Increased mitochondrial respiration of adipocytes from metabolically unhealthy obese compared to healthy obese individuals.

Sci Rep. 2020 07 24;10(1):12407

Authors: Böhm A, Keuper M, Meile T, Zdichavsky M, Fritsche A, Häring HU, de Angelis MH, Staiger H, Franko A

Abstract
Among obese subjects, metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Insulin resistance and obesity are known to associate with alterations in mitochondrial density, morphology, and function. Therefore, we assessed mitochondrial function in human subcutaneous preadipocytes as well as in differentiated adipocytes derived from well-matched donors. Primary subcutaneous preadipocytes from 4 insulin-resistant (MUHO) versus 4 insulin-sensitive (MHO), non-diabetic, morbidly obese Caucasians (BMI > 40 kg/m2), matched for sex, age, BMI, and percentage of body fat, were differentiated in vitro to adipocytes. Real-time cellular respiration was measured using an XF24 Extracellular Flux Analyzer (Seahorse). Lipolysis was stimulated by forskolin (FSK) treatment. Mitochondrial respiration was fourfold higher in adipocytes versus preadipocytes (p = 1.6*10-9). In adipocytes, a negative correlation of mitochondrial respiration with donors' insulin sensitivity was shown (p = 0.0008). Correspondingly, in adipocytes of MUHO subjects, an increased basal respiration (p = 0.002), higher proton leak (p = 0.04), elevated ATP production (p = 0.01), increased maximal respiration (p = 0.02), and higher spare respiratory capacity (p = 0.03) were found, compared to MHO. After stimulation with FSK, the differences in ATP production, maximal respiration and spare respiratory capacity were blunted. The differences in mitochondrial respiration between MUHO/MHO were not due to altered mitochondrial content, fuel switch, or lipid metabolism. Thus, despite the insulin resistance of MUHO, we could clearly show an elevated mitochondrial respiration of MUHO adipocytes. We suggest that the higher mitochondrial respiration reflects a compensatory mechanism to cope with insulin resistance and its consequences. Preserving this state of compensation might be an attractive goal for preventing or delaying the transition from insulin resistance to overt diabetes.

PMID: 32709986 [PubMed - indexed for MEDLINE]

Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma.

Front Oncol. 2020;10:567289

Authors: Sabbatino F, Liguori L, Malapelle U, Schiavi F, Tortora V, Conti V, Filippelli A, Tortora G, Ferrone CR, Pepe S

Abstract
Introduction: Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.
Case presentation: We present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.
Conclusion: These findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.

PMID: 33330039 [PubMed]

Pharmacodynamic Gene Testing in Prader-Willi Syndrome.

Front Genet. 2020;11:579609

Authors: Forster J, Duis J, Butler MG

Abstract
Prader-Willi syndrome (PWS) is a rare genetic disorder with a complex neurobehavioral phenotype associated with considerable psychiatric co-morbidity. This clinical case series, for the first time, describes the distribution and frequency of polymorphisms of pharmacodynamic genes (serotonin transporter, serotonin 2A and 2C receptors, catechol-o-methyltransferase, adrenergic receptor 2A, methylene tetrahydrofolate reductase, and human leucocytic antigens) across the two major molecular classes of PWS in a cohort of 33 referred patients who met medical criteria for testing. When results were pooled across PWS genetic subtypes, genotypic and allelic frequencies did not differ from normative population data. However, when the genetic subtype of PWS was examined, there were differences observed across all genes tested that may affect response to psychotropic medication. Due to small sample size, no statistical significance was found, but results suggest that pharmacodynamic gene testing should be considered before initiating pharmacotherapy in PWS. Larger scale studies are warranted.

PMID: 33329716 [PubMed]

TERT-Regulation and Roles in Cancer Formation.

Front Immunol. 2020;11:589929

Authors: Dratwa M, Wysoczańska B, Łacina P, Kubik T, Bogunia-Kubik K

Abstract
Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex TERT changes such as gene amplifications, TERT structural variants, TERT promoter germline and somatic mutations, TERT epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level. TERT expression is regulated in tumors via multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity via TERT expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of TERT in different mechanisms of cancer development and regulation.

PMID: 33329574 [PubMed - in process]

Treatment of Sarcoidosis: A Multidisciplinary Approach.

