Transgenic Overexpression of Steroid Sulfatase Alleviates Cholestasis.

Liver Res. 2017 Jun;1(1):63-69

Authors: Jiang M, Xu M, Ren S, Selcer KW, Xie W

Abstract
Background and Aim: Sulfotransferase (SULT)-mediated sulfation and steroid sulfatase (STS)-mediated desulfation represent two critical mechanisms that regulate the chemical and functional homeostasis of endogenous and exogenous molecules. STS catalyzes the hydrolysis of steroid sulfates to form hydroxysteroids. Oxygenated cholesterol derivative oxysterols are known to be endogenous ligands of the liver X receptor (LXR), a nuclear receptor with anti-cholestasis activity, whereas the sulfated oxysterols antagonize LXR signaling. The conversion of sulfated oxysterols to their non-sulfated counterparts is catalyzed by STS. The aim of this study is to determine whether STS can alleviate cholestasis by increasing the activity of LXR.
Methods: Liver-specific STS transgenic mice were created and subject to the lithocholic acid (LCA)-induced model of cholestasis.
Results: Transgenic overexpression of STS in the liver promoted bile acid elimination and alleviated LCA-induced cholestasis. The protective effect of the STS transgene was associated with the activation of LXR and induction of LXR target genes, likely because of the increased conversion of the antagonistic oxysterol sulfates to the agonistic oxysterols.
Conclusions: STS has a novel function in controlling the homeostasis of bile acids by regulating endogenous LXR ligands.

PMID: 29130021 [PubMed]

Older Adults Affected by Gene Mutations When Taking Multiple Medications.

J Calif Dent Assoc. 2017 01;45(1):10

Authors:

PMID: 29053238 [PubMed - indexed for MEDLINE]

Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

Mol Psychiatry. 2017 Aug;22(8):1155-1163

Authors: Jukić MM, Opel N, Ström J, Carrillo-Roa T, Miksys S, Novalen M, Renblom A, Sim SC, Peñas-Lledó EM, Courtet P, Llerena A, Baune BT, de Quervain DJ, Papassotiropoulos A, Tyndale RF, Binder EB, Dannlowski U, Ingelman-Sundberg M

Abstract
The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.

PMID: 27895323 [PubMed - indexed for MEDLINE]

Divergent Expression and Metabolic Functions of Human Glucuronosyltransferases through Alternative Splicing.

Cell Rep. 2016 Sep 27;17(1):114-124

Authors: Rouleau M, Tourancheau A, Girard-Bock C, Villeneuve L, Vaucher J, Duperré AM, Audet-Delage Y, Gilbert I, Popa I, Droit A, Guillemette C

Abstract
Maintenance of cellular homeostasis and xenobiotic detoxification is mediated by 19 human UDP-glucuronosyltransferase enzymes (UGTs) encoded by ten genes that comprise the glucuronidation pathway. Deep RNA sequencing of major metabolic organs exposes a substantial expansion of the UGT transcriptome by alternative splicing, with variants representing 20% to 60% of canonical transcript expression. Nearly a fifth of expressed variants comprise in-frame sequences that may create distinct structural and functional features. Follow-up cell-based assays reveal biological functions for these alternative UGT proteins. Some isoforms were found to inhibit or induce inactivation of drugs and steroids in addition to perturbing global cell metabolism (energy, amino acids, nucleotides), cell adhesion, and proliferation. This work highlights the biological relevance of alternative UGT expression, which we propose increases protein diversity through the evolution of metabolic regulators from specific enzymes.

PMID: 27681425 [PubMed - indexed for MEDLINE]

American Ginseng Attenuates Colitis-Associated Colon Carcinogenesis in Mice: Impact on Gut Microbiota and Metabolomics.

