Posttraumatic stress disorder symptom severity is associated with reduced default mode network connectivity in individuals with elevated genetic risk for psychopathology.

Depress Anxiety. 2017 May 11;:

Authors: Miller DR, Logue MW, Wolf EJ, Maniates H, Robinson ME, Hayes JP, Stone A, Schichman S, McGlinchey RE, Milberg WP, Miller MW

Abstract
BACKGROUND: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) is associated with disrupted default mode network (DMN) connectivity, but findings across studies have not been uniform. Individual differences in relevant genes may account for some of the reported variability in the relationship between DMN connectivity and PTSD. In this study, we investigated this possibility using genome-wide association study (GWAS) derived polygenic risk scores (PRSs) for relevant psychiatric traits. We hypothesized that the association between PTSD and DMN connectivity would be moderated by genetic risk for one or more psychiatric traits such that individuals with elevated polygenic risk for psychopathology and severe PTSD would exhibit disrupted DMN connectivity.
METHODS: Participants were 156 white, non-Hispanic veterans of the wars in Iraq and Afghanistan who were genotyped and underwent resting state functional magnetic resonance imaging and clinical assessment. PRSs for neuroticism, anxiety, major depressive disorder, and cross-disorder risk (based on five psychiatric disorders) were calculated using summary statistics from published large-scale consortia-based GWASs.
RESULTS: Cross-disorder polygenic risk influenced the relationship between DMN connectivity and PTSD symptom severity such that individuals at greater genetic risk showed a significant negative association between PTSD symptom severity and connectivity between the posterior cingulate cortex and right middle temporal gyrus. Polygenic risk for neuroticism, anxiety, and major depressive disorder did not influence DMN connectivity directly or through an interaction with PTSD.
CONCLUSIONS: Findings illustrate the potential power of genome-wide PRSs to advance understanding of the relationship between PTSD and DMN connectivity, a putative neural endophenotype of the disorder.

PMID: 28494120 [PubMed - as supplied by publisher]

P2Y6 receptors are involved in mediating the effect of inactivated avian influenza virus H5N1 on IL-6 & CXCL8 mRNA expression in respiratory epithelium.

PLoS One. 2017;12(5):e0176974

Authors: Huipao N, Borwornpinyo S, Wiboon-Ut S, Campbell CR, Lee IH, Hiranyachattada S, Sukasem C, Thitithanyanont A, Pholpramool C, Cook DI, Dinudom A

Abstract
One of the key pathophysiologies of H5N1 infection is excessive proinflammatory cytokine response (cytokine storm) characterized by increases in IFN-β, TNF-α, IL-6, CXCL10, CCL4, CCL2 and CCL5 in the respiratory tract. H5N1-induced cytokine release can occur via an infection-independent mechanism, however, detail of the cellular signaling involved is poorly understood. To elucidate this mechanism, the effect of inactivated (β-propiolactone-treated) H5N1 on the cytokine and chemokine mRNA expression in 16HBE14o- human respiratory epithelial cells was investigated. We found that the inactivated-H5N1 increased mRNA for IL-6 and CXCL8 but not TNF-α, CCL5 or CXCL10. This effect of the inactivated-H5N1 was inhibited by sialic acid receptor inhibitor (α-2,3 sialidase), adenosine diphosphatase (apyrase), P2Y receptor (P2YR) inhibitor (suramin), P2Y6R antagonist (MRS2578), phospholipase C inhibitor (U73122), protein kinase C inhibitors (BIM and Gö6976) and cell-permeant Ca2+ chelator (BAPTA-AM). Inhibitors of MAPK signaling, including of ERK1/2 (PD98059), p38 MAPK (SB203580) and JNK (SP600125) significantly suppressed the inactivated-H5N1-induced mRNA expression of CXCL8. On the other hand, the inactivated-H5N1-induced mRNA expression of IL-6 was inhibited by SB203580, but not PD98059 or SP600125, whereas SN-50, an inhibitor of NF-κB, inhibited the effect of virus on mRNA expression of both of IL-6 and CXCL8. Taken together, our data suggest that, without infection, inactivated-H5N1 induces mRNA expression of IL-6 and CXCL8 by a mechanism, or mechanisms, requiring interaction between viral hemagglutinin and α-2,3 sialic acid receptors at the cell membrane of host cells, and involves activation of P2Y6 purinergic receptors.

