Cardiovascular Pharmacogenomics: Does It Matter If You're Black or White?

Annu Rev Pharmacol Toxicol. 2018 Oct 08;:

Authors: De T, Park CS, Perera MA

Abstract
Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, most pharmacogenomic studies have focused on individuals of European and East Asian ancestry, resulting in a substantial disparity in the clinical utility of genetic prediction for drug response in US minority populations. In this review, we discuss the genetic factors that underlie variability to drug response and known pharmacogenomic associations and how these differ between populations, with an emphasis on the current knowledge in cardiovascular pharmacogenomics. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 30296897 [PubMed - as supplied by publisher]

1H NMR based pharmacometabolomics analysis of metabolic phenotype on predicting metabolism characteristics of losartan in healthy volunteers.

J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Sep 15;1095:15-23

Authors: He C, Liu Y, Wang Y, Tang J, Tan Z, Li X, Chen Y, Huang Y, Chen X, Ouyang D, Zhou H, Peng J

Abstract
Inter-individual variability in drug metabolism and disposition is common in both preclinical and clinical researches. Losartan and its active metabolite EXP3174 present a high degree of inter-individual differences in blood concentrations that affect drug efficacy and side effect. Pharmacometabolomics has been increasingly applied on predicting the drug responses by analyzing the differences in metabolic profile. A pre-dose metabolic phenotype was investigated to interpret inter-individual variations in the metabolism characteristics of losartan. 1H Nuclear Magnetic Resonance (NMR) spectroscopy-based metabolic profiles were performed on 36 healthy Chinese male volunteers by measuring their pre-dose plasma samples. After oral administration of losartan, the concentrations of losartan and its bioactive metabolite EXP3174 were monitored by liquid chromatography-mass spectrometry (LC-MS). Orthogonal partial least-squares (O-PLS) model was conducted to select potential biomarkers that substantially contributed to the inter-individual variations in the metabolism features via analyzing the ratio of pharmacokinetics (PK) parameters of its metabolite to parent drug. Potential metabolites such as glycine, phosphorylcholine, choline, creatine, creatinine, lactate, citrate, α-glucose, and lipids showed strong correlations with metabolism features of losartan. In addition, the pathway analysis revealed that baseline lipid metabolism, the glycine, serine and threonine pathway, and glycolysis or gluconeogenesis metabolism pathway were significantly associated with the ratio of PK parameters of EXP3174 to losartan. Step-wise multiple linear regression (MLR) was constructed to investigate the potential roles of the selected biomarkers in predicting individualized metabolism characteristics of losartan. These results showed that the pre-dose individual metabolic traits may be a useful approach for characterizing individual differences in losartan metabolism characteristics and therefore for expediting personalized dose-setting in further clinical studies.

PMID: 30041085 [PubMed - indexed for MEDLINE]

Polymorphisms of CYP27B1 are associated with IFN efficacy in HBeAg-positive patients.

J Clin Lab Anal. 2018 Jun;32(5):e22367

Authors: Wu Y, Zeng Y, Wu W, Lin J, Ou Q

Abstract
BACKGROUND: Host single nucleotide polymorphisms were associated with antiviral therapy in CHB patients. The CYP27B1 gene, encoding 25(OH)D3 -1α hydroxylase, might activate 25(OH)D3 to 1,25(OH)2 D3 in kidney resulted in influencing the efficacy of interferon (IFN). The aim of the study was to investigate the association between CYP27B1 polymorphisms and the response to IFN in HBeAg-positive patients.
METHODS: Eighty-seven HBeAg-positive CHB patients infected with HBV genotype B or C were included in the study. All patients were treated with IFN at least 1 year. According to the response to PEG-IFN therapy, they were divided into three groups: 16 complete responses (CR), 42 partial responses (PR), and 29 nonresponses (NR). Sanger-sequencing was utilized to genotype the CYP27B1 SNPs(rs4646536 and rs10877012).
RESULTS: In logistic regression analysis, the frequency of rs4646536 CC genotype was observed to be higher in the NR group. Besides, the GG genotype of rs10877012 differed significantly among the three groups. The GG genotype was prevalent in patients with CR, and patients with TT genotype result in NR at the end of IFN treatment. The most common haplotype TG was independently associated with CR, after adjustment, and haplotype CT appeared to be associated with NR and PR, rather than CR. The data also showed that patients with baseline 1,25(OH)2 D3 > 39.39 pg/mL had higher CR rates at the end of IFN therapy.
CONCLUSION: These results suggested CYP28B1 gene polymorphisms may be independently associated with the efficacy of IFN in HBeAg-positive patients.