Cancer Prev Res (Phila). 2016 Oct;9(10):803-811

Authors: Wang CZ, Yu C, Wen XD, Chen L, Zhang CF, Calway T, Qiu Y, Wang Y, Zhang Z, Anderson S, Wang Y, Jia W, Yuan CS

Abstract
Inflammatory bowel disease is a risk factor for colorectal cancer initiation and development. In this study, the effects of American ginseng on chemically induced colitis and colon carcinogenesis were evaluated using an azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model. During the acute phase on day 15, the oral administration of ginseng (15 and 30 mg/kg/day) significantly suppressed AOM/DSS-induced colitis, as demonstrated by the disease activity index and colon tissue histology. During the chronic phase in week 13, AOM/DSS-induced tumor multiplicity was significantly suppressed by ginseng. Ginseng significantly attenuated the increase of inflammatory cytokines, such as IL1α, IL1β, IL6, G-CSF, and GM-CSF. Serum metabolomics data in the PCA plots showed good separation between the AOM/DSS model and ginseng-treated mice, and the most important endogenous metabolite changes were identified. The 16S rRNA data showed that after AOM/DSS, the microbiome community in the model group was obviously changed, and ginseng inhibited these changes. Fecal metabolomics analysis supported these findings. In conclusion, oral ginseng significantly decreased AOM/DSS-induced colitis and colon carcinogenesis by inhibiting inflammatory cytokines and restoring the metabolomics and microbiota profiles accordingly. Selective endogenous small molecules could be used as biomarkers to elucidate the effects of ginseng treatment. Cancer Prev Res; 9(10); 803-11. ©2016 AACR.

PMID: 27443884 [PubMed - indexed for MEDLINE]

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice.

Elife. 2016 May 17;5:

Authors: Tsokas P, Hsieh C, Yao Y, Lesburguères E, Wallace EJC, Tcherepanov A, Jothianandan D, Hartley BR, Pan L, Rivard B, Farese RV, Sajan MP, Bergold PJ, Hernández AI, Cottrell JE, Shouval HZ, Fenton AA, Sacktor TC

Abstract
PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.

PMID: 27187150 [PubMed - indexed for MEDLINE]

Early changes of blood lipid levels during psychotropic drug treatment as predictors of long-term lipid changes and of new onset dyslipidemia.

J Clin Lipidol. 2017 Oct 16;:

Authors: Delacrétaz A, Vandenberghe F, Gholam-Rezaee M, Saigi Morgui N, Glatard A, Thonney J, Solida-Tozzi A, Kolly S, Gallo SF, Baumann P, Berney S, Zulauff SV, Aubry JM, Hasler R, Ebbing K, von Gunten A, Conus P, Eap CB

Abstract
BACKGROUND: Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels.
OBJECTIVE: This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development.
METHODS: Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment.
RESULTS: Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (≥5%) for TC, LDL-C, TG, and non-HDL-C and decrease (≥5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (≥30% TC, ≥40% LDL-C, ≥45% TG, ≥55% non-HDL-C increase, and ≥20% HDL-C decrease; sensitivity 70%-100%, specificity 53%-72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort (P ≤ .03) as well as in a replication cohort (n = 79; P ≤ .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others (P ≤ .01).
CONCLUSION: Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia.

PMID: 29128242 [PubMed - as supplied by publisher]

Concepts of Genomics in Kidney Transplantation.

Curr Transplant Rep. 2017 Jun;4(2):116-123

Authors: Oetting WS, Dorr C, Remmel RP, Matas AJ, Israni AK, Jacobson PA

Abstract
Purpose of review: Identification of genetic variants to aid in individualized treatment of solid organ allograft recipients would improve graft survival. We will review the current state of knowledge for associations of variants with transplant outcomes.
Recent findings: Many studies have yet to exhibit robust and reproducible results, however, pharmacogenomic studies focusing on cytochrome P450 (CYP) enzymes, transporters and HLA variants have shown strong associations with outcomes and have relevance towards drugs used in transplant. Genome wide association study data for the immunosuppressant tacrolimus have identified multiple variants in the CYP3A5 gene associated with trough concentrations. Additionally, APOL1 variants had been shown to confer risk to the development of end stage renal disease in African Americans.
Summary: The field is rapidly evolving and new technology such as next generation sequencing, along with larger cohorts, will soon be commonly applied in transplantation to understand genetic association with outcomes and personalized medicine.

PMID: 29123971 [PubMed]

New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels.