PMID: 28494003 [PubMed - in process]

Personalized Therapeutics and Pharmacogenomics: Integral to Personalized Health Care.

Pharm Res. 2017 May 10;:

Authors: Sadee W

PMID: 28493098 [PubMed - as supplied by publisher]

Cold-inducible RNA-binding protein through TLR4 signaling induces mitochondrial DNA fragmentation and regulates macrophage cell death after trauma.

Cell Death Dis. 2017 May 11;8(5):e2775

Authors: Li Z, Fan EK, Liu J, Scott MJ, Li Y, Li S, Xie W, Billiar TR, Wilson MA, Jiang Y, Wang P, Fan J

Abstract
Trauma is a major cause of systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Macrophages (Mφ) direct trauma-induced inflammation, and Mφ death critically influences the progression of the inflammatory response. In the current study, we explored an important role of trauma in inducing mitochondrial DNA (mtDNA) damage in Mφ and the subsequent regulation of Mφ death. Using an animal pseudo-fracture trauma model, we demonstrated that tissue damage induced NADPH oxidase activation and increased the release of reactive oxygen species via cold-inducible RNA-binding protein (CIRP)-TLR4-MyD88 signaling. This in turn, activates endonuclease G, which serves as an executor for the fragmentation of mtDNA in Mφ. We further showed that fragmented mtDNA triggered both p62-related autophagy and necroptosis in Mφ. However, autophagy activation also suppressed Mφ necroptosis and pro-inflammatory responses. This study demonstrates a previously unidentified intracellular regulation of Mφ homeostasis in response to trauma.

PMID: 28492546 [PubMed - in process]

Enteric-coated and highly standardized cranberry extract reduces antibiotic and nonsteroidal anti-inflammatory drug use for urinary tract infections during radiotherapy for prostate carcinoma.

Res Rep Urol. 2017;9:65-69

Authors: Bonetta A, Roviello G, Generali D, Zanotti L, Cappelletti MR, Pacifico C, Di Pierro F

Abstract
INTRODUCTION: Worldwide, bacterial resistance to antibiotic therapy is a major concern for the medical community. Antibiotic resistance mainly affects Gram-negative bacteria that are an important cause of lower urinary tract infections (LUTIs). Pelvic irradiation for prostate cancer is a risk factor for LUTIs. Cranberry extract is reported to reduce the incidence of LUTIs. The prophylactic role of an enteric-coated, highly standardized cranberry extract (VO370(®)) in reducing LUTI episodes, urinary discomfort, and nonsteroidal anti-inflammatory drug (NSAID) and antibiotic use during radiotherapy for prostate carcinoma was evaluated.
METHODS: A total of 924 patients with prostate carcinoma treated by radiotherapy to the prostatic and pelvic areas were randomized to receive (n=489) or not (n=435) the enteric-coated, highly standardized cranberry extract for 6-7 weeks concurrently with irradiation. Outcomes were analyzed by using Mann-Whitney U test and Pearson's χ(2) test. Primary endpoint was the number of patients with LUTI; secondary endpoints were incidence of recurrence, days of treatment with antibiotics and number of subjects treated with NSAIDs, and incidence of dysuria.
RESULTS: The treatment was very well tolerated, and there were no serious side effects. All enrolled patients completed the study. Urinary infections were detected in 53 of the 489 patients (10.8%) treated with enteric-coated, highly standardized cranberry extract, while 107 of the 435 patients (24.6%) in the control group developed LUTIs (p=0.0001). A clear and significant reduction in urinary discomfort of ~50% was seen in treated subjects. The treatment also resulted in ~50% reduction in the use of anti-inflammatory drugs and antibiotics.
CONCLUSION: The enteric-coated, highly standardized cranberry extract could be used as a prophylactic to reduce the incidence of LUTIs and decrease antibiotic therapy in patients receiving pelvic irradiation for prostate cancer.

PMID: 28491861 [PubMed - in process]

Therapeutic Risk and Benefits of Concomitantly Using Herbal Medicines and Conventional Medicines: From the Perspectives of Evidence Based on Randomized Controlled Trials and Clinical Risk Management.

