Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics.

Pharmacogenet Genomics. 2016 Jan;26(1):28-39

Authors: Chan SL, Samaranayake N, Ross CJ, Toh MT, Carleton B, Hayden MR, Teo YY, Dissanayake VH, Brunham LR

Abstract
BACKGROUND: Interpopulation differences in drug responses are well documented, and in some cases they correspond to differences in the frequency of associated genetic markers. Understanding the diversity of genetic markers associated with drug response across different global populations is essential to infer population rates of drug response or risk for adverse drug reactions, and to guide implementation of pharmacogenomic testing. Sri Lanka is a culturally and linguistically diverse nation, but little is known about the population genetics of the major Sri Lankan ethnic groups. The objective of this study was to investigate the diversity of pharmacogenomic variants in the major Sri Lankan ethnic groups.
METHODS: We examined the allelic diversity of more than 7000 variants in genes involved in drug biotransformation and response in the three major ethnic populations of Sri Lanka (Sinhalese, Sri Lankan Tamils, and Moors), and compared them with other South Asian, South East Asian, and European populations using Wright's Fixation Index, principal component analysis, and STRUCTURE analysis.
RESULTS: We observed overall high levels of similarity within the Sri Lankan populations (median FST=0.0034), and between Sri Lankan and other South Asian populations (median FST=0.0064). Notably, we observed substantial differentiation between Sri Lankan and European populations for important pharmacogenomic variants related to warfarin (VKORC1 rs9923231) and clopidogrel (CYP2C19 rs4986893) response.
CONCLUSION: These data expand our understanding of the population structure of Sri Lanka, provide a resource for pharmacogenomic research, and have implications for the clinical use of genetic testing of pharmacogenomic variants in these populations.

PMID: 26444257 [PubMed - indexed for MEDLINE]

Pharmacogenomics Can Enhance Prescribing of Psychiatric Medications.

South Med J. 2016 Oct;109(10):628-630

Authors: Narang P, Johnson A, Enja M, Lippmann S

Abstract
Many psychiatric patients experience pharmaceutical intolerances, and some of them do not derive optimal efficacy from their pharmacotherapies. Clinical problems such as these may result in prolonged dysfunction, adverse consequences, and repeated changes in medication treatment regimens. Pharmacogenomics is a laboratory method that aids individualized medication selection by predicting drug efficacy and adverse effect profiles. It is a technique that involves the testing of patients' genetic makeup to improve medicinal response and tolerance. Pharmacogenomics aims to clarify pharmacokinetics and pharmacodynamics in addition to focusing on hepatic cytochrome enzyme metabolism. Ultimately, it facilitates optimal selection and adjustment of medications to enhance clinical outcomes. Pharmacogenomics is most useful in cases in which routinely prescribed pharmacotherapies are either suboptimally effective or have unacceptable adverse effects. Once there has been a failure of a therapeutic drug treatment, rather than "blindly" selecting an alternative medicine, pharmacogenomic test results can provide guidance for the selection of the most appropriate drug and its dose. The intent is to yield a greater likelihood of patient success in following a therapeutic intervention.

PMID: 27706500 [PubMed - in process]

A genetic variant in Rassf1a predicts outcome in mCRC patients treated with cetuximab plus chemotherapy: results from FIRE-3 and JACCRO 05 and 06 trials.

Pharmacogenomics J. 2016 Oct 04;:

Authors: Sebio A, Stintzing S, Heinemann V, Sunakawa Y, Zhang W, Ichikawa W, Tsuji A, Takahashi T, Parek A, Yang D, Cao S, Ning Y, Stremitzer S, Matsusaka S, Okazaki S, Barzi A, Berger MD, Lenz HJ