PMID: 29457277 [PubMed - indexed for MEDLINE]

Correction to: Polymorphisms of genes involved in inflammation and blood vessel development influence the risk of varicose veins.

Clin Genet. 2018 Nov;94(5):491

Authors: Shadrina A, Tsepilov Y, Smetanina M, Voronina E, Seliverstov E, Ilyukhin E, Kirienko A, Zolotukhin I, Filipenko M

PMID: 30295924 [PubMed - in process]

Novel technologies for dipeptide drugs design and their implantation.

Curr Pharm Des. 2018 Oct 07;:

Authors: Gudasheva TA, Ostrovskaya RU, Seredenin SB

Abstract
The article is an overview of author's data obtained in the framework of the project "The Creation of dipeptide preparations" at the V.V. Zakusov Institute of Pharmacology, Moscow, Russia. Advantages of dipeptides over longer peptides consist in that they are orally active owing to higher stability and ability to penetrate biological barriers due to presence of specific ATP-dependent transporters in enterocytes and blood-brain barrier. Two original approaches for dipeptide drugs design have been developed. Both of them are based on the idea of a leading role of central dipeptide fragment of the peptide chain beta-turn in the peptide-receptor interaction. The first approach, named "peptide drug-based design" represents the transformation of known nonpeptide drug into its dipeptide topological analog. The latter usually corresponds to a beta-turn of some regulatory peptide. The second approach represents the design of tripeptoide mimetic of the beta-turn of regulatory peptide or protein. The results of the studies, which led to the discovery of endogenous prototypes of the known non-peptide drugs piracetam and sulpiride, are presented herein. The paper discusses the process, based on the above-mentioned principles, that was used in designing of nontoxic, orally available, highly effective dipeptide drugs: nootropic noopept, dipeptide analog of piracetam; antipsychotic dilept, neurotensin tripeptoid analog; selective anxiolytic GB-115, tripeptoid analog of CCK-4, and potential neuroprotector GK-2, homodimeric dipeptide analog of NGF.

PMID: 30295186 [PubMed - as supplied by publisher]

Optimization of conditions to extract high quality DNA for PCR analysis from whole blood using SDS-proteinase K method.

Saudi J Biol Sci. 2017 Nov;24(7):1465-1469

Authors: Qamar W, Khan MR, Arafah A

Abstract
In case of studies associated with human genetics, genomics, and pharmacogenetics the genomic DNA is extracted from the buccal cells, whole blood etc. Several methods are exploited by the researchers to extract DNA from the whole blood. One of these methods, which utilizes cell lysis and proteolytic properties of sodium dodecyl sulfate (SDS) and proteinase K respectively, might also be called SDS-PK method. It does not include any hazardous chemicals such as phenol or chloroform and is inexpensive. However, several researchers report the same method with different formulas and conditions. During our experiments with whole blood DNA extraction we experienced problems such as protein contamination, DNA purity and yield when followed some SDS-PK protocols reported elsewhere. A260/A280 and A260/A230 ratios along with PCR amplification give a clear idea about the procedure that was followed to extract the DNA. In an effort to increase the DNA purity from human whole blood, we pointed out some steps of the protocol that play a crucial role in determining the extraction of high quality DNA.

PMID: 30294214 [PubMed]

Long-range PCR libraries and next-generation sequencing for pharmacogenetic studies of patients treated with anti-TNF drugs.

