Losses of cytokines and chemokines are common genetic features of human cancers: the somatic copy number alterations are correlated with patient prognoses and therapeutic resistance.

Oncoimmunology. 2018;7(9):e1468951

Authors: Wong HS, Chang WC

Abstract
Intricate relationships among cytokines (including chemokines) shape the tumor microenvironment (TME) and reflect cell-cell interactions between malignant cells and other cells from the TME. Although our previous study indicated the transcriptional landscape of cytokines in 19 cancer types, the global pattern somatic copy number (SCN) alterations and the clinical relevance of cytokines have not been systematically investigated. Here, we reported a significant negative selection on cytokine genes. We also linked the SCN losses of cytokine genes to the abundance of immune infiltrates which affects cancer progression and patient prognoses. We also demonstrated and validated the correlations between SCN alterations of cytokine-containing loci and drug sensitivity. The results indicated the genomic loss of cytokines in malignant cells as a crucial theme for interrogating cancer progression, malignant cell-TME interactions, and therapeutics.

PMID: 30228934 [PubMed]

Subtype-Specific Inherited Predisposition to Pemphigus in Chinese Population.

Br J Dermatol. 2018 Sep 19;:

Authors: Zhang S, Zhou X, Zhou X, Zhang Y, Deng Y, Liao F, Yang M, Xia X, Zhou Y, Yin D, Ojaswi P, Hou Q, Wang L, Zhang D, Xia D, Deng Y, Ding L, Liu H, Yan W, Li M, Ma W, Ma JJ, Yu Q, Liu B, Yang L, Zhang W, Shu Y, Xu H, Li W

Abstract
BACKGROUND: Pemphigus is a group of rare life-threatening cutaneous autoimmune diseases, presenting mainly as two subtypes including pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Inherited predispositions to pemphigus have long been speculated but remains poorly understood.
OBJECTIVE: To identify common and specific non-genetic and genetic factors associated with pemphigus and its subtypes in Chinese population.
METHODS: Genome-wide association study was performed in 496 unrelated pemphigus patients (365 PV and 104 PF) and 1105 non-pemphigus controls.
RESULTS: Gender preference was observed only in PV (female: 57.5%) but not PF (female: 47.1%). For male patients only, the mean age at diagnosis was significantly younger in PV than in PF (P < 0.0004). The strongest association SNPs are in HLA region, rs70993900 (PV; P = 1.5 × 10-45 ) and rs9469220 (PF; P = 1.1 × 10-8 ). w ranks the top (P = 4.7 × 10-40 ; OR = 12.4) in both subtypes with significantly different risk allele frequency (RAFPV = 34.16% vs. RAFPF = 18.84% vs. RAFcontrol = 4.39%), whereas HLA-DRB1*14:01 and HLA-DRB1*04:06 exhibit PV-specific. HLA-DQB1*03:03 and HLA-DQB1*03:02 show significant subtype specificity in opposite directions. All these associations can be validated in the replication series with 147 pemphigus cases and 604 controls. Besides, multiple novel non-HLA susceptibility loci have also been identified in GWAS.
CONCLUSIONS: This study represents the largest GWAS on pemphigus in Chinese population published to date, and has allowed us to identify HLA haplotypes significantly shared between or specific to the two main subtypes of pemphigus. This article is protected by copyright. All rights reserved.

PMID: 30230522 [PubMed - as supplied by publisher]

Shortcut to success? Negotiating genetic uniqueness in global biomedicine.

Soc Stud Sci. 2018 Sep 19;:306312718801165

Authors: Tarkkala H, Tupasela A

Abstract
Since the sequencing of the human genome, as well as the completion of the first Human Genome Diversity Project, the benefits of studying one human population over another has been an ongoing debate relating to the replicability of findings in other populations. The leveraging of specific populations into research markets has made headlines in cases such as deCode in Iceland, Quebec Founder Population, and Generation Scotland. In such cases, researchers and policy makers have used the genetic and historical uniqueness of their populations to attract scientific, commercial and political interest. In this article, we explore how in countries with population isolates, such as Finland, the researchers balance considerations relating to the generalization and replicability of findings in small yet unique research populations to global biomedical research interests. This highlights challenges related to forms of competition associated with genetics research markets, as well as what counts as the 'right' population for genetic research.