Evid Based Complement Alternat Med. 2017;2017:9296404

Authors: Zhang XL, Chen M, Zhu LL, Zhou Q

Abstract
Despite increased awareness of the potential of herb-drug interactions (HDIs), the lack of rigorous clinical evidence regarding the significance provides a challenge for clinicians and consumers to make rational decisions about the safe combination of herbal and conventional medicines. This review addressed HDIs based on evidence from randomized controlled trials (RCTs). Literature was identified by performing a PubMed search till January 2017. Risk description and clinical risk management were described. Among 74 finally included RCTs, 17 RCTs (22.97%) simply addressed pharmacodynamic HDIs. Fifty-seven RCTs (77.03%) investigated pharmacokinetic HDIs and twenty-eight of them showed potential or actual clinical relevance. The extent of an HDI may be associated with the factors such as pharmacogenomics, dose of active ingredients in herbs, time course of interaction, characteristics of the object drugs (e.g., administration routes and pharmacokinetic profiles), modification of herbal prescription compositions, and coexistence of inducers and inhibitors. Clinical professionals should enhance risk management on HDIs such as increasing awareness of potential changes in therapeutic risk and benefits, inquiring patients about all currently used conventional medicines and herbal medicines and supplements, automatically detecting highly substantial significant HDI by computerized reminder system, selecting the alternatives, adjusting dose, reviewing the appropriateness of physician orders, educating patients to monitor for drug-interaction symptoms, and paying attention to follow-up visit and consultation.

PMID: 28491115 [PubMed - in process]

Pharmacokinetics, Pharmacodynamics and Pharmacogenetics associated with Nonsteroidal Anti-Inflammatory Drugs and Opioids in Pediatric Cancer Patients.

Expert Opin Drug Metab Toxicol. 2017 May 11;:

Authors: Constance J, Campbell S, Somani AA, Yellepeddi V, Owens K, Sherwin C

Abstract
INTRODUCTION: Advancing appropriate and adequate analgesic pharmacotherapy in pediatric patients with cancer is an area of clinical need. Few studies have been performed to evaluate the selection of an analgesic and appropriate dosing corresponding to analgesic effect among pediatric cancer patients. This review describes information related to pharmacokinetic, pharmacodynamic, and pharmacogenomic (when applicable) considerations for analgesics that are commonly used to manage pain experienced by pediatric patients with cancer. Areas covered: Analgesics commonly used to treat pediatric patients with malignancy patterned after the World Health Organization's "analgesic ladder" for cancer pain management. Expert opinion: Addressing pain management safely and effectively in pediatric patients with cancer will require advances in both drug development, to increase the armament of analgesics available for children, and our pharmacologic understanding of those analgesics in current use. However, performing the necessary types of studies to develop new analgesics, or gain knowledge of existing therapy, within a population that is relatively small, diverse, and who experience pain originating from a variety of sources, is a tremendous challenge.

PMID: 28490206 [PubMed - as supplied by publisher]

Pharmacogenomics of Angiotensin-Receptor/Neprilysin Inhibitor and its Long-Term Side Effects.

Cardiovasc Ther. 2017 May 10;:

Authors: Krittanawong C, Kitai T

Abstract
The development of the promising agent sacubitril/valsartan, known as an angiotensin receptor blocker-neprilysin inhibitor (ARNI), to improve heart failure (HF) management, may benefit morbidity, mortality, and readmission rates in patients with HF. The PARADIGM-HF trial demonstrated that the ARNI can reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), while ongoing PARAMOUNT and PARAGON-HF trials determined whether the ARNI has morbidity and mortality benefits in patients with heart failure with preserved ejection fraction (HFpEF). However, the risk of long-term side effects of the ARNI such as cognitive dysfunction or Alzheimer's disease (AD) remains unknown. In fact, neprilysin (NEP), encoded by NEP or MME gene, is a principal peptidase involved in the degradation of β-amyloid (Aβ) protein. Several studies have demonstrated that polymorphisms of the NEP gene may be associated with AD and cerebral amyloid angiopathy (CAA). Pharmacogenomics, the study of variability in drug response due to genetic polymorphisms, can potentially explain the variability in the effect of the ARNI and their side effects. Therefore, we have attempted to highlight pharmacogenomic factors and potential long-term side effects of the ARNI. Physicians should carefully monitor elderly patients with genetic risk factors for AD and CAA. In the future, genetic and genomic testing for NEP polymorphisms may play an important role in monitoring long-term side effects in ARNI-treated HF patients. This article is protected by copyright. All rights reserved.