Sci Rep. 2017 Nov 09;7(1):15126

Authors: Sadacca B, Hamy-Petit AS, Laurent C, Gestraud P, Bonsang-Kitzis H, Pinheiro A, Abecassis J, Neuvial P, Reyal F

Abstract
One of the most challenging problems in the development of new anticancer drugs is the very high attrition rate. The so-called "drug repositioning process" propose to find new therapeutic indications to already approved drugs. For this, new analytic methods are required to optimize the information present in large-scale pharmacogenomics datasets. We analyzed data from the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia studies. We focused on common cell lines (n = 471), considering the molecular information, and the drug sensitivity for common drugs screened (n = 15). We propose a novel classification based on transcriptomic profiles of cell lines, according to a biological network-driven gene selection process. Our robust molecular classification displays greater homogeneity of drug sensitivity than cancer cell line grouped based on tissue of origin. We then identified significant associations between cell line cluster and drug response robustly found between both datasets. We further demonstrate the relevance of our method using two additional external datasets and distinct sensitivity metrics. Some associations were still found robust, despite cell lines and drug responses' variations. This study defines a robust molecular classification of cancer cell lines that could be used to find new therapeutic indications to known compounds.

PMID: 29123141 [PubMed - in process]

Synergistic gastroprotective activity of methanolic extract of a mixture of Melastoma malabathricum and Muntingia calabura leaves in rats.

BMC Complement Altern Med. 2017 Nov 09;17(1):488

Authors: Halim SZ, Zakaria ZA, Omar MH, Mohtarrudin N, Wahab IRA, Abdullah MNH

Abstract
BACKGROUND: Melastoma malabathricum L. (family Melastomaceae; MM) and Muntingia calabura L. (family Elaeocarpaceae; MC) have been separately reported to possess gastroprotective activity. In an attempt to develop a pharmaceutical product with antiulcer potential, the synergistic gastroprotective activity of methanolic extract of a mixture of MM and MC (MMMC) at various ratios was evaluated in rat models.
METHODS: Rats were pre-treated orally with 2% Tween 80 (vehicle), 100 mg/kg ranitidine (reference drug) or MMMC (ratios of 1:1, 1:3 and 3:1 (v/v); doses of 15, 150 or 300 mg/kg) and then subjected to the ethanol-induced gastric ulcer or pyloric ligation assays. Stomach of rats from the former assay was collected and subjected to the macroscopic and microscopic observations, and enzymatic and non-enzymatic antioxidant studies while the gastric juice content and tissue from the latter assay were subjected to the antisecretory activity study. The UHPLC analysis of MMMC was also performed.
RESULT: MMMC, in the ratio 1:1, demonstrated the most effective (P < 0.001) gastroprotective activity indicated by the highest reduction in ethanol-induced ulcer area formation. These macroscopic findings were supported by the microscopic observations. Except for pH and total acidity, MMMC also significantly (P < 0.001) reduced the volume of gastric content but increased the gastric wall mucus content in the pyloric-ligation test. MMMC also demonstrated remarkable antioxidant activity indicated by the highest total phenolic content (TPC) value and oxygen radical absorbance capacity (ORAC) activity with the recorded IC50 value of approximately 53 μg/mL for the 2,2- diphenyl-1-picrylhydrazyl (DPPH) scavenging activity. MMMC also improved the catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), prostaglandin E2 (PGE2) and malondialdehyde (MDA) activities of the gastric tissue intoxicated by ethanol. UHPLC analysis of MMMC confirmed the presence several flavonoid-based bioactive compounds.
CONCLUSION: MMMC, at the ratio of 1:1 (v/v), exerts gastroprotective activity partly by activating its antisecretory and antioxidant activities, and via modulation of the gastric tissue endogenous antioxidant system.

PMID: 29121900 [PubMed - in process]

Elemental Ingredients in the Macrophage Cocktail: Role of ZIP8 in Host Response to Mycobacterium tuberculosis.

Int J Mol Sci. 2017 Nov 09;18(11):

