Challenges in preclinical to clinical translation for anticancer carrier-mediated agents.

Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2016 Sep;8(5):642-53

Authors: Lucas AT, Madden AJ, Zamboni WC

Abstract
Major advances in carrier-mediated agents (CMAs), which include nanoparticles and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small-molecule counterparts, there is substantial variability in how individual CMA formulations and patient characteristics affect the pharmacology, pharmacokinetics (PK), and pharmacodynamics (PD) (efficacy and toxicity) of these agents. Development or selection of animal models is used to predict the effects within a particular human disease. A breadth of studies have begun to emphasize the importance of preclinical animal models in understanding and evaluating the interaction between CMAs and the immune system and tumor matrix, which ultimately influences CMA PK (clearance and distribution) and PD (efficacy and toxicity). It is fundamental to study representative preclinical tumor models that recapitulate patients with diseases (e.g., cancer) and evaluate the interplay between CMAs and the immune system, including the mononuclear phagocyte system (MPS), chemokines, hormones, and other immune modulators. Furthermore, standard allometric scaling using body weight does not accurately predict drug clearance in humans. Future studies are warranted to better understand the complex pharmacology and interaction of CMA carriers within individual preclinical models and their biological systems, such as the MPS and tumor microenvironment, and their application to allometric scaling across species. WIREs Nanomed Nanobiotechnol 2016, 8:642-653. doi: 10.1002/wnan.1394 For further resources related to this article, please visit the WIREs website.

PMID: 26846457 [PubMed - indexed for MEDLINE]

Urinary levels of triclosan and triclocarban in several Asian countries, Greece and the USA: Association with oxidative stress.

Environ Res. 2017 Sep 28;160:91-96

Authors: Iyer AP, Xue J, Honda M, Robinson M, Kumosani TA, Abulnaja K, Kannan K

Abstract
Triclosan (TCS) and Triclocarban (TCC) are widely used as antimicrobial preservatives in personal care products (PCPs). Because of their potential for endocrine disrupting effects, human exposure to these chemicals is a concern. Biomonitoring studies of human exposure to TCS and TCC have shown widespread exposure of populations in western European countries and the USA. However, exposure to TCC and TCS by populations in Asian countries is less well known. In this study, concentrations of TCS and TCC were determined in human urine collected from seven Asian countries (China, India, Korea, Kuwait, Japan, Saudi Arabia, and Vietnam), and Greece and the USA. A total of 430 urine samples were analyzed for TCS and TCC, of which 355 (83%) and 82 (19%), respectively, contained measurable levels of these chemicals. The overall geometric mean [GM] concentrations of TCS and TCC, were 1.36 and 0.03ng/mL, respectively. The highest mean concentration of TCS was found in urine from China (100ng/mL) and the lowest concentration was found in urine from Vietnam (2.34ng/mL). We also analyzed urinary 8-OHdG, a marker of oxidative stress, to elucidate the association with TCS and TCC levels for samples from Saudi Arabia (n=130) and a positive correlation between Ln-transformed TCC levels and 8-OHdG was found, although this was not statistically significant. This is the first study to report urinary levels of TCS and TCC in several Asian countries, especially for Vietnam, Kuwait, and Japan.

PMID: 28964967 [PubMed - as supplied by publisher]

Simplifying the Use of Pharmacogenomics in Clinical Practice: Building the Genomic Prescribing System.

J Biomed Inform. 2017 Sep 26;:

Authors: Danahey K, Borden BA, Furner B, Yukman P, Hussain S, Saner D, Volchenboum SL, Ratain MJ, O'Donnell PH