PMID: 30230417 [PubMed - as supplied by publisher]

Clinical Factors and Rate of Cough During Angiotensin-Converting Enzyme Inhibitor Treatment.

Clin Pharmacol Ther. 2018 Sep 18;:

Authors: Ren H, Luo JQ, Shu Y, Zhou HH, Zhang W

PMID: 30229862 [PubMed - as supplied by publisher]

Genetic validation study of protein tyrosine phosphatase receptor type D (PTPRD) gene variants and risk for antipsychotic-induced weight gain.

J Neural Transm (Vienna). 2018 Sep 18;:

Authors: Maciukiewicz M, Gorbovskaya I, Tiwari AK, Zai CC, Freeman N, Meltzer HY, Kennedy JL, Müller DJ

Abstract
Schizophrenia is a severe, debilitating disorder with a lifetime prevalence of 1% irrespective of gender or ethnicity and is typically treated with antipsychotic drugs. Antipsychotic-induced weight gain (AIWG) is a leading factor of patient non-compliance and has previously been shown to increase the risk of type 2 diabetes, metabolic syndrome, and cardiovascular events. The current study intends to replicate findings from a recent genome-wide association study in Han-Chinese patients implicating two gene variants (rs10977144 and rs10977154) of the protein tyrosine phosphatase receptor type D (PTPRD) in antipsychotic-induced weight gain (AIWG). We investigated a sample of European and African American ancestry (n = 201) and calculated percentage of weight change using linear regression corrected for type of antipsychotics, duration of treatment and principal components from ancestry checks. As secondary goal, we investigated additional gene variants of PTPRD previously not associated with AIWG. We found no association with rs10977144 and rs10977154. However, we found nominally significant results between PTPRD and AIWG with rs73398242 in Europeans (BETA = - 0.267, p = 0.002) and rs13294608 in African Americans (BETA = 0.423, p = 0.003). According to Haploreg, both SNPs are histone marks for enhancers and promoters across various brain regions including the cingulate gyrus and dorsolateral prefrontal cortex. In summary, our results tentatively suggest that PTPRD might be associated with AIWG although different SNPS might be involved in different ethnic groups.

PMID: 30229349 [PubMed - as supplied by publisher]

Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro.

Xenobiotica. 2018 Sep 19;:1-33

Authors: San SN, Matsumoto J, Saito Y, Koike M, Sakaue H, Kato Y, Fujiyoshi M, Ariyoshi N, Yamada H

Abstract
1. Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. 2. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5), and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3, or CYP3A5*3/*3. 3. The intrinsic clearance (CLint, Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. 4. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. 5. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.

PMID: 30227770 [PubMed - as supplied by publisher]

RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy.

Biomed Res Int. 2018;2018:7675286

Authors: Olejarz W, Łacheta D, Głuszko A, Migacz E, Kukwa W, Szczepański MJ, Tomaszewski P, Nowicka G

Abstract
Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors' pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.

PMID: 30225265 [PubMed - in process]

Vitamin D status during pregnancy and in cord blood in a large prospective French cohort.

Clin Nutr. 2018 Aug 31;:

Authors: Courbebaisse M, Souberbielle JC, Baptiste A, Taieb J, Tsatsaris V, Guibourdenche J, Senat MV, Haidar H, Jani J, Guizani M, Jouannic JM, Haguet MC, Winer N, Masson D, Elie C, Benachi A