Abstract
The Hippo pathway is involved in colorectal cancer (CRC) development and progression. The Hippo regulator Rassf1a is also involved in the Ras signaling cascade. In this work, we tested single nucleotide polymorphisms within Hippo components and their association with outcome in CRC patients treated with cetuximab. Two cohorts treated with cetuximab plus chemotherapy were evaluated (198 RAS wild-type (WT) patients treated with first-line FOLFIRI plus Cetuximab within the FIRE-3 trial and 67 Ras WT patients treated either with first-line mFOLFOX6 or SOX plus Cetuximab). In these two populations, Rassf1a rs2236947 was associated with overall survival (OS), as patients with a CC genotype had significantly longer OS compared with those with CA or AA genotypes. This association was stronger in patients with left-side CRC (hazard ratio (HR): 1.79 (1.01-3.14); P=0.044 and HR: 2.83 (1.14-7.03); P=0.025, for Fire 3 and JACCRO cohorts, respectively). Rassf1a rs2236947 is a promising biomarker for patients treated with cetuximab plus chemotherapy.The Pharmacogenomics Journal advance online publication, 4 October 2016; doi:10.1038/tpj.2016.69.

PMID: 27698403 [PubMed - as supplied by publisher]

Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis.

Pharmacogenomics J. 2016 Oct 04;:

Authors: Sode J, Vogel U, Bank S, Andersen PS, Hetland ML, Locht H, Heegaard NH, Andersen V

Abstract
Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case-case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00-1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60-0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).The Pharmacogenomics Journal advance online publication, 4 October 2016; doi:10.1038/tpj.2016.66.

PMID: 27698401 [PubMed - as supplied by publisher]

Sex impact on biomarkers, pharmacokinetics and pharmacodynamic: Sex and drugs.

Curr Med Chem. 2016 Oct 03;:

Authors: Franconi F, Campesi I

Abstract
Sex is one of several factors influencing pharmacological responses, but research on its effects on pharmacokinetics and pharmacodynamics, although emerging remarkably, remains poor and contains many methodological issues. In this review, the current state of knowledge about sex differences in pharmacokinetics and some hints to pharmacogenomics were evaluated. Moreover, considering that many pharmacological responses are monitored through biomarkers, the influence of sex on some biomarkers has been reported. Finally, we report sex differences in pharmacodynamics, particularly analysing opioids and their use during pregnancy, labor and breastfeeding. In conclusion, a more precise sex- and gender-based approach appears necessary to achieve more evidence-based therapy in men and women.

PMID: 27697075 [PubMed - as supplied by publisher]

Dual-action Hybrid Compounds - A New Dawn in the Discovery of Multi-target Drugs: Lead Generation Approaches.

Curr Top Med Chem. 2016 Sep 27;:

Authors: Abdolmalekia A, Ghasemi JB

Abstract
Finding high quality beginning compounds is a critical job at the start of the lead generation stage for multi-target drug discovery (MTDD). Designing hybrid compounds as a selective multi-target chemical entity is a challenge, opportunity, and new idea to better act against specific multiple targets. One hybrid molecule is formed by two (or more) pharmacophore group's participation. So, these new compounds often exhibit two or more activities going about as multi-target drugs (mt-drugs) and may have superior safety or efficacy. Application of integrating a range of information and sophisticated new in silico, bioinformatics, structural biology, pharmacogenomics methods may be useful to discover/design, and synthesis of the new hybrid molecules. In this regard, many rational and screening approaches have followed by medicinal chemists for the lead generation in MTDD. Here, we review some popular lead generation approaches that have been used for designing multiple ligands (DMLs). This paper focuses on dual- acting chemical entities that incorporate a part of two drugs or bioactive compounds to compose hybrid molecules. Also, it presents some of key concepts and limitations/strengths of lead generation methods by comparing combination framework method with screening approaches. Besides, a number of examples to represent applications of hybrid molecules in the drug discovery are included.

PMID: 27697056 [PubMed - as supplied by publisher]

Pharmacogenomics of the cytochrome P450 2C family: impacts of amino acid variations on drug metabolism.