Pharmacogenomics J. 2018 Oct 08;:

Authors: Walczak M, Skrzypczak-Zielinska M, Plucinska M, Zakerska-Banaszak O, Marszalek D, Lykowska-Szuber L, Stawczyk-Eder K, Dobrowolska A, Slomski R

Abstract
Biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies significantly increased the effectiveness of autoimmune disease treatment compared with conventional medicines. However, anti-TNF-α drugs are relatively expensive and a response to the therapy is reported in only 60-70% of patients. Moreover, in up to 5% of patients adverse drug reactions occur. The various effects of biological treatment may be a potential consequence of interindividual genetic variability. Only a few studies have been conducted in this field and which refer to single gene loci. Our aim was to design and optimize a methodology for a broader application of pharmacogenetic studies in patients undergoing anti-TNF-α treatment. Based on the current knowledge, we selected 16 candidate genes: TNFRSF1A, TNFRSF1B, ADAM17, CASP9, FCGR3A, LTA, TNF, FAS, IL1B, IL17A, IL6, MMP1, MMP3, S100A8, S100A9, and S100A12, which are potentially involved in the response to anti-TNF-α therapy. As a research model, three DNA samples from Crohn's disease (CD) patients were used. Targeted genomic regions were amplified in 23 long-range (LR) PCR reactions and after enzymatic fragmentation amplicon libraries were prepared and analyzed by next-generation sequencing (NGS). Our results indicated 592 sequence variations located in all fragments with coverage range of 5-1089. We demonstrate a highly sensitive, flexible, rapid, and economical approach to the pharmacogenetic investigation of anti-TNF-α therapy using amplicon libraries and NGS technology.

PMID: 30293984 [PubMed - as supplied by publisher]

Clinical Issues in Severe Asthma: Consensus and Controversies on the Road to Precision Medicine.

Chest. 2018 Oct;154(4):982-983

Authors: Bleecker ER, Panettieri RA, Wenzel SE

Abstract
As seen in this CME online activity (available at http://courses.elseviercme.com/708e), the various forms of asthma affect > 300 million people globally and > 25 million people in the United States. Asthma-related symptoms and exacerbations result in nearly 2 million ED visits annually, and many of these visits lead to inpatient hospital stays. There is an urgent need to improve the care of the estimated 5% to 15% of patients who have severe asthma. Importantly, studies have shown that severe asthma accounts for an outsized proportion of the disease-related morbidity, mortality, and health-care costs. Examining cohorts from several large patient networks that were created to better understand clinical presentations, biopsychosocial consequences, and long-term outcomes of severe asthma revealed substantial disease burden, significant gaps in longitudinal care, and a clear need for additional treatment options. This CME-accredited Clinical Issues program is intended for allergists/clinical immunologists, pulmonologists, and other health-care providers involved in the management of patients with severe asthma. During the activity, a panel of expert faculty will discuss and debate a series of topics related to the evaluation and long-term treatment of various severe asthma phenotypes. Activity topics include education regarding (1) The classification of severe asthma to differentially diagnose patients with disease that is uncontrolled despite relatively intensive therapy; (2) potential phenotypes and available biomarkers, including strengths, limitations, and how to translate results into the selection of therapies; and (3) the different mechanisms of action, efficacy, and safety of biologic therapies that target the pathophysiology of severe asthma. The goal is to provide clinician learners with the latest evidence and a fresh perspective on evolving management paradigms for severe asthma.

PMID: 30290932 [PubMed - in process]

Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide.

Pharmacogenet Genomics. 2018 Oct 04;:

Authors: Singh S, Wang Z, Shahin MH, Langaee TY, Gong Y, Turner ST, Chapman AB, Gums JG, McDonough CW, Bailey KR, Beitelshees AL, Cooper-DeHoff RM, Scherer S, Boerwinkle E, Johnson JA

Abstract
Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.

PMID: 30289819 [PubMed - as supplied by publisher]

Sterol-modified PEG lipids: alteration of the bilayer anchoring moiety has an unexpected effect on liposome circulation.

Chem Commun (Camb). 2018 Oct 05;:

Authors: Dolor A, Kierstead P, Dai Z, Szoka FC

Abstract
We synthesized and characterized two novel sterol-anchored polyethylene glycols (PEG) as potential alternatives to conventional phosphatidylethanolamine-PEGs. Liposomes containing the dicholesterol anchored PEG at 5 mole percent exhibit canonical PEGgylated-liposome behaviors including retention of encapsulated small molecules, low serum protein adsorption, and reduced cellular uptake yet they do not exhibit long circulation.

PMID: 30288531 [PubMed - as supplied by publisher]

Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience.