Abstract
BACKGROUND: A barrier to the use of genomic information during prescribing is the limited number of software solutions that combine a user-friendly interface with complex medical data. We built and designed an online, secure, electronic custom interface termed the Genomic Prescribing System (GPS).
METHODS: Actionable pharmacogenomic (PGx) information was reviewed, collected, and stored in the back-end of GPS to enable creation of customized drug- and variant-specific clinical decision support (CDS) summaries. The database architecture utilized the star schema to store information. Patient raw genomic data underwent transformation via custom-designed algorithms to enable gene and phenotype-level associations. Multiple external data sets (PubMed, The Systematized Nomenclature of Medicine (SNOMED), National Drug File - Reference Terminology (ND-FRT), and a publically-available PGx knowledgebase) were integrated to facilitate the delivery of patient, drug, disease, and genomic information. Institutional security infrastructure was leveraged to securely store patient genomic and clinical data on a HIPAA-compliant server farm.
RESULTS: As of May 17, 2016, the GPS back-end housed 257 CDS encompassing 112 genetic variants, 42 genes, and 46 PGx-actionable drugs. The GPS user interface presented patient-specific CDS alongside a recognizable traffic light symbol (green/yellow/red), denoting PGx risk for each genomic result. The number of traffic lights per visit increased with the corresponding increase in the number of available PGx-annotated drugs over time. An integrated drug and disease search functionality, links to primary literature sources, and potential alternative PGx drugs were indicated. The system, which was initially used as stand-alone CDS software within our clinical environment, was then integrated with the institutional electronic medical record for enhanced usability. There have been nearly 2000 logins in 43 months since inception, with usage exceeding 56 logins per month and system up-times of 99.99%. For all patient-provider visits encompassing >3 years of implementation, unique alert click-through rates corresponded to genomic risk: red lights clicked 100%, yellow lights 79%, green lights 43%.
CONCLUSIONS: Successful deployment of GPS by combining complex data and recognizable iconography led to a tool that enabled point-of-care genomic delivery with high usability. Continued scalability and incorporation of additional clinical elements to be considered alongside PGx information could expand future impact.

PMID: 28963061 [PubMed - as supplied by publisher]

ncDR: A Comprehensive Resource of Non-coding RNAs Involved in Drug Resistance.

Bioinformatics. 2017 Aug 17;:

Authors: Dai E, Yang F, Wang J, Zhou X, Song Q, An W, Wang L, Jiang W

Abstract
Summary: As a promising field of individualized therapy, non-coding RNA pharmacogenomics promotes the understanding of different individual responses to certain drugs and acts as a reasonable reference for clinical treatment. However, relevant information is scattered across the published literature, which is inconvenient for researchers to explore non-coding RNAs that are involved in drug resistance. To address this, we systemically identified validated and predicted drug resistance-associated microRNAs and long non-coding RNAs through manual curation and computational analysis. Subsequently, we constructed an omnibus repository named ncDR, which furnishes a user-friendly interface that allows for convenient browsing, visualization, querying and downloading of data. Given the rapidly increasing interest in precision medicine, ncDR will significantly improve our understanding of the roles of regulatory non-coding RNAs in drug resistance and has the potential to be a timely and valuable resource.
Availability and Implementation: http://www.jianglab.cn/ncDR/ .
Contact: jiangwei@hrbmu.edu.cn , lw2247@yeah.net .
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 28961690 [PubMed - as supplied by publisher]

Novel intronic RHD variants identified in serologically D-negative blood donors.

Vox Sang. 2017 Sep 29;:

Authors: El Wafi M, El Housse H, Zaid N, Zouine S, Nourichafi N, Bouisk K, Benajiba M, Habti N

Abstract
BACKGROUND: Blood group genotyping is used to predict RhD phenotype in transfusion and obstetric medicine. Prediction of antigen D is based on molecular techniques which targets most common RHD-specific polymorphism. However, inactive RHD variants can suggest false-positive RhD phenotype. Their types and frequencies vary among ethnicities. Our study aimed to identify RHD variants among Moroccan blood donors who are serologically D negative.
STUDY DESIGN AND METHODS: DNA from 53 blood donors who are serologically D negative RhC and/or RhE positive were screened for RHD exon 10 by PCR-SSP. RHD-positive samples were further tested by multiplex PCR covering exons 3, 4, 5, 6, 7 and 9 and then sequenced by targeted next-generation sequencing method. Mutations' impact on mRNA splicing was predicted using alamut software version 2·0.
RESULTS: PCR-SSP revealed 9 of 53 (16·9%) RHD-positive samples. Five of nine samples were positive for all tested exons, two of nine were positive for exon 9, and two of nine were undetermined. Sequencing revealed four novel RHD variants based on six mutations in introns 1, 3, 5 and 6. In silico analysis revealed aberrant splicing of three mutations (RHD c.487-1024delG, RHD c.487-256T>G and RHD c.940-187_940-188del), while three other mutations (RHD c.149-682C>A, RHD c.802-37delA and RHD c.939 + 1151dup) had no effect on splicing compared to wild type.
CONCLUSIONS: All identified RHD variants contain at least one mutation that probably affects splicing to generate D-negative phenotype. Hence, ethnic RhD antigen background must be considered when developing transfusion and obstetric strategies.