Abstract
BACKGROUND & AIMS: Vitamin D status during pregnancy and in newborns has never been studied in France. This study aims at determining the vitamin D status during the first and third trimesters of pregnancy (T1, T3) and in cord blood (CB) in the middle-north of France.
METHODS: We conducted a prospective cohort study in five French centers (latitude 47.22 to 48.86°N). Serum 25(OH)-vitamin D (25(OH)D) concentrations were measured using a radioimmunoassay during T1, T3 and in CB. According to the French guidelines, pregnant women received cholecalciferol, 100,000 IU, in the seventh month.
RESULTS: Between April 2012 and July 2014, 2832 women were included, of whom 2803 were analyzed (mean ± SD age: 31.5 ± 5.0 years; phototypes 5-6: 21.8%). Three and 88.6% of participants received supplementation during the month before inclusion and in the seventh month, respectively. At T1, T3, and CB, mean 25(OH)D concentrations were 21.9 ± 10.4, 31.8 ± 11.5, and 17.0 ± 7.2 ng/mL, respectively, and 25(OH)D was <20 ng/mL in 46.5%, 14.0%, and 68.5%, respectively. At T1, body mass index ≥25 kg/m2, dark phototypes, sampling outside summer, and no supplementation before inclusion were independently associated with vitamin D insufficiency (25(OH)D < 20 ng/mL). Women who received cholecalciferol supplementation in month 7 had higher 25(OH)D at T3 than non-supplemented women (32.5 ± 11.4 versus 25.8 ± 11.4 ng/mL, p = <0.001) and marginally higher 25(OH)D in CB (17.2 ± 7.2 versus 15.5 ± 7.1 ng/mL, p = 0.004).
CONCLUSIONS: Despite the recommended supplementation, vitamin D insufficiency is frequent during pregnancy and in newborns in France.

PMID: 30224306 [PubMed - as supplied by publisher]

F13A1 Gene Variant (V34L) and Residual Circulating FXIIIA Levels Predict Short- and Long-Term Mortality in Acute Myocardial Infarction after Coronary Angioplasty.

Int J Mol Sci. 2018 Sep 14;19(9):

Authors: Ansani L, Marchesini J, Pestelli G, Luisi GA, Scillitani G, Longo G, Milani D, Serino ML, Tisato V, Gemmati D

Abstract
Factor XIIIA (FXIIIA) levels are independent predictors of early prognosis after acute myocardial infarction (AMI) and the Valine-to-Leucine (V34L) single nucleotide polymorphism (SNP) seems associated with lower AMI risk. Since the long-term AMI prognosis merits deeper investigation, we performed an observational study evaluating relationships between FXIIIA residual levels, cardiovascular risk-factors, and inherited genetic predispositions. FXIIIA V34L was genotyped in 333 AMI patients and a five-year follow-up was performed. FXIIIA levels assessed at day-zero (d0) and four days after AMI (d4), and conventional risk factors were analyzed, focusing on the development of major adverse cardiovascular events (MACE). FXIIIA assessed at d0 and d4 was also an independent MACE predictor in the long-term follow-up (FXIIIAd0, Odds Ratio (OR) = 3.02, 1.79⁻5.1, p = 0.013; FXIIIAd4, OR = 4.46, 2.33⁻8.55, p = 0.0001). FXIIIAd4 showed the strongest MACE association, suggesting that the FXIIIA protective role is maximized when high levels are maintained for longer time. Conversely, FXIIIA levels stratified by V34L predicted MACE at a lesser extent among L34-carriers (Hazard Risk (HR)VV34 = 3.89, 2.19⁻6.87, p = 0.000003; HRL34-carriers = 2.78, 1.39⁻5.57, p = 0.0039), and V34L did not predict all MACE, only multiple-MACE occurrence (p = 0.0087). Finally, in survival analysis, heart failure and death differed significantly from stroke and recurrent ischemia (p = 0.0013), with FXIIIA levels appreciably lower in the former (p = 0.05). Overall, genetically-determined FXIIIA levels have a significant long-term prognostic role, suggesting that a pharmacogenetics approach might help to select those AMI patients at risk of poor prognosis in the need of dedicated treatments.

PMID: 30223472 [PubMed - in process]

Role of Lh polymorphisms and r-hLh supplementation in GnRh agonist treated ART cycles: A cross sectional study.