PMID: 28489317 [PubMed - as supplied by publisher]

Two Single Nucleotide Polymorphisms (rs2431697 and rs2910164) of miR-146a Are Associated with Risk of Coronary Artery Disease.

Int J Environ Res Public Health. 2017 May 10;14(5):

Authors: Wang Y, Wang X, Li Z, Chen L, Zhou L, Li C, Ouyang DS

Abstract
The coronary artery disease (CAD) is one of the most severe cardiovascular diseases. MicroRNA-146a (miR-146a) influences the pathology of cardiovascular diseases. Two single nucleotide polymorphisms (SNPs) of miR-146a (rs2431697 and rs2910164) have been reported to alter the function or expression of microRNA. The purpose of this study is to evaluate the association between miR-146a gene polymorphism and the risk of CAD in the Chinese population. A total of 353 CAD patients and 368 controls were recruited, and SNPs were analyzed by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Sequenom MassARRAY system. The gene frequencies of rs2431697 and rs2910164 were significantly different between the two groups. The mutant type (T allele) of rs2431697 and wild type (C allele) of rs2910164 were more frequent in CAD patients. T allele carriers in rs2431697 had an increased CAD risk, while G allele of rs2910164 decreased the risk of CAD significantly. In conclusion, we found that the T allele of rs2431697 was a risk factor of CAD in the Chinese population. Meanwhile, we demonstrated that the G allele of rs2910164 decreased the susceptibility of CAD.

PMID: 28489066 [PubMed - in process]

Associating transcriptional modules with colon cancer survival through weighted gene co-expression network analysis.

BMC Genomics. 2017 May 09;18(1):361

Authors: Liu R, Zhang W, Liu ZQ, Zhou HH

Abstract
BACKGROUND: Colon cancer (CC) is a heterogeneous disease influenced by complex gene networks. As such, the relationship between networks and CC should be elucidated to obtain further insights into tumour biology.
RESULTS: Weighted gene co-expression network analysis, a powerful technique used to extract co-expressed gene networks from mRNA expressions, was conducted to identify 11 co-regulated modules in a discovery dataset with 461 patients. A transcriptional module enriched in cell cycle processes was correlated with the recurrence-free survival of the CC patients in the discovery (HR = 0.59; 95% CI = 0.42-0.81) and validation (HR = 0.51; 95% CI = 0.25-1.05) datasets. The prognostic potential of the hub gene Centromere Protein-A (CENPA) was also identified and the upregulation of this gene was associated with good survival. Another cell cycle phase-related gene module was correlated with the survival of the patients with a KRAS mutation CC subtype. The downregulation of several genes, including those found in this co-expression module, such as cyclin-dependent kinase 1 (CDK1), was associated with poor survival.
CONCLUSION: Network-based approaches may facilitate the discovery of biomarkers for the prognosis of a subset of patients with stage II or III CC, these approaches may also help direct personalised therapies.

PMID: 28486948 [PubMed - in process]

TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke.

Stroke. 2016 May;47(5):1180-6

Authors: Gallego-Fabrega C, Carrera C, Reny JL, Fontana P, Slowik A, Pera J, Pezzini A, Serrano-Heras G, Segura T, Martí-Fàbregas J, Muiño E, Cullell N, Montaner J, Krupinski J, Fernandez-Cadenas I

