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741. Activated IL-1RI Signaling Pathway Induces Th17 Cell Differentiation via Interferon Regulatory Factor 4 Signaling in Patients with Relapsing-Remitting Multiple Sclerosis

Title Tesim:
Activated IL-1RI Signaling Pathway Induces Th17 Cell Differentiation via Interferon Regulatory Factor 4 Signaling in Patients with Relapsing-Remitting Multiple Sclerosis
Creator:
Sha, Yonggang and Markovic-Plese, Silva
Date of publication:
2016
Abstract Tesim:
IL-1β plays a crucial role in the differentiation of human Th17 cells. We report here that IL-1RI expression is significantly increased in both naive and memory CD4+ T cells derived from relapsing-remitting multiple sclerosis (RR MS) patients in comparison to healthy controls. Interleukin 1 receptor (IL-1R)I expression is upregulated in the in vitro-differentiated Th17 cells from RR MS patients in comparison to the Th1 and Th2 cell subsets, indicating the role of IL-1R signaling in the Th17 cell differentiation in RR MS. When IL-1RI gene expression was silenced using siRNA, human naive CD4+ T cells cultured in the presence of Th17-polarizing cytokines had a significantly decreased expression of interleukin regulatory factor 4 (IRF4), RORc, IL-17A, IL-17F, IL-21, IL-22, and IL-23R genes, confirming that IL-1RI signaling induces Th17 cell differentiation. Since IL-1R gene expression silencing inhibited IRF4 expression and Th17 differentiation, and IRF4 gene expression silencing inhibited Th17 cell differentiation, our results indicate that IL-1RI induces human Th17 cell differentiation in an IRF4-dependant manner. Our study has identified that IL-1RI-mediated signaling pathway is constitutively activated, leading to an increased Th17 cell differentiation in IRF4-dependent manner in patients with RR MS.
Resource type:
Article
Affiliation Label Tesim:
Department of Neurology
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/mx8d-4q91
Identifier:
Onescience id: a221c391049a369b51a9179fe8f0f1e06aba59e1, PMID: 27965670, Publisher DOI: https://doi.org/10.3389/fimmu.2016.00543, and PMCID: PMC5126112
ISSN:
1664-3224
Journal Title:
Frontiers in Immunology
Journal Volume:
7
Keyword:
Cytokines, Interferon Regulatory Factors, IRF4, Th2 Cells, IL1B, IL17A, Multiple Sclerosis, Relapsing-Remitting, Th17 Cells, Cells, Cultured, Interleukin-17, Homo sapiens, RORC, Genes, IL23R, T-Lymphocytes, Interleukins, CD4, IL22, Gene Expression, IL17F, In Vitro Techniques, Receptors, Interleukin-1, and Cell Differentiation
Language Label:
English
ORCID:
Other Affiliation:
Department of Microbiology and Immunology
Person:
Sha, Yonggang and Markovic-Plese, Silva
Rights Statement Label:
In Copyright
Source:
v692tc75z

742. Neuroimaging of Human Balance Control: A Systematic Review

Title Tesim:
Neuroimaging of Human Balance Control: A Systematic Review
Creator:
Franz, Jason R., Thompson, Jessica, Nam, Chang S., and Wittenberg, Ellen
Date of publication:
2017
Abstract Tesim:
This review examined 83 articles using neuroimaging modalities to investigate the neural correlates underlying static and dynamic human balance control, with aims to support future mobile neuroimaging research in the balance control domain. Furthermore, this review analyzed the mobility of the neuroimaging hardware and research paradigms as well as the analytical methodology to identify and remove movement artifact in the acquired brain signal. We found that the majority of static balance control tasks utilized mechanical perturbations to invoke feet-in-place responses (27 out of 38 studies), while cognitive dual-task conditions were commonly used to challenge balance in dynamic balance control tasks (20 out of 32 studies). While frequency analysis and event related potential characteristics supported enhanced brain activation during static balance control, that in dynamic balance control studies was supported by spatial and frequency analysis. Twenty-three of the 50 studies utilizing EEG utilized independent component analysis to remove movement artifacts from the acquired brain signals. Lastly, only eight studies used truly mobile neuroimaging hardware systems. This review provides evidence to support an increase in brain activation in balance control tasks, regardless of mechanical, cognitive, or sensory challenges. Furthermore, the current body of literature demonstrates the use of advanced signal processing methodologies to analyze brain activity during movement. However, the static nature of neuroimaging hardware and conventional balance control paradigms prevent full mobility and limit our knowledge of neural mechanisms underlying balance control.
Resource type:
Article
Affiliation Label Tesim:
Joint Department of Biomedical Engineering
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/r6yy-bw22
Identifier:
PMCID: PMC5385364, Publisher DOI: https://doi.org/10.3389/fnhum.2017.00170, PMID: 28443007, and Onescience id: 17becdd9904abed8e588988daf4005bee6fe08fd
ISSN:
1662-5161
Journal Title:
Frontiers in Human Neuroscience
Journal Volume:
11
Keyword:
susceptibility to cognitive dual tasks, mechanical perturbation, static and dynamic balance control, temporal and spatial dynamics of brain activation, movement artifacts, and sensory degradation
Language Label:
English
ORCID:
Other Affiliation:
Edward P. Fitts Department of Industrial and Systems Engineering; North Carolina State University
Person:
Franz, Jason R., Thompson, Jessica, Nam, Chang S., and Wittenberg, Ellen
Rights Statement Label:
In Copyright
Source:
m039k969w