PMID: 28960314 [PubMed - as supplied by publisher]

Variants in the CYP2B6 3'UTR alter in vitro and in vivo CYP2B6 activity: Potential role of microRNAs.

Clin Pharmacol Ther. 2017 Sep 27;:

Authors: Burgess KS, Ipe J, Swart M, Metzger IF, Lu J, Gufford BT, Thong N, Desta Z, Gaedigk R, Pearce R, Gaedigk A, Liu Y, Skaar TC

Abstract
CYP2B6*6 and CYP2B6*18 are the most clinically important variants causing reduced CYP2B6 protein expression and activity. However, these variants do not account for all variability in CYP2B6 activity. Emerging evidence has shown that genetic variants in the 3'UTR may explain variable drug response by altering microRNA regulation. Five 3'UTR variants were associated with significantly altered efavirenz AUC0-48 (8-OH-EFV/EFV) ratios in healthy human volunteers. The rs70950385 (AG>CA) variant, predicted to create a microRNA binding site for miR-1275, was associated with 33% decreased CYP2B6 activity among normal metabolizers (AG/AG vs. CA/CA [p<0.05]). In vitro luciferase assays were used to confirm that the CA on the variant allele created a microRNA binding site causing a 11.3% decrease in activity compared to the AG allele when treated with miR-1275 (p=0.0035). Our results show that a 3'UTR variant contributes to variability in CYP2B6 activity. This article is protected by copyright. All rights reserved.

PMID: 28960269 [PubMed - as supplied by publisher]

CYP polymorphisms and pathological conditions related to chronic exposure to organochlorine pesticides.

Toxicol Rep. 2017;4:335-341

Authors: Docea AO, Vassilopoulou L, Fragou D, Arsene AL, Fenga C, Kovatsi L, Petrakis D, Rakitskii VN, Nosyrev AE, Izotov BN, Golokhvast KS, Zakharenko AM, Vakis A, Tsitsimpikou C, Drakoulis N

Abstract
The association between genetic variations in the cytochrome P450 (CYP) family genes and pathological conditions related to long-term exposure to organochlorine compounds (OCs) deserves further elucidation. OCs are persistent organic pollutants with bioaccumulative and lipophilic characteristics. They can act as endocrine disruptors and perturb cellular mechanisms. Prolonged exposure to OCs has been associated with different pathological manifestations. CYP genes are responsible for transcribing enzymes essential in xenobiotic metabolism. Therefore, polymorphisms in these genetic sequences a. alter the metabolic pathways, b. induce false cellular responses, and c. may provoke pathological conditions. The main aim of this review is to define the interaction between parameters a, b and c at a mechanistic/molecular level, with references in clinical cases.

PMID: 28959657 [PubMed]

Cost effectiveness analysis of HLA-B*58:01 genotyping prior to initiation of allopurinol for gout.

Rheumatology (Oxford). 2017 Oct 01;56(10):1729-1739

Authors: Plumpton CO, Alfirevic A, Pirmohamed M, Hughes DA

Abstract
Objective: To determine whether prospective testing for HLA-B*58:01, as a strategy to prevent serious adverse reactions to allopurinol in patients with gout, is cost-effective from the perspective of the National Health Service in the UK.
Methods: A systematic review and meta-analysis for the association of HLA-B*58:01 with cutaneous and hypersensitivity adverse drug reactions informed a decision analytic and Markov model to estimate lifetime costs and outcomes associated with testing vs standard care (with febuxostat prescribed for patients who test positive). Scenario analyses assessed alternative treatment assumptions and patient populations.
Results: The number of patients needed to test to prevent one case of adverse drug reaction was 11 286 (95% central range (CR): 2573, 53 594). Cost and quality-adjusted life-year (QALY) gains were small, £103 (95% CR: £98, £106) and 0.0023 (95% CR: -0.0006, 0.0055), respectively, resulting in an incremental cost-effectiveness ratio (ICER) of £44 954 per QALY gained. The probability of testing being cost-effective at a threshold of £30 000 per QALY was 0.25. Reduced costs of testing or febuxostat resulted in an ICER below £30 000 per QALY gained. The ICER for patients with chronic renal insufficiency was £38 478 per QALY gained.
Conclusion: Routine testing for HLA-B*58:01 in order to reduce the incidence of adverse drug reactions in patients being prescribed allopurinol for gout is unlikely to be cost-effective in the UK; however testing is expected to become cost-effective with reductions in the cost of genotyping, and with the future availability of cheaper, generic febuxostat.