Authors: Pyle CJ, Azad AK, Papp AC, Sadee W, Knoell DL, Schlesinger LS

Abstract
Tuberculosis (TB) is a global epidemic caused by the infection of human macrophages with the world's most deadly single bacterial pathogen, Mycobacterium tuberculosis (M.tb). M.tb resides in a phagosomal niche within macrophages, where trace element concentrations impact the immune response, bacterial metal metabolism, and bacterial survival. The manipulation of micronutrients is a critical mechanism of host defense against infection. In particular, the human zinc transporter Zrt-/Irt-like protein 8 (ZIP8), one of 14 ZIP family members, is important in the flux of divalent cations, including zinc, into the cytoplasm of macrophages. It also has been observed to exist on the membrane of cellular organelles, where it can serve as an efflux pump that transports zinc into the cytosol. ZIP8 is highly inducible in response to M.tb infection of macrophages, and we have observed its localization to the M.tb phagosome. The expression, localization, and function of ZIP8 and other divalent cation transporters within macrophages have important implications for TB prevention and dissemination and warrant further study. In particular, given the importance of zinc as an essential nutrient required for humans and M.tb, it is not yet clear whether ZIP-guided zinc transport serves as a host protective factor or, rather, is targeted by M.tb to enable its phagosomal survival.

PMID: 29120360 [PubMed - in process]

Race/ethnicity difference in the pharmacogenetics of bilirubin-related atazanavir discontinuation.

Pharmacogenet Genomics. 2017 Nov 06;:

Authors: Leger P, Chirwa S, Nwogu JN, Turner M, Richardson DM, Baker P, Leonard M, Erdem H, Olson L, Haas DW

Abstract
BACKGROUND: Atazanavir causes plasma indirect bilirubin to increase. We evaluated associations between Gilbert's polymorphism and bilirubin-related atazanavir discontinuation stratified by race/ethnicity.
PATIENTS AND METHODS: Patients had initiated atazanavir/ritonavir-containing regimens at an HIV primary care clinic in the southeastern USA, and had at least 12 months of follow-up data. Metabolizer group was defined by UGT1A1 rs887829 C→T. Genome-wide genotype data were used to adjust for genetic ancestry in combined population analyses.
RESULTS: Among 321 evaluable patients, 15 (4.6%) had bilirubin-related atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 [95% confidence interval (CI): 1.7-31.5; P=0.007]. Among 152 White patients the HR was 14.4 (95% CI: 2.6-78.7; P=0.002), but among 153 Black patients the HR was 0.8 (95% CI: 0.05-12.7; P=0.87).
CONCLUSION: Among patients who initiated atazanavir/ritonavir-containing regimens, UGT1A1 slow metabolizer genotype rs887829 T/T was associated with increased bilirubin-related discontinuation of atazanavir in White but not in Black patients, this despite T/T genotype being more frequent in Black patients.

PMID: 29117017 [PubMed - as supplied by publisher]

Treatment response heterogeneity in asthma: the role of genetic variation.

Expert Rev Respir Med. 2017 Nov 08;:

Authors: Vijverberg SJH, Farzan N, Slob EMA, Neerincx AH, Maitland-van der Zee AH

Abstract
INTRODUCTION: Asthmatic patients show a large heterogeneity in response to asthma medication. Rapidly evolving genotyping technologies have led to the identification of various genetic variants associated with treatment outcomes. Areas covered: This review focuses on the current knowledge of genetic variants influencing treatment response to the most commonly used asthma medicines: short- and long-acting beta-2 agonists (SABA/LABA), inhaled corticosteroids (ICS) and leukotriene modifiers. This review shows that various genetic variants have been identified, but none are currently used to guide asthma treatment. One of the most promising genetic variants is the Arg16 variant in the ADRB2 gene to guide LABA treatment in asthmatic children. Expert commentary: Poor replication of initially promising results and the low fraction of variability accounted for by single genetic variants inhibit pharmacogenetic findings to reach the asthma clinic. Nevertheless, the identification of genetic variation influencing treatment response does provide more insights in the complex processes underlying response and might identify novel targets for treatment. There is a need to report measures of clinical validity, to perform precision-medicine guided trials, as well as to understand how genetic variation interacts with environmental factors. In addition, systems biology approaches might be able to show a more complete picture of these complex interactions.

PMID: 29115880 [PubMed - as supplied by publisher]

ABCB1 gene polymorphisms and response to chemotherapy in breast cancer patients: A meta-analysis.