Abstract
BACKGROUND AND PURPOSE: Clopidogrel is one of the most used antiplatelet drugs in patients with cardiovascular disease. However, 16% to 50% of patients have a high on-clopidogrel platelet reactivity and an increased risk of ischemic events. The pathogenesis of high on-treatment platelet reactivity in patients with stroke is only partially explained by genetic variations. This study aims to find differentially methylated sites across the genome associated with vascular recurrence in ischemic stroke patients treated with clopidogrel.
METHODS: From a cohort of 1900 patients with ischemic stroke, we selected 42 patients treated with clopidogrel, including 21 with a recurrent vascular event and 21 without vascular recurrence during the first year of follow-up. Over 480 000 DNA methylation sites were analyzed across the genome. Differentially methylated CpG sites were identified by nonparametric testing using R. Replication analysis was performed in a new cohort of 191 subjects and results were correlated with platelet reactivity in a subset of 90 subjects using light transmission aggregometry.
RESULTS: A total of 73 differentially methylated CpG sites (P<1×10(-05)) were identified; 3 of them were selected for further replication: cg03548645 (P=1.42×10(-05), TRAF3), cg09533145 (P=7.81×10(-06), ADAMTS2), and cg15107336 (P=1.89×10(-05), XRCC1). The cg03548645 CpG remained significant in the replication study (P=0.034), a deep analysis of this region revealed another methylation site associated with vascular recurrence, P=0.037. Lower cg03548645 (TRAF3) DNA methylation levels were correlated with an increased platelet aggregation (ρ=-0.29, P=0.0075).
CONCLUSIONS: This study suggests for the first time that epigenetics may significantly contribute to the variability of clopidogrel response and recurrence of ischemic events in patients with stroke.

PMID: 27026631 [PubMed - indexed for MEDLINE]

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/05/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

HAART in HIV/AIDS Treatments, Future Trends.

Infect Disord Drug Targets. 2017 May 05;:

Authors: Lu DY, Yarla NS, Xu B, Ding J, Lu TR, Wu HY

Abstract
AIDS (acquired immune deficient syndrome) is a deadly human viral infectious disease caused by HIV (human immune-deficient virus) infection. Almost every AIDS patient losses his/her life before mid 1990s. AIDS was once the 1st disease killer in US (1993). After one decade hard work, antiviral drug cocktails-high active anti-retroviral therapy (HAART) have been invented for almost all HIV infection treatments. Due to the invention of HAART, 80-90% HIV/AIDS patients still effectively response to HAART for deadly AIDS episode controls and life saving. Yet, this type of HIV therapeutics is incurable. HIV/AIDS patients need to take HAART medications regularly and even life-long. To counteract this therapeutic drawback, more revolutionary efforts (different angles of therapeutic modes/attempts) are urgently needed. In this article, the major progresses and drawbacks of HIV/AIDS chemotherapy (HAART) to HIV/AIDS patients have been discussed. Future trends (updating pathogenesis study, next generations of drug developments, new drug target discovery, different scientific disciplinary and so on) are highlighted.

PMID: 28474549 [PubMed - as supplied by publisher]

[Genetics of bipolar disorder].

Nervenarzt. 2017 May 04;:

Authors: Budde M, Forstner AJ, Adorjan K, Schaupp SK, Nöthen MM, Schulze TG

Abstract
Bipolar disorder (BD) has a multifactorial etiology. Its development is influenced by genetic as well as environmental factors. Large genome-wide association studies (GWAS), in which genetic risk allelic variants for the disorder could be replicated for the first time, marked the breakthrough in the identification of the responsible risk genes. In addition to these common genetic variants with moderate effects identified by GWAS, rare variants with a higher penetrance are expected to play a role in disease development. The results of recent studies suggest that copy number variants might contribute to BD development, although to a lesser extent than in other psychiatric disorders, such as schizophrenia or autism. Results from the initial next generation sequencing studies indicate an enrichment of rare variants in pathways and genes that were previously found to be associated with BD. In the field of pharmacogenetics, a risk gene that influences the individual variance in the response to lithium treatment was identified for the first time in a recent large international GWAS. Currently the reported risk alleles do not sufficiently explain the phenotypic variance to be used for individual prediction of disease risk, disease course or response to medication. Future genetic research will provide important insights into the biological basis of BD by the identification of additional genes associated with BD. This knowledge of genetics will help identify potential etiological subgroups as well as cross-diagnostic disease mechanisms.

PMID: 28474173 [PubMed - as supplied by publisher]

Involvement of P2 receptors in regulation of glomerular permeability to albumin by extracellular nucleotides of intra-/extra-glomerular origins.