Eur J Obstet Gynecol Reprod Biol. 2018 Mar;222:119-125

Authors: G A R, Cheemakurthi R, Prathigudupu K, Balabomma KL, Kalagara M, Thota S, Kota M

Abstract
STUDY OBJECTIVES: To investigate the effect of N312S polymorphism in the LHCGR gene as a predictive pharmacogenetic marker on clinical and embryological parameters and determining the need of r-hLH supplementation combine with r-hFSH in patients undergoing ART treatment.
STUDY DESIGN: In a cross-sectional study, a retrospective analysis of women (n = 553), who underwent controlled ovarian stimulation treatment protocol was conducted during the years 2012-2014. R-hFSH (Gonal-F, Merck Serono) was administered to all patients undergoing ART cycle after initiating long luteal gonadotrophin-releasing hormone (GnRH) agonist down-regulation. R-hLH was supplemented based on P.C. Wong criteria. N312S genotype was determined using sequencing methodology. The mean r-hFSH, r-hLH doses, total number of oocytes, cleavage rates of embryos and clinical pregnancy were recorded. The association between the r-hLH supplementation and LHCGR N312S polymorphism and clinical pregnancy rates was determined using regression analysis by SPSS.
RESULTS: 19.7% of women were homozygous for A allele encoding asparagine (N/N), 45.7% were heterozygous (N/S) and 34.6% were homozygous (S/S) for G allele encoding serine. Women heterozygous (N/S) or homozygous (S/S) for serine showed a higher requirement for r-hLH (OR, 95% p-trend = <0.0001) compared to those homozygous for asparagine (N/N). Homozygous G allele was also associated with higher daily and total r-hLH dose per treatment cycle p-trend = <0.0001. Though, the total no of oocytes (14.87 ± 4.95 vs 12.98 ± 5.39 and 13.58 ± 5.45), Gr-I quality embryos (2.61 ± 1.81 vs 2.18 ± 1.96 and 1.98 ± 2.05) were significantly higher in women homozygous for A allele compared to women with heterozygous and homozygous for G allele, clinical pregnancy rates were significantly more in women with for G allele after excluding patients with PCOS and endometriosis conditions (P < 0.04).
CONCLUSION: The present findings reveal that women heterozygous and homozygous for G allele required higher doses of r-hLH supplementation and these women were shown to have higher clinical pregnancy rates.

PMID: 29408742 [PubMed - indexed for MEDLINE]

Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer.

Gut. 2018 10;67(10):1780-1792

Authors: Chong IY, Aronson L, Bryant H, Gulati A, Campbell J, Elliott R, Pettitt S, Wilkerson P, Lambros MB, Reis-Filho JS, Ramessur A, Davidson M, Chau I, Cunningham D, Ashworth A, Lord CJ

Abstract
OBJECTIVE: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.
DESIGN: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets.
RESULTS: By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer.
CONCLUSIONS: BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453).
TRIAL REGISTRATION NUMBER: NCT02884453; Pre-results.

PMID: 28830912 [PubMed - indexed for MEDLINE]

Novel glucosylceramide synthase inhibitor based prodrug copolymer micelles for delivery of anticancer agents.

J Control Release. 2018 Sep 14;:

Authors: Xu J, Zhao W, Sun J, Huang Y, Wang P, Venkataramanan R, Yang D, Ma X, Rana A, Li S