Surg Oncol. 2017 Dec;26(4):473-482

Authors: Madrid-Paredes A, Cañadas-Garre M, Sánchez-Pozo A, Expósito-Ruiz M, Calleja-Hernández MÁ

Abstract
The ABCB1 gene encodes the P-glycoprotein, an efflux pump for some antineoplastic agents which acts as a resistance mechanism to chemotherapy. Three SNPs (C3435T, C1236T and G2677T/A), are the most widely studied in ABCB1. The inconsistent conclusions about the association of these polymorphisms and the response to chemotherapy in breast cancer (BC) patients prompted us to conduct a meta-analysis. A total of nine (770 patients), five (566 patients) and three studies (367 patients) relating the ABCB1 C3435T, C1236T and G2677T/A polymorphisms respectively, were included. The main analysis revealed a lack of association between ABCB1 polymorphisms and response to chemotherapy in every genetic model: C3435T (dominant OR: 0.888; 95%CI: 0.558-1.413), C1236T (dominant OR: 1.968; 95%CI: 0.609-6.362) and G2677T/A (GG vs GT + GA + TT + TA + AA OR: 0.854; 95%CI: 0.418-1.744). Stratification by ethnicity, cancer type and response criteria did not change the pattern of results. The available evidence indicates that three polymorphisms within ABCB1; C3435T, C1236T and G2677T/A, cannot be considered a reliable predictor of response to chemotherapy in BC patients.

PMID: 29113667 [PubMed - in process]

Pharmacogenetic studies: a tool to improve antidepressant therapy.

Drug Metab Pers Ther. 2016 Dec 01;31(4):197-204

Authors: Ramos M, Berrogain C, Concha J, Lomba L, García CB, Ribate MP

Abstract
The World Health Organization (WHO) predicts that major depressive disorder (MDD) will be the second leading cause of death and disability by 2020. Nowadays, approximately 60-70% of patients with this disorder have shown the lack of effectiveness and tolerability of the therapy with antidepressants. The US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) are including pharmacogenetic information in the labeling of several antidepressants. The presence of this information represents the relevance of genetic polymorphisms in drug response. These pharmacogenetic studies have been based on the knowledge of genes involved in pharmacokinetic (CYP2D6, CYP2C19 and ABCB1) and pharmacodynamic (SLC6A4, HTR2A, BDNF, GNB3 and FKBP5) processes of antidepressant medications. The knowledge of the genotype of patients with MDD is an important tool for personalized therapy that can improve their clinical response to treatment. In this review, we highlight the most relevant genes involved in the metabolism of antidepressants (ADs) or the genes related to the presence of adverse reactions.

PMID: 27889704 [PubMed - indexed for MEDLINE]

Genetic variants of SULT1A1 and XRCC1 genes and risk of lung cancer in Bangladeshi population.

Tumour Biol. 2017 Nov;39(11):1010428317729270

Authors: Tasnim T, Al-Mamun MMA, Nahid NA, Islam MR, Apu MNH, Bushra MU, Rabbi SNI, Nahar Z, Chowdhury JA, Ahmed MU, Islam MS, Hasnat A

Abstract
Lung cancer is one of the most frequently occurring cancers throughout the world as well as in Bangladesh. This study aimed to correlate the prognostic and/or predictive value of functional polymorphisms in SULT1A1 (rs9282861) and XRCC1 (rs25487) genes and lung cancer risk in Bangladeshi population. A case-control study was conducted which comprises 202 lung cancer patients and 242 healthy volunteers taking into account the age, sex, and smoking status. After isolation of genomic DNA, genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method and the lung cancer risk was evaluated as odds ratio that was adjusted for age, sex, and smoking status. A significant association was found between SULT1A1 rs9282861 and XRCC1 rs25487 polymorphisms and lung cancer risk. In case of rs9282861 polymorphism, Arg/His (adjusted odds ratio = 5.06, 95% confidence interval = 3.05-8.41, p < 0.05) and His/His (adjusted odds ratio = 3.88, 95% confidence interval = 2.20-6.82, p < 0.05) genotypes were strongly associated with increased risk of lung cancer in comparison to the Arg/Arg genotype. In case of rs25487 polymorphism, Arg/Gln heterozygote (adjusted odds ratio = 4.57, 95% confidence interval = 2.79-7.46, p < 0.05) and Gln/Gln mutant homozygote (adjusted odds ratio = 4.99, 95% confidence interval = 2.66-9.36, p < 0.05) were also found to be significantly associated with increased risk of lung cancer. This study demonstrates that the presence of His allele and Gln allele in case of SULT1A1 rs9282861 and XRCC1 rs25487, respectively, involve in lung cancer prognosis in Bangladeshi population.