Front Immunol. 2020;11:545413

Authors: Gerke AK

Abstract
Sarcoidosis is a systemic disease of unknown etiology defined by the presence of noncaseating granulomatous inflammation that can cause organ damage and diminished quality of life. Treatment is indicated to protect organ function and decrease symptomatic burden. Current treatment options focus on interruption of granuloma formation and propagation. Clinical trials guiding evidence for treatment are lacking due to the rarity of disease, heterogeneous clinical course, and lack of prognostic biomarkers, all of which contribute to difficulty in clinical trial design and implementation. In this review, a multidisciplinary treatment approach is summarized, addressing immunuosuppressive drugs, managing complications of chronic granulomatous inflammation, and assessing treatment toxicity. Discovery of new therapies will depend on research into pathogenesis of antigen presentation and granulomatous inflammation. Future treatment approaches may also include personalized decisions based on pharmacogenomics and sarcoidosis phenotype, as well as patient-centered approaches to manage immunosuppression, symptom control, and treatment of comorbid conditions.

PMID: 33329511 [PubMed - in process]

Oncology and Pharmacogenomics Insights in Polycystic Ovary Syndrome: An Integrative Analysis.

Front Endocrinol (Lausanne). 2020;11:585130

Authors: Yumiceba V, López-Cortés A, Pérez-Villa A, Yumiseba I, Guerrero S, García-Cárdenas JM, Armendáriz-Castillo I, Guevara-Ramírez P, Leone PE, Zambrano AK, Paz-Y-Miño C

Abstract
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Epidemiological findings revealed that women with PCOS are prone to develop certain cancer types due to their shared metabolic and endocrine abnormalities. However, the mechanism that relates PCOS and oncogenesis has not been addressed. Herein, in this review article the genomic status, transcriptional and protein profiles of 264 strongly PCOS related genes (PRG) were evaluated in endometrial cancer (EC), ovarian cancer (OV) and breast cancer (BC) exploring oncogenic databases. The genomic alterations of PRG were significantly higher when compared with a set of non-diseases genes in all cancer types. PTEN had the highest number of mutations in EC, TP53, in OC, and FSHR, in BC. Based on clinical data, women older than 50 years and Black or African American females carried the highest ratio of genomic alterations among all cancer types. The most altered signaling pathways were p53 in EC and OC, while Fc epsilon RI in BC. After evaluating PRG in normal and cancer tissue, downregulation of the differentially expressed genes was a common feature. Less than 30 proteins were up and downregulated in all cancer contexts. We identified 36 highly altered genes, among them 10 were shared between the three cancer types analyzed, which are involved in the cell proliferation regulation, response to hormone and to endogenous stimulus. Despite limited PCOS pharmacogenomics studies, 10 SNPs are reported to be associated with drug response. All were missense mutations, except for rs8111699, an intronic variant characterized as a regulatory element and presumably binding site for transcription factors. In conclusion, in silico analysis revealed key genes that might participate in PCOS and oncogenesis, which could aid in early cancer diagnosis. Pharmacogenomics efforts have implicated SNPs in drug response, yet still remain to be found.

PMID: 33329391 [PubMed - in process]

Pharmacist Consult Reports to Support Pharmacogenomics Report Interpretation.

Pharmgenomics Pers Med. 2020;13:719-724

Authors: Bright D, Saadeh C, DeVuyst-Miller S, Sohn M, Choker A, Langerveld A

Abstract
Background: The clinical implementation of pharmacogenomics (PGx) has often involved teams that include pharmacists. PGx laboratories often provide baseline information within the laboratory report that is based on Food and Drug Administration and Clinical Pharmacogenomics Implementation Consortium guidance, but information is often provided independent of concurrent disease states or medication use, among other clinical factors. Major challenges to widescale implementation of PGx include lack of physician experience or confidence in interpreting the data. The purpose of this paper is to describe how pharmacists can help further personalize PGx information and identify clinical recommendations for a given patient.
Methods: This work was performed as a secondary objective of a study evaluating genetic biomarkers of opioid addiction risk. This portion of the study utilized a descriptive analysis of pharmacist consult reports that consist of individualized, patient-level clinical recommendations that take into account current medications, current health conditions, and PGx data. A panel of 60 common PGx targets were tested among patients being treated for chronic pain or opioid use disorder (OUD). A pharmacist consult report was generated and compared with standard laboratory reporting of general PGx information.
Results: Of the 252 patients, PGx reports for 198 (78.6%) contained red and/or yellow clinical decision support flags for medications with actionable or informative PGx guidance for currently prescribed medications. Pharmacists recommended modifications to current prescriptions for 31 (53%) of the patients with actionable flags and 17 (12%) of the patients with informative flags. Drug classes most commonly included medications for cardiology, depression and anxiety, pain (opioids) and gastrointestinal management. Taken together, 24.2% of the actionable and informative flags had immediate clinical value based on the pharmacist's review. An additional 217 (86%) received one or more clinical recommendations not related to PGx.
Conclusion: While PGx provides another opportunity for pharmacotherapy personalization, PGx data must be considered within the context of other patient-specific factors. Pharmacists were able to streamline the PGx report flags and identify other pharmacotherapy interventions following application of patient-specific data, thereby developing a brief report of recommendations for the patient's prescriber(s). Engaging clinical pharmacists in the PGx clinical decision process may help to facilitate more widespread PGx implementation.