J Physiol Pharmacol. 2016 Apr;67(2):177-83

Authors: Kasztan M, Jankowski M

Abstract
Plasma filtration through glomerular filtration barrier (GFB) is a key process to maintain fluid and electrolyte homeostasis. GFB consisting of endothelial cells, podocytes and basement membrane restricts passage of albumin but is permeable for smaller plasma molecules. Various biological agents, such as extracellular nucleotides influence activity of cells, which in turn affects permeability of GFB. Nucleotides are released from cells outside and within the glomeruli that activate the purinoceptors - P2Rs classified into ATP-gated non-selective ion channels, P2X receptors (P2XRs), and G-protein-coupled metabotropic P2Y receptors (P2YRs). P2Rs are expressed on cellular components of GFB. P2Rs activation triggers intracellular calcium concentration and calcium-dependent metabolism with subsequent affect on glomerular permeability to albumin. Purinergic-dependent glomerular cell activation also affects the biophysical properties of acelluar glomerular basement membrane (GMB). Finally, P2Rs stimulation may lead to increased proteins excretion in urine. The involvement of P2Rs in increased GFB permeability to albumin may be expected under pathophysiological conditions characterized by increased albumin excretion in urine.

PMID: 27226177 [PubMed - indexed for MEDLINE]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2017/05/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Preemptive Panel-Based Pharmacogenetic Testing: The Time is Now.

Pharm Res. 2017 May 02;:

Authors: Weitzel KW, Cavallari LH, Lesko LJ

Abstract
While recent discoveries have paved the way for the use of genotype-guided prescribing in some clinical environments, significant debate persists among clinicians and researchers about the optimal approach to pharmacogenetic testing in clinical practice. One crucial factor in this debate surrounds the timing and methodology of genotyping, specifically whether genotyping should be performed reactively for targeted genes when a single drug is prescribed, or preemptively using a panel-based approach prior to drug prescribing. While early clinical models that employed a preemptive approach were largely developed in academic health centers through multidisciplinary efforts, increasing examples of pharmacogenetic testing are emerging in community-based and primary care practice environments. However, educational and practice-based resources for these clinicians remain largely nonexistent. As such, there is a need for the health care system to shift its focus from debating about preemptive genotyping to developing and disseminating needed resources to equip frontline clinicians for clinical implementation of pharmacogenetics. Providing tools and guidance to support these emerging models of care will be essential to support the thoughtful, evidence-based use of pharmacogenetic information in diverse clinical practice environments. Specifically, the creation of efficient and accurate point-of-care resources, practice-based tools, and clinical models is needed, along with identification and dissemination of sustainable avenues for pharmacogenetic test reimbursement.

PMID: 28466392 [PubMed - as supplied by publisher]

Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease.

Respir Res. 2017 May 02;18(1):77

Authors: Weidner J, Jarenbäck L, de Jong K, Vonk JM, van den Berge M, Brandsma CA, Boezen HM, Sin D, Bossé Y, Nickle D, Ankerst J, Bjermer L, Postma DS, Faiz A, Tufvesson E

Abstract
BACKGROUND: It has been observed that mice lacking the sulfatase modifying factor (Sumf1) developed an emphysema-like phenotype. However, it is unknown if SUMF1 may play a role in Chronic Obstructive Pulmonary Disease (COPD) in humans. The aim was to investigate if the expression and genetic regulation of SUMF1 differs between smokers with and without COPD.
METHODS: SUMF1 mRNA was investigated in sputum cells and whole blood from controls and COPD patients (all current or former smokers). Expression quantitative trait loci (eQTL) analysis was used to investigate if single nucleotide polymorphisms (SNPs) in SUMF1 were significantly associated with SUMF1 expression. The association of SUMF1 SNPs with COPD was examined in a population based cohort, Lifelines. SUMF1 mRNA from sputum cells, lung tissue, and lung fibroblasts, as well as lung function parameters, were investigated in relation to genotype.
RESULTS: Certain splice variants of SUMF1 showed a relatively high expression in lung tissue compared to many other tissues. SUMF1 Splice variant 2 and 3 showed lower levels in sputum cells from COPD patients as compared to controls. Twelve SNPs were found significant by eQTL analysis and overlapped with the array used for genotyping of Lifelines. We found alterations in mRNA expression in sputum cells and lung fibroblasts associated with SNP rs11915920 (top hit in eQTL), which validated the results of the lung tissue eQTL analysis. Of the twelve SNPs, two SNPs, rs793391 and rs308739, were found to be associated with COPD in Lifelines. The SNP rs793391 was also confirmed to be associated with lung function changes.
CONCLUSIONS: We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD.

