacogenomics. 2019 Sep;20(14):983-988

Authors: Athreya AP, Iyer R, Wang L, Weinshilboum RM, Bobo WV

PMID: 31559920 [PubMed - in process]

Characterizing the pharmacogenome using molecular inversion probes for targeted next-generation sequencing.

Pharmacogenomics. 2019 Sep;20(14):1005-1020

Authors: Suzuki O, Dong OM, Howard RM, Wiltshire T

Abstract
Aim: This study assesses the technical performance and cost of a targeted next-generation sequencing (NGS) multigene pharmacogenetic (PGx) test. Materials & methods: A genetic test was developed for 21 PGx genes using molecular inversion probes to generate library fragments for NGS. Performance of this test was assessed using 53 unique reference control cell lines from the Genetic Testing Reference Materials Coordination Program (GeT-RM). Results: 93.7% of variants were successfully called and the repeatability rate was 99.9%. Reference calls were available for 78.4% of diplotype calls resulting from PGx testing, and concordance for the test was 85.7%. Cost per sample was $32-$56. Conclusion: A targeted NGS assay using molecular inversion probe technology is able to characterize the pharmacogenome efficiently.

PMID: 31559919 [PubMed - in process]

Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants.

Pharmacogenomics. 2019 Sep;20(14):989-1003

Authors: Sadhasivam S, Brandom BW, Henker RA, McAuliffe JJ

Abstract
Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.

PMID: 31559918 [PubMed - in process]

miRNAs in drug response variability: potential utility as biomarkers for personalized medicine.

Pharmacogenomics. 2019 Sep;20(14):1049-1059

Authors: Latini A, Borgiani P, Novelli G, Ciccacci C

Abstract
MicroRNAs (miRNAs) are 18-22 nucleotide RNA molecules that modulate the expression of multiple protein-encoding genes at the post-transcriptional level. Almost all physiological conditions are probably modulated by miRNAs, including pharmacological response. Indeed, acting on the regulation of numerous genes involved in the pharmacokinetics and pharmacodynamics of drugs, differences in the levels of circulating miRNAs or genetic variants in the sequences of the miRNA genes can contribute to interindividual variability in drug response, both in terms of toxicity and efficacy. For their stability in body fluids and the easy availability and accurate quantification, miRNAs could be ideal biomarkers of individual response to drugs. This review aims to give an overview on the available studies that have investigated the relationship between miRNAs and response to drugs in different classes of diseases and considered their possible clinical application as therapy response predictive biomarkers. A comprehensive search was conducted from the international web database PubMed. We included papers that investigated the relationship between miRNAs and response to drugs, published before January 2019.

PMID: 31559917 [PubMed - in process]