PMID: 33328756 [PubMed]

Biomarkers to Personalize the Treatment of Rheumatoid Arthritis: Focus on Autoantibodies and Pharmacogenetics.

Biomolecules. 2020 Dec 14;10(12):

Authors: Conti V, Corbi G, Costantino M, De Bellis E, Manzo V, Sellitto C, Stefanelli B, Colucci F, Filippelli A

Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that is very complex and heterogeneous. If not adequately treated, RA patients are likely to manifest excess of morbidity and disability with an important impact on the quality of life. Pharmacological treatment is based on the administration of the disease-modifying antirheumatic drugs (DMARDs), subdivided into conventional synthetic (csDMARDs), targeted synthetic (tsDMARDs), and biological (bDMARDs). bDMARDs are now frequently administered in patients, both as alternative treatment and together with csDMARDs. Unfortunately, there is a therapeutic response variability both to old and new drugs. Therefore, to identify pre-therapeutic and on-treatment predictors of response is a priority. This review aims to summarize recent advances in understanding the causes of the variability in treatment response in RA, with particular attention to predictive potential of autoantibodies and DMARD pharmacogenetics. In recent years, several biomarkers have been proposed to personalize the therapy. Unfortunately, a magic bullet does not exist, as many factors concur to disease susceptibility and treatment outcomes, acting around the patient's congenital background. Models integrating demographic, clinical, biochemical, and genetic data are needed to enhance the predictive capacity of specific factors singularly considered to optimize RA treatment in light of multidisciplinary patient management.

PMID: 33327600 [PubMed - in process]

HLA-DRB1*07:01 and *08:02 Alleles Confer a Protective Effect Against ACPA-Positive Rheumatoid Arthritis in a Latin American Admixed Population.

Biology (Basel). 2020 Dec 14;9(12):

Authors: Castro-Santos P, Olloquequi J, Verdugo RA, Gutiérrez MA, Pinochet C, Quiñones LA, Díaz-Peña R

Abstract
HLA-DRB1 shared epitope (SE) alleles are important genetic contributors for the risk of developing anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis (RA), particularly in Caucasians. We aimed to analyze the contribution of HLA-DRB1 alleles and single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) region to the susceptibility to develop ACPA-positive RA in a Latin American (LA) population with admixed ancestry. A total of 289 ACPA-positive RA patients and 510 controls were enrolled in this study. The presence of HLA-DRB1*04:01, *09:01 and *10:01 was increased in ACPA-positive RA patients compared with healthy controls (p < 0.0001, p < 0.001 and p < 0.01, respectively), whereas DRB1*07:01 and *08:02 was associated with a decreased risk of ACPA-positive RA (p < 0.001 and p < 0.01, respectively). These results showed a strong correlation with estimates from studies in Asians but not in Caucasian populations. The present study describes the protective effects of the HLA-DRB1*07:01 and *08:02 alleles in ACPA-positive RA patients in a LA population for the first time. Identifying relationships between HLA-DRB1 alleles and RA is important for identifying disease associations in different ethnic groups in order to reach a better understanding of RA worldwide.

PMID: 33327594 [PubMed]

Reply to: "QT prolongation with hydroxychloroquine and azithromycin for the treatment of COVID-19: The need for pharmacogenetic insights".

J Cardiovasc Electrophysiol. 2020 10;31(10):2795

Authors: Hummel JP, Akar JG

PMID: 32864768 [PubMed - indexed for MEDLINE]

Frequencies of Genetic Polymorphisms of Clinically Relevant Gene-Drug Pairs in a German Psychiatric Inpatient Population.