Dose Response. 2018 Oct-Dec;16(4):1559325818803042

Authors: Murphy C, Byrne S, Ahmed G, Kenny A, Gallagher J, Harvey H, O'Farrell E, Bird B

Abstract
Background: Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity.
Methods: All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed.
Results: Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios.
Conclusions: The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

PMID: 30288154 [PubMed]

Association between SOST gene polymorphisms and response to alendronate treatment in postmenopausal Chinese women with low bone mineral density.

Pharmacogenomics J. 2018 Oct 05;:

Authors: Wang WJ, Fu WZ, He JW, Wang C, Zhang ZL

Abstract
The aim of this study was to explore the allelic association between SOST polymorphisms and the variance of clinical effects of alendronate in postmenopausal Chinese women with osteoporosis or osteopenia. In the study, 500 postmenopausal women in Shanghai area with osteoporosis or osteopenia were included. All participants were treated with weekly oral alendronate 70 mg, daily calcium 600 mg and vitamin D 125 IU for 12 months. Nine tagging single-nucleotide polymorphisms (SNPs) in SOST gene were genotyped. Bone mineral density of lumbar spine (L1-L4), left femoral neck and total hip were measured at baseline and after 1 year of treatment, respectively. In the study, 450 subjects completed the 1-year follow-up. The rs865429 was significantly associated with the % change of BMD at the femoral neck (P = 0.007). GG carriers seemed to be at an advantage after treatment of alendronate. Compared with AG and AA heterozygote, GG homozygote had the highest % change of BMD (3.100 ± 2.899%) at femoral neck. The odds ratio (95% confidence) of GG homozygote to be responders at femoral neck was 1.921 (1.211-3.048). Two haplotypes GG and AC constituted by rs865429 and rs851057 were associated with the % change of BMD at femoral neck and total hip, respectively. Therefore, the common variation of SOST gene contribute to the therapeutic response to alendronate treatment in Chinese women with osteoporosis or osteopenia.

PMID: 30287911 [PubMed - as supplied by publisher]

Pharmacogenomics in epithelial ovarian cancer first-line treatment outcome: validation of GWAS-associated NRG3 rs1649942 and BRE rs7572644 variants in an independent cohort.

Pharmacogenomics J. 2018 Oct 05;:

Authors: Pinto R, Assis J, Nogueira A, Pereira C, Coelho S, Brandão M, Dias J, Alves S, Pereira D, Medeiros R

Abstract
The identification of predictive biomarkers for the first-line treatment of epithelial ovarian cancer (EOC) remains a challenge. Although genome-wide association studies (GWAS) have identified several genetic polymorphisms as predictors of EOC clinical outcome, the subsequent validation has not yet been performed. This study aims to validate the influence of Neuregulin 3 (NRG3) rs1649942 and Brain and reproductive organ-expressed (TNFRSF1A modulator) (BRE) rs7572644 GWAS-identified variants in an independent cohort of EOC patients from the North region of Portugal (n = 339) submitted to first-line treatment. Polymorphism genotypes were determined by real-time PCR using validated assays. Patients carrying the NRG3 rs1649942 A allele presented a significantly longer overall survival (OS) when compared to GG-genotype patients (log-rank test, P = 0.011) in the FIGO IV stage subgroup. No impact was observed for early-stage patients or considering disease-free survival (DFS) as an outcome. For FIGO I/II stage patients, BRE rs7572644 C allele carriers exhibit a decreased OS (P = 0.014) and DFS (P = 0.032) when compared to TT-homozygous patients. Furthermore, a Multivariate Cox regression analysis revealed a three-fold increase in the risk of death (HR, 3.09; P = 0.015) and recurrence (HR, 3.33; P = 0.009) for FIGO I/II C allele carriers. No significant impact was observed for late-stage patients. The BRE rs7572644 and NRG3 rs1649942 genetic variants were validated in an independent cohort of EOC Portuguese patients, particularly in specific subgroups considering FIGO staging. Further functional post-GWAS analyses are indispensable to understand the biological mechanisms underlying the observed results.