PMID: 28957559 [PubMed - in process]

Accurate clinical genetic testing for autoinflammatory diseases using the next-generation sequencing platform MiSeq.

Biochem Biophys Rep. 2017 Mar;9:146-152

Authors: Nakayama M, Oda H, Nakagawa K, Yasumi T, Kawai T, Izawa K, Nishikomori R, Heike T, Ohara O

Abstract
Autoinflammatory diseases occupy one of a group of primary immunodeficiency diseases that are generally thought to be caused by mutation of genes responsible for innate immunity, rather than by acquired immunity. Mutations related to autoinflammatory diseases occur in 12 genes. For example, low-level somatic mosaic NLRP3 mutations underlie chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID). In current clinical practice, clinical genetic testing plays an important role in providing patients with quick, definite diagnoses. To increase the availability of such testing, low-cost high-throughput gene-analysis systems are required, ones that not only have the sensitivity to detect even low-level somatic mosaic mutations, but also can operate simply in a clinical setting. To this end, we developed a simple method that employs two-step tailed PCR and an NGS system, MiSeq platform, to detect mutations in all coding exons of the 12 genes responsible for autoinflammatory diseases. Using this amplicon sequencing system, we amplified a total of 234 amplicons derived from the 12 genes with multiplex PCR. This was done simultaneously and in one test tube. Each sample was distinguished by an index sequence of second PCR primers following PCR amplification. With our procedure and tips for reducing PCR amplification bias, we were able to analyze 12 genes from 25 clinical samples in one MiSeq run. Moreover, with the certified primers designed by our short program-which detects and avoids common SNPs in gene-specific PCR primers-we used this system for routine genetic testing. Our optimized procedure uses a simple protocol, which can easily be followed by virtually any office medical staff. Because of the small PCR amplification bias, we can analyze simultaneously several clinical DNA samples with low cost and can obtain sufficient read numbers to detect a low level of somatic mosaic mutations.

PMID: 28956000 [PubMed]

COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls.

Neurology. 2017 Sep 27;:

Authors: Rannikmäe K, Sivakumaran V, Millar H, Malik R, Anderson CD, Chong M, Dave T, Falcone GJ, Fernandez-Cadenas I, Jimenez-Conde J, Lindgren A, Montaner J, O'Donnell M, Paré G, Radmanesh F, Rost NS, Slowik A, Söderholm M, Traylor M, Pulit SL, Seshadri S, Worrall BB, Woo D, Markus HS, Mitchell BD, Dichgans M, Rosand J, Sudlow CLM, Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC)

Abstract
OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.
METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.
RESULTS: A locus in COL4A2 was associated (significance threshold p < 3.5 × 10(-4)) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, p = 6.62 × 10(-8)) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, p = 5.76 × 10(-5)). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10(-4)) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, p = 1.90 × 10(-4)) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.
CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

PMID: 28954878 [PubMed - as supplied by publisher]

Pharmacoepidemiological safety studies in children: a systematic review.