PMID: 28464818 [PubMed - in process]

Functional characterization of the neuron-restrictive silencer element in the human tryptophan hydroxylase 2 gene expression.

J Neurochem. 2017 May 02;:

Authors: Nawa Y, Kaneko H, Oda M, Tsubonoya M, Hiroi T, Gentile MT, Colucci-D'Amato L, Takahashi R, Matsui H

Abstract
Tryptophan hydroxylase 2 (TPH2) is the key enzyme in the synthesis of neuronal serotonin. Although previous studies suggest that TPH2 NRSE (neuron-restrictive silencer element) functions as a negative regulator dependent on NRSF (neuron-restrictive silencer factor) activity, the underlying mechanisms are yet to be fully elucidated. Here, we show a detailed analysis of the NRSE-mediated repression of the human TPH2 (hTPH2) promoter activity in RN46A cells, a cell line derived from rat raphe neurons. Quantitative real-time RT-PCR analysis revealed the expression of serotonergic marker genes (Mash1, Nkx2.2, Gata2, Gata3, Lmx1b, Pet-1, 5-Htt, and Vmat2) and Nrsf gene in RN46A cells. Tph1 mRNA is the prevalent form expressed in RN46A cells; Tph2 mRNA is also expressed but at a lower level. Electrophoretic mobility shift assays and reporter assays showed that hTPH2 NRSE is necessary for the efficient DNA binding of NRSF and for the NRSF-dependent repression of the hTPH2 promoter activity. The hTPH2 promoter activity was increased by knockdown of NRSF, or overexpression of the engineered NRSF (a dominant-negative mutant or a DNA-binding domain and activation domain fusion protein). MS-275, a class I histone deacetylase (HDAC) inhibitor, was found to be more potent than MC-1568, a class II HDAC inhibitor, in enhancing the hTPH2 promoter activity. Furthermore, treatment with the ubiquitin-specific protease 7 (USP7) deubiquitinase inhibitors, P-22077 or HBX 41108, increased the hTPH2 promoter activity. Collectively, our data demonstrate that the hTPH2 NRSE-mediated promoter repression via NRSF involves class I HDACs and is modulated by the USP7-mediated deubiquitination and stabilization of NRSF. This article is protected by copyright. All rights reserved.

PMID: 28464229 [PubMed - as supplied by publisher]

Evaluating the association of single-nucleotide polymorphisms with tenofovir exposure in a diverse prospective cohort of women living with HIV.

Pharmacogenomics J. 2017 May 02;:

Authors: Baxi SM, Greenblatt RM, Bacchetti P, Cohen M, DeHovitz JA, Anastos K, Gange SJ, Young MA, Aouizerat BE

Abstract
Higher exposure to tenofovir (TFV) increases the risk for kidney function decline, but the impact of genetic factors on TFV exposure is largely unknown. We investigated whether single-nucleotide polymorphisms (SNPs, n=211) in 12 genes are potentially involved in TFV exposure. Participants (n=91) from the Women's Interagency HIV Study, underwent a 24 h intensive pharmacokinetic sampling of TFV after witnessed dose and TFV area under the time-concentration curves (AUCs) were calculated for each participant. SNPs were assayed using a combination of array genotyping and Sanger sequencing. Linear regression models were applied to logarithmically transformed AUC. Those SNPs that met an a priori threshold of P<0.001 were considered statistically associated with TFV AUC. ABCG2 SNP rs2231142 was associated with TFV AUC with rare allele carriers displaying 1.51-fold increase in TFV AUC (95% confidence interval: 1.26, 1.81; P=1.7 × 10(-5)). We present evidence of a moderately strong effect of the rs2231142 SNP in ABCG2 on a 24 h TFV AUC.The Pharmacogenomics Journal advance online publication, 2 May 2017; doi:10.1038/tpj.2017.3.

PMID: 28462920 [PubMed - as supplied by publisher]