Abstract
In order to improve the efficacy of chemotherapy for cancers, we have developed a novel prodrug micellar formulation to co-deliver ceramide-generating anticancer agents and ceramide degradation inhibitor (PPMP). The prodrug nanocarrier is based on a well-defined POEG-b-PPPMP diblock copolymer. The hydrophilic block of POEG-b-PPPMP is POEG, and the hydrophobic block is composed of a number of PPMP units, which could work synergistically with loaded anticancer drugs. POEG-b-PPPMP was readily synthesized via a one-step reversible addition-fragment transfer (RAFT) polymerization from a PPMP monomer. The newly synthesized polymers were self-assembled into micelles and served as a carrier for several hydrophobic anticancer drugs including DOX, PTX and C6-ceramide. POEG-b-PPPMP prodrug polymer exhibited intrinsic antitumor activity in vitro and in vivo. In addition, POEG-b-PPPMP prodrug polymer was comparable to free PPMP in selectively enhancing the production of pro-apoptotic ceramide species as well as down-regulating the mRNA expression of GCS. DOX-loaded POEG-b-PPPMP micelles exhibited an excellent stability of 42 days at 4 °C. Moreover, DOX loaded in POEG-b-PPPMP micelles showed higher levels of cytotoxicity than DOX loaded in a pharmacologically inert polymer (POEG-b-POM) and Doxil formulation in several tumor cell lines. Consistently, in a 4T1.2 murine breast cancer model, the tumor inhibition followed the order of DOX/POEG-b-PPPMP > DOX/POEG-b-POM ≥ Doxil > POEG-b-PPPMP > POEG-b-POM. Our data suggest that POEG-b-PPPMP micelles are a promising dual-functional carrier that warrants more studies in the future.

PMID: 30223045 [PubMed - as supplied by publisher]

Cumulative Antidepressant Use and Risk of Dementia in a Prospective Cohort Study.

J Am Geriatr Soc. 2018 Sep 17;:

Authors: Heath L, Gray SL, Boudreau DM, Thummel K, Edwards KL, Fullerton SM, Crane PK, Larson EB

Abstract
OBJECTIVES: To determine whether antidepressant use is associated with dementia risk.
DESIGN: Prospective cohort study.
SETTING: Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system.
PARTICIPANTS: Community-dwelling individuals aged 65 and older without dementia and with 10 years or more of KPWA enrollment at baseline (N=3,059).
MEASUREMENTS: Primary exposures were selective serotonin reuptake inhibitors (paroxetine vs other), tricyclic antidepressants, and serotonin antagonist and reuptake inhibitors. Using health plan pharmacy data, we calculated cumulative medication exposure, defined as total standardized daily doses (TSDDs), over rolling 10-year windows. Exposure in the most recent year was excluded to avoid use related to prodromal symptoms. The Cognitive Abilities Screening Instrument was administered every 2 years; low scores triggered clinical evaluation and consensus diagnosis procedures. Dementia risk was estimated according to medication use using Cox proportional hazards models.
RESULTS: During a mean follow-up of 7.7 years, 775 participants (25%) developed dementia; 659 (22%) developed possible or probable Alzheimer's disease. Individual antidepressant classes were not associated with differences in dementia risk, although paroxetine use was associated with higher risk of dementia for all TSDD categories than no use (0-90 TSDDs: hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.18-2.42; 91-365 TSDDs: HR=1.40, 95% CI=0.88-2.23; 366-1095 TSDDs: HR=2.13, 95% CI=1.32-3.43; ≥1095 TSDDs: HR=1.42, 95% CI=0.82-2.46).
CONCLUSION: Most commonly prescribed nonanticholinergic depression medications used in late life do not appear to be associated with dementia risk. Paroxetine and other anticholinergic antidepressants may be exceptions in older individuals. Future studies are warranted to improve scientific understanding of potential associations in other settings and populations.

PMID: 30221747 [PubMed - as supplied by publisher]

Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe?

Molecules. 2018 Apr 17;23(4):

Authors: Dzobo K, Hassen N, Senthebane DA, Thomford NE, Rowe A, Shipanga H, Wonkam A, Parker MI, Mowla S, Dandara C