Pharmacoepidemiol Drug Saf. 2016 Aug;25(8):861-70

Authors: Osokogu OU, Dukanovic J, Ferrajolo C, Dodd C, Pacurariu AC, Bramer WM, 'tJong G, Weibel D, Sturkenboom MC, Kaguelidou F

Abstract
PURPOSE: In order to identify challenges in pediatric pharmacoepidemiological safety studies, we assessed the characteristics of such (published) studies.
METHODS: Relevant articles from inception to 2013 were retrieved from Embase and Medline. We sequentially screened titles, abstracts and full texts with independent validation. We systematically collected data regarding general information, study methods and results.
RESULTS: Out of 4825 unique articles, 268 full texts (5.6%) were retained; 147 (54.9%) pertained to drugs rather than vaccines. Considering the 268 studies, 202 (75.4%) concerned children and adolescents (2 to 11 years) and 14 (5.3%) included preterm newborns. Most studies originated from North America (154 [57.5%]) or Europe (92 [34.3%]). Only 47 studies (17.5%) were privately funded. The majority (174 [64.9%]) were cohort studies. Out of 268 studies, 196 (73.1%) collected data retrospectively; paper medical charts were the most common data source for the exposures (85 [31.7%]) and outcomes (122 [45.5%]). Only 3 (2.0%) drug-only studies investigated rarely used drugs. Considering all 268 studies, only 27 (10.1%) reported sample size or power calculation. Most (75 [51.0%]) drug-only studies corrected confounding by multivariate modeling unlike stratification in 66 (55.9%) vaccine-only studies. Considering 75 child-only studies without any statistically significant result, 41 (54.7%) did not discuss lack of power.
CONCLUSIONS: Although the field of pediatric pharmacoepidemiology is steadily developing evaluation seldom includes neonates, is mainly focused on few drug classes and safety outcomes and concerns mainly drug use in developed countries. Small study size is a specific challenge in pediatrics. Reporting should be improved. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

PMID: 27255559 [PubMed - indexed for MEDLINE]

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 2017/09/28

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.

Metastasis-associated in colon cancer 1: A promising biomarker for the metastasis and prognosis of colorectal cancer.

Oncol Lett. 2017 Oct;14(4):3899-3908

Authors: Li H, Chen YX, Wen JG, Zhou HH

Abstract
Colorectal cancer (CRC) is the fourth most frequent type of malignancy in the world. Metastasis accounts for >90% mortalities in patients with CRC. The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as a novel biomarker for the prediction of metastasis and disease prognosis, particularly for patients with early-stage disease. Previous clinical studies demonstrated that MACC1 expression and polymorphisms in CRC tissues were indicators of metastasis, and that circulating transcripts in plasma were also significantly associated with the survival of patients. The present review describes the use of MACC1 beyond its utility in the clinic. By elucidating the upstream and downstream signal pathways of MACC1, the well-known mechanisms of MACC1-mediated cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) are summarized, as well as the potential signaling pathways. Furthermore, the underlying mechanisms by which the overexpression of MACC1 causes cisplatin resistance are emphasized.

PMID: 28943898 [PubMed]

Whole Transcriptome Profiling: An RNA-Seq Primer and Implications for Pharmacogenomics Research.

Clin Transl Sci. 2017 Sep 25;:

Authors: Costa Sá AC, Sadee W, Johnson JA

Abstract
Pharmacogenomics has revealed compelling genetic signals associated with variability in drug response. Gene expression studies represent an additional approach to identify candidate genes accounting for drug response variability. This review focuses on insights that might be gained through analysis of the transcriptome to reveal the influence of gene expression on variable drug response. We provide a basic overview of RNA-Sequencing (RNA-Seq) and its applications, and outline advances in pharmacogenomics achievable with RNA-Seq data. This article is protected by copyright. All rights reserved.

PMID: 28945944 [PubMed - as supplied by publisher]

Clinical and molecular characteristics of non-small cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.

Ann Oncol. 2017 Jul 28;:

Authors: Leduc C, Merlio JP, Besse B, Blons H, Debieuvre D, Bringuier PP, Monnet I, Rouquette I, Fraboulet-Moreau S, Lemoine A, Pouessel D, Mosser J, Vaylet F, Langlais A, Missy P, Morin F, Moro-Sibilot D, Cadranel J, Barlesi F, Beau-Faller M, French Cooperative Thoracic Intergroup (IFCT)