Drug Discov Today. 2016 Sep 27;:

Authors: Isvoran A, Louet M, Vladoiu DL, Craciun D, Loriot MA, Villoutreix BO, Miteva MA

Abstract
Pharmacogenomics investigates DNA and RNA variations in the human genome related to drug responses. Cytochrome P450 (CYP) is a supergene family of drug-metabolizing enzymes responsible for the metabolism of approximately 90% of human drugs. Among the major CYP isoforms, the CYP2C subfamily is of clinical significance because it metabolizes approximately 20% of clinically administrated drugs and represents several variant alleles leading to adverse drug reactions or altering drug efficacy. Here, we review recent progress on understanding the interindividual variability of the CYP2C members and the functional and clinical impact on drug metabolism. We summarize current advances in the molecular modeling of CYP2C polymorphisms and discuss the structural bases and molecular mechanisms of amino acid variants of CYP2C members that affect drug metabolism.

PMID: 27693711 [PubMed - as supplied by publisher]

K-Ras and its inhibitors towards personalized cancer treatment: Pharmacological and structural perspectives.

Eur J Med Chem. 2016 Sep 16;125:299-314

Authors: Asati V, Mahapatra DK, Bharti SK

Abstract
The discovery of genetic, genomic and clinical biomarkers have revolutionized the treatment option in the form of personalized medicine which allows to accurately predict a person's susceptibility/progression of disease, the patient's response to therapy, and maximize the therapeutic outcome in terms of low/no toxicity for a particular patient. Recently, the U.S. Food and Drug Administration has realized the contribution of pharmacogenomics in better healthcare and advocated the consideration of pharmacogenomic principles in making safer and more effective drug. Many anticancer drugs show reduced or no response in cancer patients with tumor specific gene mutations such as B-Raf and K-Ras. The high incidence of K-Ras mutation has been reported in pancreatic, colon, and lung carcinomas. The identification of K-Ras as a clinical biomarker and potential therapeutic target has attracted the scientific community to develop effective and precise anticancer drug. Inhibitors which block farnesylation of Ras have been developed or under clinical trial studies. Tipifarnib, approved by USFDA for the treatment of elderly acute leukemia is a Ras pathway inhibitor. Some peptidomimetics and bi-substrate inhibitors like FTI 276, FTI 277, B956, B1086, L731, L735, L739, L750, BMS-214662, L778123, and L778123 are under clinical trials. Recently mutant K-Ras has been considered as potential biomarker and target for precise cancer therapy. This review focuses primarily on the Ras/Raf/MEK/ERK signaling pathway including K-Ras mutation as therapeutic target, inhibitors and their structure activity relationships (SARs) for the design and development of anticancer agents.

PMID: 27688185 [PubMed - as supplied by publisher]

Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals.

J Hum Genet. 2015 Oct;60(10):581-7

Authors: Kawai Y, Mimori T, Kojima K, Nariai N, Danjoh I, Saito R, Yasuda J, Yamamoto M, Nagasaki M

Abstract
The Tohoku Medical Megabank Organization constructed the reference panel (referred to as the 1KJPN panel), which contains >20 million single nucleotide polymorphisms (SNPs), from whole-genome sequence data from 1070 Japanese individuals. The 1KJPN panel contains the largest number of haplotypes of Japanese ancestry to date. Here, from the 1KJPN panel, we designed a novel custom-made SNP array, named the Japonica array, which is suitable for whole-genome imputation of Japanese individuals. The array contains 659,253 SNPs, including tag SNPs for imputation, SNPs of Y chromosome and mitochondria, and SNPs related to previously reported genome-wide association studies and pharmacogenomics. The Japonica array provides better imputation performance for Japanese individuals than the existing commercially available SNP arrays with both the 1KJPN panel and the International 1000 genomes project panel. For common SNPs (minor allele frequency (MAF)>5%), the genomic coverage of the Japonica array (r(2)>0.8) was 96.9%, that is, almost all common SNPs were covered by this array. Nonetheless, the coverage of low-frequency SNPs (0.5%<MAF⩽5%) of the Japonica array reached 67.2%, which is higher than those of the existing arrays. In addition, we confirmed the high quality genotyping performance of the Japonica array using the 288 samples in 1KJPN; the average call rate 99.7% and the average concordance rate 99.7% to the genotypes obtained from high-throughput sequencer. As demonstrated in this study, the creation of custom-made SNP arrays based on a population-specific reference panel is a practical way to facilitate further association studies through genome-wide genotype imputations.