743. Multi-Modal Integration of EEG-fNIRS for Brain-Computer Interfaces – Current Limitations and Future Directions

Title Tesim:
Multi-Modal Integration of EEG-fNIRS for Brain-Computer Interfaces – Current Limitations and Future Directions
Creator:
Jun, Sung C. and Ahn, Sangtae
Date of publication:
2017
Abstract Tesim:
Multi-modal integration, which combines multiple neurophysiological signals, is gaining more attention for its potential to supplement single modality’s drawbacks and yield reliable results by extracting complementary features. In particular, integration of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) is cost-effective and portable, and therefore is a fascinating approach to brain-computer interface (BCI). However, outcomes from the integration of these two modalities have yielded only modest improvement in BCI performance because of the lack of approaches to integrate the two different features. In addition, mismatch of recording locations may hinder further improvement. In this literature review, we surveyed studies of the integration of EEG/fNIRS in BCI thoroughly and discussed its current limitations. We also suggested future directions for efficient and successful multi-modal integration of EEG/fNIRS in BCI systems.
Resource type:
Article
Affiliation Label Tesim:
Department of Psychiatry
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/69s2-ds63
Identifier:
Onescience id: b88b4cd7c26d0663859b757ee429dadd7de5a2e5, PMCID: PMC5651279, PMID: 29093673, and Publisher DOI: https://doi.org/10.3389/fnhum.2017.00503
ISSN:
1662-5161
Journal Title:
Frontiers in Human Neuroscience
Journal Volume:
11
Keyword:
multi-modal integration, Feature integration, functional near-infrared spectroscopy (fNIRS), combination of EEG-fNIRS, brain-computer interface (BCI), electroencephalography (EEG), and Simultaneous EEG-fNIRS
Language Label:
English
ORCID:
Other Affiliation:
School of Electrical Engineering and Computer Science; Gwangju Institute of Science and Technology
Person:
Jun, Sung C. and Ahn, Sangtae
Rights Statement Label:
In Copyright
Source:
pg15bk68b