Abstract
Background: EGFR mutations cause inconsistent response to EGFR tyrosine kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR -mutated NSCLC collected in the Biomarkers France database.
Patients and methods: Of 17,664 patients, 1,837 (11%) with EGFR -mutated non-small cell lung cancer (NSCLC) were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 Stage IV patients.
Results: EGFR exon 18, 19, 20, and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%), and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type (WT) (exon 19: hazard ratio [HR]=0.51 [95% confidence interval [CI]: 0.41-0.64], p < 0.0001 ; exon 21: HR = 0.76 [95% CI: 0.61-0.95], p = 0.002 ; exon 20: HR = 1.56, [95% CI: 1.02-2.38], p = 0.004 ). EGFR mutation type was prognostic of progression-free survival (PFS) versus WT (exon 19: HR = 0.62 [95% CI: 0.49-0.78], p < 0.0001 ; exon 20: HR = 1.46 [95% CI: 0.96-2.21], p = 0.07 ). First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved PFS versus chemotherapy (HR = 0.67 [95% CI: 0.53-0.85], p = 0.001 ). OS was longer for del19 versus L858R, which was associated with better OS compared to other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.
Conclusion: EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

PMID: 28945865 [PubMed - as supplied by publisher]

Identification of the genetic determinants responsible for retinal degeneration in families of Mexican descent.

Ophthalmic Genet. 2017 Sep 25;:1-7

Authors: Villanueva A, Biswas P, Kishaba K, Suk J, Tadimeti K, Raghavendra PB, Nadeau K, Lamontagne B, Busque L, Geoffroy S, Mongrain I, Asselin G, Provost S, Dubé MP, Nudleman E, Ayyagari R

Abstract
PURPOSE: To investigate the clinical characteristics and genetic basis of inherited retinal degeneration (IRD) in six unrelated pedigrees from Mexico.
METHODS: A complete ophthalmic evaluation including measurement of visual acuities, Goldman kinetic or Humphrey dynamic perimetry, Amsler test, fundus photography, and color vision testing was performed. Family history and blood samples were collected from available family members. DNA from members of two pedigrees was examined for known mutations using the APEX ARRP genotyping microarray and one pedigree using the APEX LCA genotyping microarray. The remaining three pedigrees were analyzed using a custom-designed targeted capture array covering the exons of 233 known retinal degeneration genes. Sequencing was performed on Illumina HiSeq. Reads were mapped against hg19, and variants were annotated using GATK and filtered by exomeSuite. Segregation and ethnicity-matched control sample analyses were performed by dideoxy sequencing.
RESULTS: Six pedigrees with IRD were analyzed. Nine rare or novel, potentially pathogenic variants segregating with the phenotype were detected in IMPDH1, USH2A, RPE65, ABCA4, and FAM161A genes. Among these, six were known mutations while the remaining three changes in USH2A, RPE65, and FAM161A genes have not been previously reported to be associated with IRD. Analysis of 100 ethnicity-matched controls did not detect the presence of these three novel variants indicating, these are rare variants in the Mexican population.
CONCLUSIONS: Screening patients diagnosed with IRD from Mexico identified six known mutations and three rare or novel potentially damaging variants in IMPDH1, USH2A, RPE65, ABCA4, and FAM161A genes that segregated with disease.

PMID: 28945494 [PubMed - as supplied by publisher]

Influence of polygenic risk scores on lipid levels and dyslipidemia in a psychiatric population receiving weight gain-inducing psychotropic drugs.

Pharmacogenet Genomics. 2017 Sep 21;:

Authors: Delacrétaz A, Lagares Santos P, Saigi Morgui N, Vandenberghe F, Glatard A, Gholam-Rezaee M, von Gunten A, Conus P, Eap CB

Abstract
OBJECTIVES: Dyslipidemia represents a major health issue in psychiatry. We determined whether weighted polygenic risk scores (wPRSs) combining multiple single-nucleotide polymorphisms (SNPs) associated with lipid levels in the general population are associated with lipid levels [high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides] and/or dyslipidemia in patients receiving weight gain-inducing psychotropic drugs. We also determined whether genetics improve the predictive power of dyslipidemia.
PATIENTS AND METHODS: The influence of wPRS on lipid levels was firstly assessed in a discovery psychiatric sample (n=332) and was then tested for replication in an independent psychiatric sample (n=140). The contribution of genetic markers to predict dyslipidemia was evaluated in the combined psychiatric sample.
RESULTS: wPRSs were significantly associated with the four lipid traits in the discovery (P≤0.02) and in the replication sample (P≤0.03). Patients whose wPRS was higher than the median wPRS had significantly higher LDL, TC, and triglyceride levels (0.20, 0.32 and 0.26 mmol/l, respectively; P≤0.004) and significantly lower HDL levels (0.13 mmol/l; P<0.0001) compared with others. Adding wPRS to clinical data significantly improved dyslipidemia prediction of HDL (P=0.03) and a trend for improvement was observed for the prediction of TC dyslipidemia (P=0.08).
CONCLUSION: Population-based wPRSs have thus significant effects on lipid levels in the psychiatric population. As genetics improved the predictive power of dyslipidemia development, only 24 patients need to be genotyped to prevent the development of one case of HDL hypocholesterolemia. If confirmed by further prospective investigations, the present results could be used for individualizing psychotropic treatment.