PMID: 26108142 [PubMed - indexed for MEDLINE]

Pharmacogenomics and chemical library screens reveal a novel SCF(SKP2) inhibitor that overcomes bortezomib resistance in multiple myeloma.

Leukemia. 2016 Sep 28;

Authors: Malek E, Abdel-Malek MA, Jagannathan S, Vad N, Karns R, Jegga AG, Broyl A, van Duin M, Sonneveld P, Cottini F, Anderson KC, Driscoll JJ

Abstract
While clinical benefit of the proteasome inhibitor (PI) bortezomib for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin (Ub) ligase Skp1-Cullin-1-Skp2 (SCF(Skp2)) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF(Skp2) activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here, we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138(+) cells isolated from bortezomib-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138(+) cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCF(Skp2) complex, stabilized p27 and increased the number of annexin-V positive cells after bortezomib treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced bortezomib-induced apoptosis. DT204 co-treatment with bortezomib overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof-of-concept for rationally-designed drug combinations that incorporate SCF(Skp2) inhibitors to treat bortezomib resistant disease.Leukemia accepted article preview online, 28 September 2016. doi:10.1038/leu.2016.258.

PMID: 27677741 [PubMed - as supplied by publisher]

Impact of a personal CYP2D6 testing workshop on physician assistant student attitudes toward pharmacogenetics.

Pharmacogenomics. 2016 Mar;17(4):341-52

Authors: O'Brien TJ, LeLacheur S, Ward C, Lee NH, Callier S, Harralson AF

Abstract
AIM: We assessed the impact of personal CYP2D6 testing on physician assistant student competency in, and attitudes toward, pharmacogenetics (PGx).
MATERIALS & METHODS: Buccal samples were genotyped for CYP2D6 polymorphisms. Results were discussed during a 3-h PGx workshop. PGx knowledge was assessed by pre- and post-tests. Focus groups assessed the impact of the workshop on attitudes toward the clinical utility of PGx.
RESULTS: Both student knowledge of PGx, and its perceived clinical utility, increased immediately following the workshop. However, exposure to PGx on clinical rotations following the workshop seemed to influence student attitudes toward PGx utility.
CONCLUSION: Personal CYP2D6 testing improves both knowledge and comfort with PGx. Continued exposure to PGx concepts is important for transfer of learning.

PMID: 26907849 [PubMed - indexed for MEDLINE]

Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients.

Pharmacogenomics. 2016 Mar;17(4):393-403

Authors: Chalikiopoulou C, Tavianatou AG, Sgourou A, Kourakli A, Kelepouri D, Chrysanthakopoulou M, Kanelaki VK, Mourdoukoutas E, Siamoglou S, John A, Symeonidis A, Ali BR, Katsila T, Papachatzopoulou A, Patrinos GP

Abstract
AIM: Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes.
PATIENTS & METHODS: Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies.
RESULTS: We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients.
CONCLUSION: These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.

PMID: 26895070 [PubMed - indexed for MEDLINE]

Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses.

Pharmacogenomics. 2016 Mar;17(4):435-51

Authors: Campbell JM, Bateman E, Peters MDj, Bowen JM, Keefe DM, Stephenson MD

Abstract
Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.

PMID: 26894782 [PubMed - indexed for MEDLINE]

Pharmacogenomics of anti-TNF response in psoriasis, where are we?

Pharmacogenomics. 2016 Mar;17(4):323-6

Authors: Julià A, Marsal S

PMID: 26871199 [PubMed - indexed for MEDLINE]

Polymorphisms associated with low bone mass and high risk of atraumatic fracture.