744. Motor Unit Activity during Fatiguing Isometric Muscle Contraction in Hemispheric Stroke Survivors

Title Tesim:
Motor Unit Activity during Fatiguing Isometric Muscle Contraction in Hemispheric Stroke Survivors
Creator:
McManus, Lara, Suresh, Nina L., Lowery, Madeleine M., Rymer, William Z., and Hu, Xiaogang
Date of publication:
2017
Abstract Tesim:
Enhanced muscle weakness is commonly experienced following stroke and may be accompanied by increased susceptibility to fatigue. To examine the contributions of central and peripheral factors to isometric muscle fatigue in stroke survivors, this study investigates changes in motor unit (MU) mean firing rate, and action potential duration during, and directly following, a sustained submaximal fatiguing contraction at 30% maximum voluntary contraction (MVC). A series of short contractions of the first dorsal interosseous muscle were performed pre- and post-fatigue at 20% MVC, and again following a 10-min recovery period, by 12 chronic stroke survivors. Individual MU firing times were extracted using surface EMG decomposition and used to obtain the spike-triggered average MU action potential waveforms. During the sustained fatiguing contraction, the mean rate of change in firing rate across all detected MUs was greater on the affected side (-0.02 ± 0.03 Hz/s) than on the less-affected side (-0.004 ± 0.003 Hz/s, p = 0.045). The change in firing rate immediately post-fatigue was also greater on the affected side than less-affected side (-13.5 ± 20 and 0.1 ± 19%, p = 0.04). Mean MU firing rates increased following the recovery period on the less-affected side when compared to the affected side (19.3 ± 17 and 0.5 ± 20%, respectively, p = 0.03). MU action potential duration increased post-fatigue on both sides (10.3 ± 1.2 to 11.2 ± 1.3 ms on the affected side and 9.9 ± 1.7 to 11.2 ± 1.9 ms on the less-affected side, p = 0.001 and p = 0.02, respectively), and changes in action potential duration tended to be smaller in subjects with greater impairment (p = 0.04). This study presents evidence of both central and peripheral fatigue at the MU level during isometric fatiguing contraction for the first time in stroke survivors. Together, these preliminary observations indicate that the response to an isometric fatiguing contraction differs between the affected and less-affected side post-stroke, and may suggest that central mechanisms observed here as changes in firing rate are the dominant processes leading to task failure on the affected side.
Resource type:
Article
Affiliation Label Tesim:
Joint Department of Biomedical Engineering
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/pvhj-p775
Identifier:
PMID: 29225574, Onescience id: a527ab372813f245c9c318a01da23f1a878b67ab, Publisher DOI: https://doi.org/10.3389/fnhum.2017.00569, and PMCID: PMC5705653
ISSN:
1662-5161
Journal Title:
Frontiers in Human Neuroscience
Journal Volume:
11
Keyword:
stroke, Isometric fatigue, motor unit action potential, motor unit firing rate, Stroke, motor unit, Motor Unit Action Potential, surface EMG decomposition, and isometric fatigue
Language Label:
English
ORCID:
Other Affiliation:
Neuromuscular Systems Lab; School of Electrical and Electronic Engineering; University College Dublin, Department of Physical Medicine and Rehabilitation; Northwestern University, and Shirley Ryan AbilityLab
Person:
McManus, Lara, Suresh, Nina L., Lowery, Madeleine M., Rymer, William Z., and Hu, Xiaogang
Rights Statement Label:
In Copyright
Source:
j3860c868

745. Emotional Granularity Effects on Event-Related Brain Potentials during Affective Picture Processing

Title Tesim:
Emotional Granularity Effects on Event-Related Brain Potentials during Affective Picture Processing
Creator:
Lee, Ja Y., Nam, Chang S., and Lindquist, Kristen A.
Date of publication:
2017
Abstract Tesim:
There is debate about whether emotional granularity, the tendency to label emotions in a nuanced and specific manner, is merely a product of labeling abilities, or a systematic difference in the experience of emotion during emotionally evocative events. According to the Conceptual Act Theory of Emotion (CAT) (Barrett, 2006), emotional granularity is due to the latter and is a product of on-going temporal differences in how individuals categorize and thus make meaning of their affective states. To address this question, the present study investigated the effects of individual differences in emotional granularity on electroencephalography-based brain activity during the experience of emotion in response to affective images. Event-related potentials (ERP) and event-related desynchronization and synchronization (ERD/ERS) analysis techniques were used. We found that ERP responses during the very early (60–90 ms), middle (270–300 ms), and later (540–570 ms) moments of stimulus presentation were associated with individuals’ level of granularity. We also observed that highly granular individuals, compared to lowly granular individuals, exhibited relatively stable desynchronization of alpha power (8–12 Hz) and synchronization of gamma power (30–50 Hz) during the 3 s of stimulus presentation. Overall, our results suggest that emotional granularity is related to differences in neural processing throughout emotional experiences and that high granularity could be associated with access to executive control resources and a more habitual processing of affective stimuli, or a kind of “emotional complexity.” Implications for models of emotion are also discussed.
Resource type:
Article
Affiliation Label Tesim:
Department of Psychology and Neuroscience
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/pv80-8z91
Identifier:
PMID: 28392761, PMCID: PMC5364149, Publisher DOI: https://doi.org/10.3389/fnhum.2017.00133, and Onescience id: c092d56bb470522f80c1387e5124e6464e19c047
ISSN:
1662-5161
Journal Title:
Frontiers in Human Neuroscience
Journal Volume:
11
Keyword:
event-related desynchronization and synchronization, electroencephalography, event-related potentials, emotional granularity, and affective stimulus processing
Language Label:
English
ORCID:
Other Affiliation:
Industrial and Systems Engineering; University of Wisconsin-Madison and Industrial and Systems Engineering; North Carolina State University
Person:
Lee, Ja Y., Nam, Chang S., and Lindquist, Kristen A.
Rights Statement Label:
In Copyright
Source:
5138jk69v

746. COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function

Title Tesim:
COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function
Creator:
Smith, Christopher T., Boettiger, Charlotte A., Parrish, Michael H., and Elton, Amanda
Date of publication:
2017
Abstract Tesim:
Evidence suggests that dopamine levels in the prefrontal cortex (PFC) modulate executive functions. A key regulator of PFC dopamine is catechol-O-methyltransferase (COMT). The activity level of the COMT enzyme are influenced by sex and the Val158Met polymorphism (rs4680) of the COMT gene, with male sex and Val alleles both being associated with higher bulk enzyme activity, and presumably lower PFC dopamine. COMT genotype has not only been associated with individual differences in frontal dopamine-mediated behaviors, but also with variations in neuroimaging measures of brain activity and functional connectivity. In this study, we investigated whether COMT genotype predicts individual differences in neural activity and connectivity, and whether such effects are sex-dependent. We tested 93 healthy adults (48 females), genotyped for the Val158Met polymorphism, in a delay discounting task and at rest during fMRI. Delay discounting behavior was predicted by an interaction of COMT genotype and sex, consistent with a U-shaped relationship with enzyme activity. COMT genotype and sex similarly exhibited U-shaped relationships with individual differences in neural activation, particularly among networks that were most engaged by the task, including the default-mode network. Effects of COMT genotype and sex on functional connectivity during rest were also U-shaped. In contrast, flexible reorganization of network connections across task conditions varied linearly with COMT among both sexes. These data provide insight into the potential influences of COMT-regulated variations in catecholamine levels on brain function, which may represent endophenotypes for disorders of impulsivity.
Resource type:
Article
Affiliation Label Tesim:
University of North Carolina at Chapel Hill and Department of Psychology and Neuroscience
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/2xmk-4h65
Identifier:
PMID: 29270116, Publisher DOI: https://doi.org/10.3389/fnhum.2017.00578, PMCID: PMC5723646, and Onescience id: 64835750158eb8eeda63706abdb66d4a4aa80ec4
ISSN:
1662-5161
Journal Title:
Frontiers in Human Neuroscience
Journal Volume:
11
Keyword:
dopamine, sex differences, delay discounting, fMRI, and COMT
Language Label:
English
ORCID:
Other Affiliation:
University of North Carolina at Chapel Hill, School of Medicine, and Biomedical Research Imaging Center
Person:
Smith, Christopher T., Boettiger, Charlotte A., Parrish, Michael H., and Elton, Amanda
Rights Statement Label:
In Copyright
Source:
mw22vb23k

747. A Voxel-Based Morphometry Study Reveals Local Brain Structural Alterations Associated with Ambient Fine Particles in Older Women