PMID: 28945215 [PubMed - as supplied by publisher]

Pharmacogenetics of Lipid-Lowering Agents: an Update Review on Genotype-Dependent Effects of HDL-Targetingand Statin Therapies.

Curr Atheroscler Rep. 2017 Sep 25;19(11):43

Authors: Messas N, Dubé MP, Tardif JC

Abstract
PURPOSE OF REVIEW: High-density lipoproteins (HDL) are involved in reverse cholesterol transport. Results from randomized trials of HDL-targeting therapies, including cholesteryl ester transfer protein (CETP) inhibitors, have shown a lack of benefit in unsegmented populations. These observations could be explained by inter-individual variability of clinical responses to such agents depending on the patients' genotypes. In parallel, although lowering of LDL cholesterol (LDL-c) with statin therapy reduces the risk of vascular events in a wide range of individuals, inter-individual variability exists with regard to LDL-c-lowering response as well as efficacy in reducing major cardiovascular events.
RECENT FINDINGS: Pharmacogenomic analyses were performed in the dal-OUTCOMES and dal-PLAQUE-2 studies. Beneficial and concordant results were observed in patients with the favorable genotype when treated with the CETP inhibitor dalcetrapib. Similarly, previous studies revealed genetic variants associated with differential LDL-c response to statin therapy. In this review, we discuss the pharmacogenetic determinants of HDL-targeting and statin therapy responses in light of the latest available published data, and their potential therapeutic applications.

PMID: 28944433 [PubMed - in process]

Gene-specific DNA methylation may mediate atypical antipsychotic-induced insulin resistance.

Bipolar Disord. 2016 Aug;18(5):423-32

Authors: Burghardt KJ, Goodrich JM, Dolinoy DC, Ellingrod VL

Abstract
OBJECTIVES: Atypical antipsychotics (AAPs) carry a significant risk of cardiometabolic side effects, including insulin resistance. It is thought that the insulin resistance resulting from the use of AAPs may be associated with changes in DNA methylation. We aimed to identify and validate a candidate gene associated with AAP-induced insulin resistance by using a multi-step approach that included an epigenome-wide association study (EWAS) and validation with site-specific methylation and metabolomics data.
METHODS: Subjects with bipolar disorder treated with AAPs or lithium monotherapy were recruited for a cross-sectional visit to analyze peripheral blood DNA methylation and insulin resistance. Epigenome-wide DNA methylation was analyzed in a discovery sample (n = 48) using the Illumina 450K BeadChip. Validation analyses of the epigenome-wide findings occurred in a separate sample (n = 72) using site-specific methylation with pyrosequencing and untargeted metabolomics data. Regression analyses were conducted controlling for known confounders in all analyses and a mediation analysis was performed to investigate if AAP-induced insulin resistance occurs through changes in DNA methylation.
RESULTS: A differentially methylated probe associated with insulin resistance was discovered and validated in the fatty acyl CoA reductase 2 (FAR2) gene of chromosome 12. Functional associations of this DNA methylation site with untargeted phospholipid-related metabolites were also detected. Our results identified a mediating effect of this FAR2 methylation site on AAP-induced insulin resistance.
CONCLUSIONS: Going forward, prospective, longitudinal studies assessing comprehensive changes in FAR2 DNA methylation, expression, and lipid metabolism before and after AAP treatment are required to assess its potential role in the development of insulin resistance.

PMID: 27542345 [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 2017/09/25

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.