Physiol Res. 2015;64(5):621-31

Authors: Zofkova I, Nemcikova P, Kuklik M

Abstract
Osteoporosis is a serious disease characterized by high morbidity and mortality due to atraumatic fractures. In the pathogenesis of osteoporosis, except environment and internal factors, such as hormonal imbalance and genetic background, are also in play. In this study candidate genes for osteoporosis were classified according to metabolic or hormonal pathways, which regulate bone mineral density and bone quality (estrogen, RANKL/RANK/OPG axis, mevalonate, the canonical circuit and genes regulating the vitamin D system). COL1A1 and/or COL1A2 genes, which encode formation of the procollagen 1 molecule, were also studied. Mutations in these genes are well-known causes of the inborn disease 'osteogenesis imperfecta'. In addition to this, polymorphisms in COL1A1 and/or COL1A2 have been found to be associated with parameters of bone quality in adult subjects. The authors discuss the perspectives for the practical utilization of pharmacogenetics (identification of single candidate genes using PCR) and pharmacogenomics (using genome wide association studies (GWAS) to choose optimal treatment for osteoporosis). Potential predictors of antiresorptive therapy efficacy include the following well established genes: ER, FDPS, Cyp19A1, VDR, Col1A1, and Col1A2, as well as the gene for the canonical (Wnt) pathway. Unfortunately, the positive outcomes seen in most association studies have not been confirmed by other researchers. The controversial results could be explained by the use of different methodological approaches in individual studies (different sample size, homogeneity of investigated groups, ethnic differences, or linkage disequilibrium between genes). The key pitfall of association studies is the low variability (7-10 %) of bone phenotypes associated with the investigated genes. Nevertheless, the identification of new genes and the verification of their association with bone density and/or quality (using both PCR and GWAS), remain a great challenge in the optimal prevention and treatment of osteoporosis.

PMID: 25804099 [PubMed - indexed for MEDLINE]

Moving toward personalized medicine in rheumatoid arthritis: SNPs in methotrexate intracellular pathways are associated with methotrexate therapeutic outcome.

Pharmacogenomics. 2016 Sep 27;

Authors: Lima A, Bernardes M, Azevedo R, Seabra V, Medeiros R

Abstract
AIM: Evaluate the potential of selected SNPs as predictors of methotrexate (MTX) therapeutic outcome.
PATIENTS & METHODS: In total, 35 SNPs in 14 genes involved in MTX intracellular pathways and Phase II reactions were genotyped in 233 rheumatoid arthritis (RA) patients treated with MTX. Binary logistic regressions were performed by genotype/haplotype-based approaches. Non-Response- and Toxicity-Genetic Risk Indexes (Non-RespGRI and ToxGRI) were created.
RESULTS: MTX nonresponse was associated to eight genotypes and three haplotypes: MTHFR rs1801131 AA and rs1801133 TT; MS rs1805087 AA; MTRR rs1801394 A carriers; ATIC rs2372536 C carriers, rs4673993 T carriers, rs7563206 T carriers and rs12995526 T carriers; CC for GGH rs3758149 and rs12681874; CGTTT for ATIC combination 1; and CTTTC for ATIC combination 2. From overall Non-RespGRI patients with indexes 6-8 had more than sixfold increased risk for MTX nonresponse than those patients with indexes 0-5. MTX-related toxicity was associated to five genotypes and two haplotypes: ATIC rs2372536 G carriers, rs3821353 T carriers, rs7563206 CC and rs12995526 CC; ADORA2A rs2267076 T; CTTCC for ATIC combination 1; and TC for ADORA2A rs2267076 and rs2298383. From overall ToxGRI, patients with indexes 3-4 had more than sevenfold increased risk for MTX-related toxicity than those patients with indexes 1-2.
CONCLUSION: Genotyping may be helpful to identify which RA patients will not benefit from MTX treatment and, consequently, important to personalized medicine in RA. Nevertheless, further studies are required to validate these findings.

PMID: 27676277 [PubMed - as supplied by publisher]

Pharmacogenomic approaches to lipid-regulating trials.

Curr Opin Lipidol. 2016 Sep 26;