PMID: 29110586 [PubMed - in process]

Genetics and clinical response to warfarin and edoxaban in patients with venous thromboembolism.

Heart. 2017 Nov;103(22):1800-1805

Authors: Vandell AG, Walker J, Brown KS, Zhang G, Lin M, Grosso MA, Mercuri MF

Abstract
OBJECTIVE: The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin.
METHODS: Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in CYP2C9 and VKORC1 genes were divided into three warfarin sensitivity types (normal, sensitive and highly sensitive) based on their genotypes. An exploratory analysis was also conducted comparing normal responders to pooled sensitive responders (ie, sensitive and highly sensitive responders).
RESULTS: The analysis included 47.7% (3956/8292) of the patients in Hokusai VTE. Among 1978 patients randomised to warfarin, 63.0% (1247) were normal responders, 34.1% (675) were sensitive responders and 2.8% (56) were highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders had heparin therapy discontinued earlier (p<0.001), had a decreased final weekly warfarin dose (p<0.001), spent more time overanticoagulated (p<0.001) and had an increased bleeding risk with warfarin (sensitive responders HR 1.38 [95% CI 1.11 to 1.71], p=0.0035; highly sensitive responders 1.79 [1.09 to 2.99]; p=0.0252).
CONCLUSION: In this study, CYP2C9 and VKORC1 genotypes identified patients with VTE at increased bleeding risk with warfarin.
TRIAL REGISTRATION NUMBER: NCT00986154.

PMID: 28689179 [PubMed - indexed for MEDLINE]

Incorporation of Herbal Supplements into a Pharmacogenomic Medication Therapy Management Practice.

Consult Pharm. 2017 Feb 01;32(2):99-104

Authors: Wieruszewski PM, Schuh MJ

Abstract
Personalized medicine, including direct-to-consumer (DTC) testing, is becoming a more common patient-centered approach to pharmacotherapy. However, DTC testing companies may not provide adequate information and follow-up to patients after genetic testing is done. This article is the first report describing a medication therapy management pharmacotherapy service that specializes in pharmacogenomic counseling, specifically geared toward identifying implications of dietary and herbal supplements. A pharmacist provides a comprehensive review of pharmacokinetic and pharmacodynamic consequences of a patient's herbal substances, and counseling is provided on subsequent drug therapy effects. If properly implemented, offering a pharmacogenomic medication therapy management service that specializes in the use of herbal supplements provides patients with education on the safe use of these substances based on their genetic factors.

PMID: 28569661 [PubMed - indexed for MEDLINE]

Identification of pharmacogenetic markers of treatment response to biologic therapies in psoriasis - is there a benefit?

Br J Dermatol. 2017 05;176(5):1127-1128

Authors: Ryan C

PMID: 28504390 [PubMed - indexed for MEDLINE]

The Value of FLG Null Mutations in Predicting Treatment Response in Atopic Dermatitis: An Observational Study in Finnish Patients.

Acta Derm Venereol. 2017 Apr 06;97(4):456-463

Authors: Luukkonen TM, Kiiski V, Ahola M, Mandelin J, Virtanen H, Pöyhönen M, Kivirikko S, Surakka I, Reitamo S, Palotie A, Heliövaara M, Jakkula E, Remitz A

Abstract
The contribution of filaggrin null mutations to predicting atopic dermatitis (AD) treatment response is not clear, nor have such mutations been studied in the Finnish population. This study tested the association of the 4 most prevalent European FLG null mutations, the 2 Finnish enriched FLG null mutations, the FLG 12-repeat allele, and 50 additional epidermal barrier gene variants, with risk of AD, disease severity, clinical features, risk of other atopic diseases, age of onset, and treatment response in 501 patients with AD and 1,710 controls. AD, early-onset AD, palmar hyperlinearity, and asthma showed significant associations with the combined FLG null genotype. Disease severity and treatment response were independent of patient FLG status. Carrier frequencies of R501X, 2282del4, and S3247X were notably lower in Finns compared with reported frequencies in other populations. This data confirms FLG mutations as risk factors for AD in Finns, but also questions their feasibility as biomarkers in predicting treatment response.

PMID: 27840886 [PubMed - indexed for MEDLINE]