Pharmacopsychiatry. 2020 Dec 16;:

Authors: Hahn M, Müller DJ, Roll SC

Abstract
INTRODUCTION: Genetic variation is known to affect enzymatic activities allowing differentiating various metabolizer types (e. g., slow or rapid metabolizers), in particular CYP2C19 and CYP2D6.
METHODS: PGx-testing was conducted in adult major depressive disorder inpatients admitted to the Vitos Klinik Eichberg between 11/2016 and 7/2017 (n=108, 57% female). We conducted a two-sided Z-Test (p=0.05) to analyze and compare frequencies of CYP2D6, CYP2C19, CYP3A4, CYP3A5 and CYP2C9 metabolizer groups with other European and psychiatric inpatient cohorts. The HLA-A and -B genes were also analyzed.
RESULTS: Non-normal metabolizer status of CYP2D6 were present in 47%. More specifically, 35 % were intermediate, 7% poor and 4% ultra-rapid metabolizers. 68% were CYP2C19 non-normal metabolizers. 8% were ultra-rapid and 31% rapid metabolizers. Notably, only 13% were NM for CYP2C19 and NM for CYP2D6 (activity score of 1 or more). For CYP2C9 we found 16% to be intermediate metabolizers, 1.0% poor metabolizer. CYP3A4 and CYP3A5 genetic polymorphisms were present in 25% and 19% respectively. HLA-B TAG- SNPs for *15:01 was positive in 25 patients, showing the need for different Tag-SNPs in Caucasians. HLA-B *57:01 TAG-SNP was positive in 8% of the patients, HLA-A TAG-SNP for *31:01 in Caucasians was positive in 9%. Z-Test showed statistical significance for our results.
DISCUSSION: Our results suggest that our psychiatric inpatients were enriched with genotypes consistent with non-normal drug metabolism compared to reference populations. We therefore conclude that pharmacogenetic testing should be implemented in clinical practice to guide drug therapy.

PMID: 33327018 [PubMed - as supplied by publisher]

Characterizing Pharmacogenetic Testing Among Children's Hospitals.

Clin Transl Sci. 2020 Dec 16;:

Authors: Brown JT, Ramsey LB, Van Driest SL, Aka I, Colace SI

Abstract
Although pharmacogenetic testing is becoming increasingly common across medical subspecialties, a broad range of utilization and implementation exists across pediatric centers. Large pediatric institutions that routinely use pharmacogenetics in their patient care have published their practices and experiences; however, minimal data exist regarding the full spectrum of pharmacogenetic implementation among children's hospitals. The primary objective of this nationwide survey was to characterize the availability, concerns, and barriers to pharmacogenetic testing in children's hospitals in the Children's Hospital Association. Initial responses identifying a contact person were received from 18 institutions. Of those 18 institutions, 14 responses (11 complete and 3 partial) to a more detailed survey regarding pharmacogenetic practices were received. The majority of respondents were from urban institutions (72%) and held a Doctor of Pharmacy degree (67%). Among all respondents, the three primary barriers to implementing pharmacogenetic testing identified were test reimbursement, test cost, and money. Conversely, the three least concerning barriers were potential for genetic discrimination, sharing results with family members, and availability of tests in certified laboratories. Low-use sites rated several barriers significantly higher than the high-use sites, including knowledge of pharmacogenetics (P = 0.03), pharmacogenetic interpretations (P = 0.04), and pharmacogenetic-based changes to therapy (P = 0.03). In spite of decreasing costs of pharmacogenetic testing, financial barriers are one of the main barriers perceived by pediatric institutions attempting clinical implementation. Low-use sites may also benefit from education/outreach in order to reduce perceived barriers to implementation.

PMID: 33325650 [PubMed - as supplied by publisher]

Author Correction: Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration.

Nat Neurosci. 2020 Dec 15;:

Authors: Joshi AU, Minhas PS, Liddelow SA, Haileselassie B, Andreasson KI, Dorn GW, Mochly-Rosen D

PMID: 33324000 [PubMed - as supplied by publisher]

Does the RAAS play a role in loss of taste and smell during COVID-19 infections?

Pharmacogenomics J. 2020 Dec 15;:

Authors: Luchiari HR, Giordano RJ, Sidman RL, Pasqualini R, Arap W

PMID: 33323946 [PubMed - as supplied by publisher]

Pharmacogenetics factors influencing smoking cessation success; the importance of nicotine metabolism.