PMID: 30287910 [PubMed - as supplied by publisher]

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

Pharmacogenomics J. 2018 Oct 05;:

Authors: Canet LM, Sánchez-Maldonado JM, Cáliz R, Ramos AR, Lupiañez CB, Canhão H, Martínez-Bueno M, Escudero A, Segura-Catena J, Sorensen SB, Hetland ML, Soto-Pino MJ, Ferrer MA, García A, Glintborg B, Filipescu I, Pérez-Pampin E, González-Utrilla A, Nevot MÁL, Conesa-Zamora P, Broeder AD, De Vita S, Jacobsen SEH, Collantes-Estevez E, Quartuccio L, Canzian F, Fonseca JE, Coenen MJH, Andersen V, Sainz J

Abstract
The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.

PMID: 30287909 [PubMed - as supplied by publisher]

Arsenic exposure, profiles of urinary arsenic species, and polymorphism effects of glutathione-s-transferase and metallothioneins.

Chemosphere. 2018 Dec;212:927-936

Authors: González-Martínez F, Sánchez-Rodas D, Cáceres DD, Martínez MF, Quiñones LA, Johnson-Restrepo B

Abstract
This study assessed the effects of polymorphic variants of gutathione-S-transferase and metallothioneins on profiles of urinary arsenic species. Drinking groundwater from Margarita and San Fernando, Colombia were analyzed and the lifetime average daily dose (LADD) of arsenic was determined. Specific surveys were applied to collect demographic information and other exposure factors. In addition, GSTT1-null, GSTM1-null, GSTP1-rs1695 and MT-2A-rs28366003 genetic polymorphisms were evaluated, either by direct PCR or PCR-RFLP. Urinary speciated arsenic concentrations were determined by HPLC-HG-AFS for species such as AsIII, AsV, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and total urinary As (TuAs). Primary methylation index (PMI) and secondary methylation index (SMI) were also calculated as indicators of the metabolic capacity. Polymorphisms effects were tested using multivariate analysis, adjusted by potential confounders. The As concentrations in groundwater were on average 34.6 ± 24.7 μg/L greater than the WHO guideline for As (10 μg/L). There was a correlation between As concentrations in groundwater and TuAs (r = 0.59; p = 0.000). Urinary inorganic arsenic (%InAs) was associated with GSTP1, LADD, GSTP1*Age, GSTP1*alcohol consumption (r2 = 0.43; likelihood-ratio test, p = 0.000). PMI was associated with sex (r2 = 0.20; likelihood-ratio test, p = 0.007). GSTP1 (AG + GG) homozygotes/heterozygotes could increase urinary %InAs and decrease the PMI ratio in people exposed to low and high As from drinking groundwater. Therefore, the explanatory models showed the participation of some covariates that could influence the effects of the polymorphisms on these exposure biomarkers to As.

PMID: 30286549 [PubMed - in process]

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea.

Hum Genomics. 2018 Oct 01;12(1):45

Authors: Chondrou V, Stavrou EF, Markopoulos G, Kouraklis-Symeonidis A, Fotopoulos V, Symeonidis A, Vlachaki E, Chalkia P, Patrinos GP, Papachatzopoulou A, Sgourou A

Abstract
BACKGROUND: We aimed to clarify the emerging epigenetic landscape in a group of genes classified as "modifier genes" of the β-type globin genes (HBB cluster), known to operate in trans to accomplish the two natural developmental switches in globin expression, from embryonic to fetal during the first trimester of conception and from fetal to adult around the time of birth. The epigenetic alterations were determined in adult sickle cell anemia (SCA) homozygotes and SCA/β-thalassemia compound heterozygotes of Greek origin, who are under hydroxyurea (HU) treatment. Patients were distinguished in HU responders and HU non-responders (those not benefited from the HU) and both, and in vivo and in vitro approaches were implemented.
RESULTS: We examined the CpG islands' DNA methylation profile of BCL11A, KLF1, MYB, MAP3K5, SIN3A, ZBTB7A, and GATA2, along with γ-globin and LRF/ZBTB7A expression levels. In vitro treatment of hematopoietic stem cells (HSCs) with HU induced a significant DNA hypomethylation pattern in ZBTB7A (p*, 0.04) and GATA2 (p*, 0.03) CpGs exclusively in the HU non-responders. Also, this group of patients exhibited significantly elevated baseline methylation patterns in ZBTB7A, before the HU treatment, compared to HU responders (p*, 0.019) and to control group of healthy individuals (p*, 0.021), which resembles a potential epigenetic barrier for the γ-globin expression. γ-Globin expression in vitro matched with detected HbF levels during patients' monitoring tests (in vivo) under HU treatment, implying a good reproducibility of the in vitro HU epigenetic effect. LRF/ZBTB7A expression was elevated only in the HU non-responders under the influence of HU.
CONCLUSIONS: This is one of the very first pharmacoepigenomic studies indicating that the hypomethylation of ZBTB7A during HU treatment enhances the LRF expression, which by its turn suppresses the HbF resumption in the HU non-responders. Its role as an epigenetic regulator of hemoglobin switching is also supported by the wide distribution of ZBTB7A-binding sites within the 5' CpG sequences of all studied human HBB cluster "modifier genes." Also, the baseline methylation level of selective CpGs in ZBTB7A and GATA2 could be an indicator of the negative HU response among the β-type hemoglobinopathy patients.

