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A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.
Mosley JD, Shaffer CM, Van Driest SL, Weeke PE, Wells QS, Karnes JH, Velez Edwards DR, Wei WQ, Teixeira PL, Bastarache L, Crawford DC, Li R, Manolio TA, Bottinger EP, McCarty CA, Linneman JG, Brilliant MH, Pacheco JA, Thompson W, Chisholm RL, Jarvik GP, Crosslin DR, Carrell DS, Baldwin E, Ralston J, Larson EB, Grafton J, Scrol A, Jouni H, Kullo IJ, Tromp G, Borthwick KM, Kuivaniemi H, Carey DJ, Ritchie MD, Bradford Y, Verma SS, Chute CG, Veluchamy A, Siddiqui MK, Palmer CN, Doney A, MahmoudPour SH, Maitland-van der Zee AH, Morris AD, Denny JC, Roden DM
(2016) Pharmacogenomics J 16: 231-7
MeSH Terms: Angiotensin-Converting Enzyme Inhibitors, Case-Control Studies, Computational Biology, Cough, Databases, Genetic, Electronic Health Records, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kv Channel-Interacting Proteins, Logistic Models, Male, Multivariate Analysis, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Scotland, United States
Show Abstract · Added February 22, 2016
The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.
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5 Members
0 Resources
22 MeSH Terms
Proteomic analyses of native brain K(V)4.2 channel complexes.
Marionneau C, LeDuc RD, Rohrs HW, Link AJ, Townsend RR, Nerbonne JM
(2009) Channels (Austin) 3: 284-94
MeSH Terms: Animals, Brain Chemistry, Chromatography, Liquid, Kv Channel-Interacting Proteins, Mice, Mice, Mutant Strains, Proteomics, Shal Potassium Channels, Tandem Mass Spectrometry
Show Abstract · Added February 20, 2015
Somatodendritic A-type (I(A)) voltage-gated K(+) (K(V)) channels are key regulators of neuronal excitability, functioning to control action potential waveforms, repetitive firing and the responses to synaptic inputs. Rapidly activating and inactivating somatodendritic I(A) channels are encoded by K(V)4 alpha subunits and accumulating evidence suggests that these channels function as components of macromolecular protein complexes. Mass spectrometry (MS)-based proteomic approaches were developed and exploited here to identify potential components and regulators of native brain K(V)4.2-encoded I(A) channel complexes. Using anti-K(V)4.2 specific antibodies, K(V)4.2 channel complexes were immunoprecipitated from adult wild type mouse brain. Parallel control experiments were performed on brain samples isolated from (K(V)4.2(-/-)) mice harboring a targeted disruption of the KCND2 (K(V)4.2) locus. Three proteomic strategies were employed: an in-gel approach, coupled to one-dimensional liquid chromatography-tandem MS (1D-LC-MS/MS), and two in-solution approaches, followed by 1D- or 2D-LC-MS/MS. The targeted in-gel 1D-LC-MS/MS analyses demonstrated the presence of the K(V)4 alpha subunits (K(V)4.2, K(V)4.3 and K(V)4.1) and the K(V)4 accessory, KChIP (KChIP1-4) and DPP (DPP6 and 10), proteins in native brain K(V)4.2 channel complexes. The more comprehensive, in-solution approach, coupled to 2D-LC-MS/MS, also called Multidimensional Protein Identification Technology (MudPIT), revealed that additional regulatory proteins, including the K(V) channel accessory subunit K(V)beta1, are also components of native brain K(V)4.2 channel complexes. Additional biochemical and functional approaches will be required to elucidate the physiological roles of these newly identified K(V)4 interacting proteins.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Downstream regulatory element antagonistic modulator regulates islet prodynorphin expression.
Jacobson DA, Cho J, Landa LR, Tamarina NA, Roe MW, Buxbaum JD, Philipson LH
(2006) Am J Physiol Endocrinol Metab 291: E587-95
MeSH Terms: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer, Animals, Calcium, Cell Line, Cell Nucleus, DNA, Dynorphins, Electrophoretic Mobility Shift Assay, Enkephalins, Gene Expression Regulation, Glucagon, Glucagon-Secreting Cells, Glucose, Humans, Insulin-Secreting Cells, Islets of Langerhans, Kv Channel-Interacting Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Naltrexone, Protein Binding, Protein Precursors, Receptors, Opioid, kappa, Repressor Proteins
Show Abstract · Added February 12, 2015
Calcium-binding proteins regulate transcription and secretion of pancreatic islet hormones. Here, we demonstrate neuroendocrine expression of the calcium-binding downstream regulatory element antagonistic modulator (DREAM) and its role in glucose-dependent regulation of prodynorphin (PDN) expression. DREAM is distributed throughout beta- and alpha-cells in both the nucleus and cytoplasm. As DREAM regulates neuronal dynorphin expression, we determined whether this pathway is affected in DREAM(-/-) islets. Under low glucose conditions, with intracellular calcium concentrations of <100 nM, DREAM(-/-) islets had an 80% increase in PDN message compared with controls. Accordingly, DREAM interacts with the PDN promoter downstream regulatory element (DRE) under low calcium (<100 nM) conditions, inhibiting PDN transcription in beta-cells. Furthermore, beta-cells treated with high glucose (20 mM) show increased cytoplasmic calcium (approximately 200 nM), which eliminates DREAM's interaction with the DRE, causing increased PDN promoter activity. As PDN is cleaved into dynorphin peptides, which stimulate kappa-opioid receptors expressed predominantly in alpha-cells of the islet, we determined the role of dynorphin A-(1-17) in glucagon secretion from the alpha-cell. Stimulation with dynorphin A-(1-17) caused alpha-cell calcium fluctuations and a significant increase in glucagon release. DREAM(-/-) islets also show elevated glucagon secretion in low glucose compared with controls. These results demonstrate that PDN transcription is regulated by DREAM in a calcium-dependent manner and suggest a role for dynorphin regulation of alpha-cell glucagon secretion. The data provide a molecular basis for opiate stimulation of glucagon secretion first observed over 25 years ago.
0 Communities
1 Members
0 Resources
25 MeSH Terms