Abstract
Background: Environmental pollution such as exposure to pro-carcinogens including benzo-&alpha;-pyrene is becoming a major problem globally. Moreover, the effects of benzo-&alpha;-pyrene (BaP) on drug pharmacokinetics, pharmacodynamics, and drug resistance warrant further investigation, especially in cancer outpatient chemotherapy where exposure to environmental pollutants might occur. Method: We report here on the effects of benzo-&alpha;-pyrene on esophageal cancer cells in vitro, alone, or in combination with chemotherapeutic drugs cisplatin, 5-flurouracil, or paclitaxel. As the study endpoints, we employed expression of proteins involved in cell proliferation, drug metabolism, apoptosis, cell cycle analysis, colony formation, migration, and signaling cascades in the WHCO1 esophageal cancer cell line after 24 h of treatment. Results: Benzo-&alpha;-pyrene had no significant effect on WHCO1 cancer cell proliferation but reversed the effect of chemotherapeutic drugs by reducing drug-induced cell death and apoptosis by 30&ndash;40% compared to drug-treated cells. The three drugs significantly reduced WHCO1 cell migration by 40&ndash;50% compared to control and BaP-treated cells. Combined exposure to drugs was associated with significantly increased apoptosis and reduced colony formation. Evaluation of survival signaling cascades showed that although the MEK-ERK and Akt pathways were activated in the presence of drugs, BaP was a stronger activator of the MEK-ERK and Akt pathways than the drugs. Conclusion: The present study suggest that BaP can reverse the effects of drugs on cancer cells via the activation of survival signaling pathways and upregulation of anti-apoptotic proteins such as Bcl-2 and Bcl-xL. Our data show that BaP contribute to the development of chemoresistant cancer cells.

PMID: 29673198 [PubMed - indexed for MEDLINE]

Qualitative user evaluation of a revised pharmacogenetic educational toolkit.

Pharmgenomics Pers Med. 2018;11:139-146

Authors: Mills R, Haga SB

Abstract
Introduction: Pharmacogenetic (PGx) testing is a leading application for personalized and precision medicine; however, there are barriers, including limited provider and patient understanding, which affect its uptake. There is a need for tools that can enhance the patient and provider experience with testing and promoting the shared and informed decision-making.
Materials and methods: In this study, we sought to gather additional feedback on a PGx toolkit comprised of four educational tools that had been previously evaluated through an online survey by pharmacists. Specifically, we conducted semi-structured interviews with pharmacists and members of the public regarding their understanding and utility of the toolkit and its individual components.
Results: Participants found three of the four toolkit components, a test information sheet, flipbook, and results sheet, to be useful and important. The fourth component, results card, was viewed less favorably. Participants differed in their preference for medical jargon and detailed results nomenclature (namely star * alleles).
Conclusion: User input during the development of educational materials is essential for optimizing utilization, effectiveness, and comprehension.

PMID: 30214267 [PubMed]

Pharmacokinetics and pharmacogenomics of mycophenolic acid and its clinical correlations in maintenance immunosuppression for lupus nephritis.

Nephrol Dial Transplant. 2018 Sep 11;:

Authors: Yap DYH, Tam CH, Yung S, Wong S, Tang CSO, Mok TMY, Yuen CKY, Ma MKM, Lau CS, Chan TM

Abstract
Background: There is little data on mycophenolic acid (MPA) pharmacokinetics and pharmacogenomics and optimal MPA exposure in lupus nephritis (LN) patients during long-term maintenance.
Methods: We measured blood MPA levels at 1, 2, 4, 8, 10 and 12-h post-dose (i.e. C1, C2, C4, C8, C10 and C12) in 88 stable LN patients receiving maintenance prednisolone and mycophenolate mofetil, repeated every 6 months. The relationship between MPA exposure and single nucleotide polymorphisms (SNPs) of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2; rs2273697, rs3740066, rs717620 and rs17222723), organic anion-transporting polypeptides (OATPs; rs7311358 and rs4149117) and uridine diphosphate glucuronosyltransferase (UGT; rs17863762, rs6714486, rs17868320 and rs72551330) was also investigated.
Results: C1, C2 and C12 were 8.3 ± 6.6 , 7.2 ± 5.2 and 2.0 ± 1.4 mg/L and all correlated with the 12-h area under the curve (AUC0-12; r = 0.51, 0.85 and 0.73; P = 0.02, <0.001 and <0.001, respectively). C12 inversely correlated with hemoglobin, immunoglobulins and leukocyte levels (P < 0.05 for all). Five renal flares, 11 episodes of infection and 10 episodes of anemia (hemoglobin <10 g/dL) occurred over 96 weeks, with a corresponding C12 of 1.3 ± 0.5, 4.3 ± 2.6 and 2.9 ± 1.5 mg/L, respectively (versus 2.4 ± 1.2, 1.8 ± 1.2 and 1.7 ± 1.1 mg/L in patients without these complications; P = 0.041, <0.001 and 0.004). SNP rs2273697 A/G in the ABCC2 gene was associated with lower MPA exposure compared with G/G (1075.9 ± 239.9 versus 1891.5 ± 918.9 mgh/L per g/kg; P = 0.003). SNPs of OATP and UGT were unrelated to MPA level.
Conclusion: MPA C12 correlates with the AUC0-12 and is related to renal flare, infection and anemia. SNP rs2273697 A/G is associated with lower MPA exposure.