PMID: 30285874 [PubMed - in process]

Genomics of drug sensitivity in bladder cancer: an integrated resource for pharmacogenomic analysis in bladder cancer.

BMC Med Genomics. 2018 Oct 03;11(1):88

Authors: Ansari AA, Park I, Kim I, Park S, Ahn SM, Lee JL

Abstract
BACKGROUND: Bladder cancer has numerous genomic features that are potentially actionable by targeted agents. Nevertheless, both pre-clinical and clinical research using molecular targeted agents have been very limited in bladder cancer.
RESULTS: We created the Genomics of Drug Sensitivity in Bladder Cancer (GDBC) database, an integrated database (DB) to facilitate the genomic understanding of bladder cancer in relation to drug sensitivity, in order to promote potential therapeutic applications of targeted agents in bladder cancer treatment. The GDBC database contains two separate datasets: 1) in-house drug sensitivity data, in which 13 targeted agents were tested against 10 bladder cancer cell lines; 2) data extracted and integrated from public databases, including the Cancer Therapeutics Research Portal, Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, Kyoto Encyclopedia of Genes and Genomes, and the Cancer Gene Census databases, as well as bladder cancer genomics data and synthetic lethality/synthetic dosage lethality connections.
CONCLUSIONS: GDBC is an integrated DB of genomics and drug sensitivity data with a specific focus on bladder cancer. With a user-friendly web-interface, GDBC helps users generate genomics-based hypotheses that can be tested experimentally using drugs and cell lines included in GDBC.

PMID: 30285760 [PubMed - in process]

VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX.

BMC Biol. 2018 Oct 02;16(1):109

Authors: Bonin F, Taouis K, Azorin P, Petitalot A, Tariq Z, Nola S, Bouteille N, Tury S, Vacher S, Bièche I, Rais KA, Pierron G, Fuhrmann L, Vincent-Salomon A, Formstecher E, Camonis J, Lidereau R, Lallemand F, Driouch K

Abstract
BACKGROUND: The WW domain-containing oxidoreductase (WWOX) gene, frequently altered in breast cancer, encodes a tumor suppressor whose function is mediated through its interactions with cancer-related proteins, such as the pro-apoptotic protein p73α.
RESULTS: To better understand the involvement of WWOX in breast tumorigenesis, we performed a yeast two-hybrid screen and co-immunoprecipitation assays to identify novel partners of this protein. We characterized the vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) as a new regulator of WWOX. In breast cancer cells, VOPP1 sequestrates WWOX in lysosomes, impairs its ability to associate with p73α, and inhibits WWOX-dependent apoptosis. Overexpressed VOPP1 potentiates cellular transformation and enhances the growth of transplanted tumors in vivo. VOPP1 is overexpressed in breast tumors, especially in tumors that retain WWOX. Moreover, increased expression of VOPP1 is associated with reduced survival of patients with WWOX-positive, but not with WWOX-negative, tumors.
CONCLUSIONS: These findings emphasize the importance of the sequestration of WWOX by VOPP1 in addition to WWOX loss in breast tumors and define VOPP1 as a novel oncogene promoting breast carcinogenesis by inhibiting the anti-tumoral effect of WWOX.