Expert Opin Drug Metab Toxicol. 2020 Dec 16;:

Authors: Perez-Paramo YX, Lazarus P

Abstract
Introduction: Smoking remains a worldwide epidemic, and despite an increase in public acceptance of the harms of tobacco use, it remains the leading cause of preventable death. It is estimated that up to 70% of all smokers express a desire to quit, but only 3-5% of them are successful. Areas covered: The goal of this review was to evaluate the current status of smoking cessation treatments and the feasibility of implementing personalized-medicine approaches to these pharmacotherapies. We evaluated the genetics associated with higher levels of nicotine addiction and follow with an analysis of the genetic variants that affect the nicotine metabolic ratio (NMR) and the FDA approved treatments for smoking cessation. We also highlighted the gaps in the process of translating current laboratory understanding into clinical practice, and the benefits of personalized treatment approaches for a successful smoking cessation strategy. Expert opinion: Evidence supports the use of tailored therapies to ensure that the most efficient treatments are utilized in an individual's smoking cessation efforts. An understanding of the genetic effects on the efficacy of individualized smoking cessation pharmacotherapies is key to smoking cessation, ideally utilizing a polygenetic risk score that considers all genetic variation.

PMID: 33322962 [PubMed - as supplied by publisher]

A Mediterranean Dietary Intervention in Female Carriers of BRCA Mutations: Results from an Italian Prospective Randomized Controlled Trial.

Cancers (Basel). 2020 Dec 11;12(12):

Authors: Bruno E, Oliverio A, Paradiso AV, Daniele A, Tommasi S, Tufaro A, Terribile DA, Magno S, Filippone A, Venturelli E, Morelli D, Baldassari I, Cravana ML, Manoukian S, Pasanisi P

Abstract
Background: Women carriers of BRCA1/2 mutations face a high lifetime risk (penetrance) of developing breast and/or ovarian cancer. Insulin-like growth factor I (IGF-I), body weight and markers of insulin resistance affect BRCA penetrance. We conducted a multicenter prospective two-armed (1:1) randomized controlled trial (NCT03066856) to investigate whether a Mediterranean dietary intervention with moderate protein restriction reduces IGF-I and other metabolic modulators of BRCA penetrance. Methods: BRCA carriers, with or without a previous cancer, aged 18-70 years and without metastases were randomly assigned to an active dietary intervention group (IG) or to a control group (CG). The primary endpoint of the intervention was the IGF-I reduction. Results: 416 women (216 in the IG and 200 in the CG) concluded the six-month dietary intervention. The IG showed significantly lowered serum levels of IGF-I (-11.3 ng/mL versus -1.3 ng/mL, p = 0.02), weight (-1.5 Kg versus -0.5 Kg, p < 0.001), waist circumference (-2 cm versus -0.7 cm, p = 0.01), hip circumference (-1.6 cm versus -0.5 cm, p = 0.01), total cholesterol (-10.2 mg/dL versus -3.6 mg/dL, p = 0.04) and triglycerides (-8.7 mg/dL versus + 5.5 mg/dL, p = 0.01) with respect to the CG. Conclusions: A Mediterranean dietary intervention with moderate protein restriction is effective in reducing IGF-I and other potential modulators of BRCA penetrance.

PMID: 33322597 [PubMed]

Genomic Association of Single Nucleotide Polymorphisms with Blood Pressure Response to Hydrochlorothiazide among South African Adults with Hypertension.

J Pers Med. 2020 Dec 09;10(4):

Authors: Masilela C, Pearce B, Ongole JJ, Adeniyi OV, Benjeddou M

Abstract
This study described single nucleotide polymorphisms (SNPs) in hydrochlorothiazide-associated genes and further assessed their correlation with blood pressure control among South African adults living with hypertension. A total of 291 participants belonging to the Nguni tribes of South Africa on treatment for hypertension were recruited. Nineteen SNPs in hydrochlorothiazide pharmacogenes were selected and genotyped using MassArray. Uncontrolled hypertension was defined as blood pressure ≥140/90 mmHg. The association between genotypes, alleles and blood pressure response to treatment was determined by conducting multivariate logistic regression model analysis. The majority of the study participants were female (73.19%), Xhosa (54.98%) and had blood pressure ≥140/90 mmHg (68.73%). Seventeen SNPs were observed among the Xhosa tribe, and two (rs2070744 and rs7297610) were detected among Swati and Zulu participants. Furthermore, alleles T of rs2107614 (AOR = 6.69; 95%CI 1.42-31.55; p = 0.016) and C of rs2776546 (AOR = 3.78; 95%CI 1.04-13.74; p = 0.043) were independently associated with uncontrolled hypertension, whilst rs2070744 TC (AOR = 38.76; 95%CI 5.54-270.76; p = 0.00023), CC (AOR = 10.44; 95%CI 2.16-50.29; p = 0.003) and allele T of rs7297610 (AOR = 1.86; 95%CI 1.09-3.14; p = 0.023) were significantly associated with uncontrolled hypertension among Zulu and Swati participants. We confirmed the presence of SNPs associated with hydrochlorothiazide, some of which were significantly associated with uncontrolled hypertension in the study sample. Findings open doors for further studies on personalized therapy for hypertension in the country.