PMID: 30215770 [PubMed - as supplied by publisher]

Whole genome sequencing identifies high-impact variants in well-known pharmacogenomic genes.

Pharmacogenomics J. 2018 Sep 14;:

Authors: Choi J, Tantisira KG, Duan QL

Abstract
More than 1100 genetic loci have been correlated with drug response outcomes but disproportionately few have been translated into clinical practice. One explanation for the low rate of clinical implementation is that the majority of associated variants may be in linkage disequilibrium (LD) with the causal variants, which are often elusive. This study aims to identify and characterize likely causal variants within well-established pharmacogenomic genes using next-generation sequencing data from the 1000 Genomes Project. We identified 69,319 genetic variations within 160 pharmacogenomic genes, of which 8207 variants are in strong LD (r2>0.8) with known pharmacogenomic variants. Of the latter, eight are coding or structural variants predicted to have high impact, with 19 additional missense variants that are predicted to have moderate impact. In conclusion, we identified putatively functional variants within known pharmacogenomics loci that could account for the association signals and represent the missing causative variants underlying drug response phenotypes.

PMID: 30214008 [PubMed - as supplied by publisher]

Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan.

Pharmacol Res. 2018 Sep 10;:

Authors: Salvador-Martín S, García-González X, García MI, Blanco C, García-Alfonso P, Robles L, Grávalos C, Pachón V, Longo F, Martínez V, Sanjurjo M, López-Fernández LA

Abstract
Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.

PMID: 30213564 [PubMed - as supplied by publisher]

Reducing anthracycline-induced cardiotoxicity through pharmacogenetics.

Pharmacogenomics. 2018 Sep 14;:

Authors: Scott E, Hasbullah JS, Ross CJ, Carleton BC

PMID: 30213233 [PubMed - as supplied by publisher]

[Personalized medicine in psychiatry: nightmare of the industry?]

Neuropsychopharmacol Hung. 2016 09;18(3):137-142

Authors: Lazary J, Elemery M, Csala I, Faludi G

Abstract
Personalized medicine is a hot topic in the literature of the psychiatric field but it seems that regular clinical application of valid tests are awaited. Urgent requirement of objective tools for screening high-risk patients is postulated by prominent authors because long-term set up time, serious side effects or ineffectiveness of psychiatric agents mean a great challenge for clinicians to find optimal therapy on time. Unwanted suffering from inaccurate medicine, progression of the disorder and mistrust or in adherence of the patients are dramatic consequences of the delay of adequate therapy which is linked with irreversible health and mental damages and financial loss. On the other hand, a growing body of data are published on pharmacogenomic studies in association with psychiatric conditions. Although several pharmacogenetic tests are commercially available, accurate use of these tools are absent from clinical protocols. Here we give a short review on the most important pharmacogenomic results and a discussion on possible conflict of interests around pharmacogenetic tests. We conclude that all participants of the health care system could benefit from personalized medicine in psychiatry.

PMID: 27824309 [PubMed - indexed for MEDLINE]