PMID: 30285739 [PubMed - in process]

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease.

Front Pharmacol. 2018;9:1039

Authors: Li H, Zhang YJ, Li MP, Hu XL, Song PY, Peng LM, Ma QL, Tang J, Zhang W, Chen XP

Abstract
Dual antiplatelet treatment with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI). However, a portion of patients suffer from clopidogrel resistance (CR) and consequently with recurrence of cardiovascular events. Genetic factors such as loss-of-function variants of CYP2C19 contribute a lot to CR. Recently, the N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) rs2254638 polymorphism is reported to be associated with clopidogrel response. To validate the association between N6AMT1 rs2254638 polymorphism and clopidogrel response, 435 Chinese CAD patients receiving aspirin and clopidogrel were recruited. N6AMT1 rs2254638 and CYP2C19 * 2/ * 3 polymorphisms were genotyped. Platelet reaction index (PRI) was measured by VASP-phosphorylation assay after treated with a 300 mg loading dose (LD) clopidogrel or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days. There was a significant difference in PRI between LD cohort and MD cohort. Carriers of CYP2C19 * 2 allele showed significantly increased PRI in the entire cohort and in respective of the MD and LD cohorts (p < 0.001, p = 0.003, p < 0.001, respectively). However, carriers of CYP2C19 * 3 allele exhibited significantly higher PRI only in the entire cohort and LD cohort (p = 0.023, p = 0.023 respectively). PRI value was significantly higher in CYP2C19 PM genotyped patients as compared with those carrying the IM genotypes and EM genotype (p < 0.001). Besides, carriers of the rs2254638 C allele showed significantly higher PRI in entire cohort and in the LD cohort (p = 0.023, p = 0.008, respectively). When the patients were grouped into clopidogrel resistance (CR) and non-clopidogrel resistance (non-CR) groups, CYP2C19 * 2 was associated with increased risk of CR in the entire cohort, the LD cohort and the MD cohort (p < 0.001, p < 0.001, and p = 0.019, respectively). Carriers of the rs2254638 C allele also showed increased risk of CR in the entire cohort and the LD cohort (p = 0.024, and p = 0.028, respectively). N6AMT1 rs2254638 remained as a strong predictor for CR (TC vs. TT: OR = 1.880, 95% CI = 1.099-3.216,p = 0.021; CC vs. TT: OR = 1.930, 95% CI = 1.056-3.527, p = 0.032; TC + CC vs. TT: OR = 1.846, 95%CI = 1.126-3.026, p = 0.015) after adjustment for confounding factors. Our study confirmed the influence of CYP2C19 *2 and rs2254638 polymorphisms on clopidogrel resistance in Chinese CAD patients. Both CYP2C19 * 2 and N6AMT1 rs2254638 polymorphism may serve as independent biomarkers to predict CR.

PMID: 30283338 [PubMed]

Investigation of the HSPG2 Gene in Tardive Dyskinesia - New Data and Meta-Analysis.

Front Pharmacol. 2018;9:974

Authors: Zai CC, Lee FH, Tiwari AK, Lu JY, de Luca V, Maes MS, Herbert D, Shahmirian A, Cheema SY, Zai GC, Atukuri A, Sherman M, Shaikh SA, Tampakeras M, Freeman N, King N, Müller DJ, Greenbaum L, Lerer B, Voineskos AN, Potkin SG, Lieberman JA, Meltzer HY, Remington G, Kennedy JL

Abstract
Tardive dyskinesia (TD) is a movement disorder that may occur after extended use of antipsychotic medications. The etiopathophysiology is unclear; however, genetic factors play an important role. The Perlecan (HSPG2) gene was found to be significantly associated with TD in Japanese schizophrenia patients, and this association was subsequently replicated by an independent research group. To add to the evidence for this gene in TD, we conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with TD occurrence, while also adding our unpublished genotype data. Overall, we found a significant association of the G allele with TD occurrence (p = 0.0001); however, much of the effect appeared to originate from the discovery dataset. Nonetheless, most study samples exhibit the same trend of association with TD for the G allele. Our findings encourage further genetic and molecular studies of HSPG2 in TD.

PMID: 30283332 [PubMed]