PMID: 33316892 [PubMed]

Pharmacogenomic Testing for Medication Selection: A Rapid Qualitative Review

Book. 2020 08 24

Authors: Smith A, Loshak H

Abstract
Pharmacogenomics is a rapidly expanding field that studies how a patient’s genetic factors can influence how they respond to medications.1 Estimates are that medications are effective in just 30%-60% of patients because of differences in how individuals respond to medications.2 Pharmacogenomic (PGx) testing can also predict which patients will suffer from adverse effects. Clinicians can use PGx testing in deciding which medications to give a patient, and at what dosage. Health care systems are exploring ways to implement PGx testing to support getting more patients onto the right treatment quickly.”1 By minimizing adverse effects and tailoring effective dosing, PGx testing may reduce unnecessary medications, hospital admissions, and health care use and expenditure.1 Currently, PGx tests have been developed for a wide range of conditions from depression to cancer. Within Canada, a number of direct-to-consumer pharmacogenomic tests like myDNA3 and Genecept Assay4 are currently available. With their increasing availability and use, it is important to understand how those engaging with PGx testing understand and experience them.5 The purpose of this review is to examine qualitative studies and methods to describe how patients and providers view, use and experience PGx testing for medication selection, and how PGx testing fits into existing health care pathways and systems.

PMID: 33320483

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus.

Circ Genom Precis Med. 2020 Dec;13(6):e002769

Authors: van Zuydam NR, Ladenvall C, Voight BF, Strawbridge RJ, Fernandez-Tajes J, Rayner NW, Robertson NR, Mahajan A, Vlachopoulou E, Goel A, Kleber ME, Nelson CP, Kwee LC, Esko T, Mihailov E, Mägi R, Milani L, Fischer K, Kanoni S, Kumar J, Song C, Hartiala JA, Pedersen NL, Perola M, Gieger C, Peters A, Qu L, Willems SM, Doney ASF, Morris AD, Zheng Y, Sesti G, Hu FB, Qi L, Laakso M, Thorsteinsdottir U, Grallert H, van Duijn C, Reilly MP, Ingelsson E, Deloukas P, Kathiresan S, Metspalu A, Shah SH, Sinisalo J, Salomaa V, Hamsten A, Samani NJ, März W, Hazen SL, Watkins H, Saleheen D, Morris AP, Colhoun HM, Groop L, McCarthy MI, Palmer CNA, SUMMIT Steering Committee; CARDIOGRAMplusC4D Steering Committee*

Abstract
BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D).
METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D).
RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background.
CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

PMID: 33321069 [PubMed - as supplied by publisher]

Recent advances in the personalized treatment of estrogen receptor-positive breast cancer with tamoxifen: a focus on pharmacogenomics.

Expert Opin Drug Metab Toxicol. 2020 Dec 15;:

Authors: Slanař O, Hronová K, Bartošová O, Šíma M

Abstract
INTRODUCTION: Tamoxifen is still an important drug in hormone-dependent breast cancer therapy. Personalization of its clinical use beyond hormone receptor positivity could improve the substantial variability of the treatment response.
AREAS COVERED: The overview on the current evidence for the treatment personalization using therapeutic drug monitoring, or using genetic biomarkers including CYP2D6 is provided. Although many studies focused on the PK aspects or the impact of CYP2D6 variability the translation into clinical routine is not clearly defined due to the inconsistent clinical outcome data.
EXPERT OPINION: We believe that at least the main candidate factors, i.e. CYP2D6 polymorphism, CYP2D6 inhibition, endoxifen serum levels may become important predictors of clinical relevance for tamoxifen treatment personalization in the future. To achieve this aim, however, further research should take into consideration more precise characterization of the disease, epigenetic factors and also utilize an appropriately powered multifactorial approach instead of a single gene evaluating studies.

PMID: 33320718 [PubMed - as supplied by publisher]