Authors: Bertrand MJ, Dubé MP, Tardif JC

Abstract
PURPOSE OF REVIEW: Randomized clinical outcome trials are costly, long, and often yield neutral or modestly positive results, and these issues have impeded cardiovascular drug development in the past decade. Despite the significant reduction of cardiovascular morbidity and mortality with statins, substantial residual risk of major cardiovascular events remains. This could be because of the difficulty of demonstrating benefits of new drugs in addition to the current standard of care in unselected populations as well as the interindividual variability in drug response. Pharmacogenomics is a promising avenue for the development of novel or failed drugs and for the repurposing of other medications.
RECENT FINDINGS: Several variants were identified in genes that were associated with the effects of statins on plasma lipids. Genomic studies of mutations in genes that encode drug targets have the potential to inform on the link between drug therapy acting on those targets and clinical outcomes. Recently, ADCY9 gene variants were shown to be significantly associated with responses to dalcetrapib in terms of clinical outcomes, atherosclerosis imaging, cholesterol efflux, and inflammation, which provided support for the conduct of a new prospective clinical trial in a genetically determined population.
SUMMARY: Pharmacogenomics hold great potential in future lipid trials to decrease failure rates in drug development and to identify patients who will respond with greater benefits and smaller risk.

PMID: 27676198 [PubMed - as supplied by publisher]

Integrating Pharmacovigilance and Pharmacogenomics: Croatian Experience.

Clin Ther. 2016 Oct 6;38(10S):e23

Authors: Bozina N, Mirosevic Skvrce N, Ganoci L, Mas P, Klarica Domjanovic I, Simic I

PMID: 27673639 [PubMed - as supplied by publisher]

Genes differentially expressed by methylprednisolone in vivo in CD4 T lymphocytes from multiple sclerosis patients: potential biomarkers.

Pharmacogenomics J. 2016 Sep 27;

Authors: De Andres C, García MI, Goicoechea H, Martínez-Ginés ML, García-Domínguez JM, Martín ML, Romero-Delgado F, Benguría A, Sanjurjo M, López-Fernández LA

Abstract
Intravenous methylprednisolone (IVMP) is the gold standard treatment in acute relapses of multiple sclerosis. Knowing the response to IVMP in advance could facilitate earlier selection of patients for subsequent courses of therapy. However, molecular mechanisms and changes in gene expression induced by methylprednisolone remain unknown. The aim of the study was to identify in vivo differentially expressed genes in relapsing-remitting multiple sclerosis patients after 3-6 days of treatment with IVMP. For this purpose, whole-genome transcription profiling of CD4+ T lymphocytes was performed before and after treatment with IVMP in 8 relapsing-remitting multiple sclerosis patients during relapse using Human GE 4x44K v2 microarrays. Differentially expressed genes were identified using a paired t test on GeneSpring v13.0 software. A P-value <0.001 and a twofold change were considered significant. Microarray data were confirmed using real-time PCR. Microarray revealed changes in gene expression: four genes were downregulated (B3GNT3, ZNF683, IFNG and TNF) and seven upregulated (DEFA4, CTSG, DEFA8P, AZU1, MPO, ELANE and PRTN3). Pathway analysis revealed the transforming growth factor-β signaling pathway to be affected. Comparison with previously published data on in vitro methylprednisolone-regulated genes showed that SMAD7, TNF and CHI3L1 were also downregulated in vivo in relapsing-remitting multiple sclerosis patients. In summary, we performed the first in vivo transcriptome analysis in CD4+ T lymphocytes before and after the treatment with IVMP in patients with multiple sclerosis. Identification of differentially expressed genes in patients receiving IVMP could improve our understanding of the molecular mechanisms underlying the therapeutic effects of IVMP and highlight potential biomarkers of the response to IVMP.The Pharmacogenomics Journal advance online publication, 27 September 2016; doi:10.1038/tpj.2016.71.

PMID: 27670768 [PubMed - as supplied by publisher]

Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.

Pharmacogenomics J. 2016 Sep 27;

Authors: Chang SW, McDonough CW, Gong Y, Johnson TA, Tsunoda T, Gamazon ER, Perera MA, Takahashi A, Tanaka T, Kubo M, Pepine CJ, Johnson JA, Cooper-DeHoff RM

Abstract
We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a β-blocker-based strategy (β-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 10(-)(8)). rs11124945 G allele carriers had lower odds for NOD when exposed to the β-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 10(-)(5)), whereas A/A homozygotes exposed to the β-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 10(-)(4)). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.The Pharmacogenomics Journal advance online publication, 27 September 2016; doi:10.1038/tpj.2016.67.

PMID: 27670767 [PubMed - as supplied by publisher]