Title Tesim:
A Voxel-Based Morphometry Study Reveals Local Brain Structural Alterations Associated with Ambient Fine Particles in Older Women
Creator:
Espeland, Mark A., Driscoll, Ira, Casanova, Ramon, Chen, Jiu-Chiuan, Reyes, Jeanette, Resnick, Susan M., Serre, Marc L., Akita, Yasuyuki, Wang, Xinhui, Vizuete, William, and Chui, Helena C.
Date of publication:
2016
Abstract Tesim:
Objective: Exposure to ambient fine particulate matter (PM2.5: PM with aerodynamic diameters < 2.5 μm) has been linked with cognitive deficits in older adults. Using fine-grained voxel-wise analyses, we examined whether PM2.5 exposure also affects brain structure.
Resource type:
Article
Affiliation Label Tesim:
University of North Carolina at Chapel Hill
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/fmr0-ks98
Identifier:
Onescience id: e9468d5c0d6bace71f0f5222edb1f8364509db18, Publisher DOI: https://doi.org/10.3389/fnhum.2016.00495, PMID: 27790103, and PMCID: PMC5061768
ISSN:
1662-5161
Journal Title:
Frontiers in Human Neuroscience
Journal Volume:
10
Keyword:
Magnetic Resonance Imaging, Homo sapiens, Gray Matter, Particulate Matter, Occipital Lobe, Neuroimaging, Brain, Frontal Lobe, Linear Models, White Matter, and Air
Language Label:
English
ORCID:
Other Affiliation:
Department of Biostatistical Sciences; Wake Forest School of Medicine, Department of Psychology; University of Wisconsin-Milwaukee, Department of Preventive Medicine; University of Southern California, Laboratory of Behavioral Neuroscience; National Institute on Aging; National Institutes of Health, and Department of Neurology; University of Southern California
Person:
Espeland, Mark A., Driscoll, Ira, Casanova, Ramon, Chen, Jiu-Chiuan, Reyes, Jeanette, Resnick, Susan M., Serre, Marc L., Akita, Yasuyuki, Wang, Xinhui, Vizuete, William, and Chui, Helena C.
Rights Statement Label:
In Copyright
Source:
n009w7099

748. The Emerging Role of the Cytoskeleton in Chromosome Dynamics

Title Tesim:
The Emerging Role of the Cytoskeleton in Chromosome Dynamics
Creator:
Fabre, Emmanuelle and Spichal, Maya
Date of publication:
2017
Abstract Tesim:
Chromosomes underlie a dynamic organization that fulfills functional roles in processes like transcription, DNA repair, nuclear envelope stability, and cell division. Chromosome dynamics depend on chromosome structure and cannot freely diffuse. Furthermore, chromosomes interact closely with their surrounding nuclear environment, which further constrains chromosome dynamics. Recently, several studies enlighten that cytoskeletal proteins regulate dynamic chromosome organization. Cytoskeletal polymers that include actin filaments, microtubules and intermediate filaments can connect to the nuclear envelope via Linker of the Nucleoskeleton and Cytoskeleton (LINC) complexes and transfer forces onto chromosomes inside the nucleus. Monomers of these cytoplasmic polymers and related proteins can also enter the nucleus and play different roles in the interior of the nucleus than they do in the cytoplasm. Nuclear cytoskeletal proteins can act as chromatin remodelers alone or in complexes with other nuclear proteins. They can also act as transcription factors. Many of these mechanisms have been conserved during evolution, indicating that the cytoskeletal regulation of chromosome dynamics is an essential process. In this review, we discuss the different influences of cytoskeletal proteins on chromosome dynamics by focusing on the well-studied model organism budding yeast.
Resource type:
Article
Affiliation Label Tesim:
Department of Genetics
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/asrp-7s88
Identifier:
Publisher DOI: https://doi.org/10.3389/fgene.2017.00060, PMID: 28580009, Onescience id: bb360eb357bafbe1321fd10a432852522804ee3c, and PMCID: PMC5437106
ISSN:
1664-8021
Journal Title:
Frontiers in Genetics
Journal Volume:
8
Keyword:
yeast, chromosomes, Chromosomes, Cytoskeleton, dynamics, nucleus, and cytoskeleton
Language Label:
English
ORCID:
Other Affiliation:
Equipe Biologie et Dynamique des Chromosomes; Institut Universitaire d'Hématologie; CNRS UMR 7212; INSERM U944; Hôpital St. Louis 1
Person:
Fabre, Emmanuelle and Spichal, Maya
Rights Statement Label:
In Copyright
Source:
7d279016p

749. Genetics of Tinnitus: Time to Biobank Phantom Sounds

Title Tesim:
Genetics of Tinnitus: Time to Biobank Phantom Sounds
Creator:
Kähler, Anna K., Sullivan, Patrick F., Cederroth, Christopher R., and Lopez-Escamez, Jose A.
Date of publication:
2017
Abstract Tesim:
Tinnitus is a common phantom sensation resulting most often from sensory deprivation, and for which little knowledge on the molecular mechanisms exists. While the existing evidence for a genetic influence on the condition has been until now sparse and underpowered, recent data suggest that specific forms of tinnitus have a strong genetic component revealing that not all tinnitus percepts are alike, at least in how they are genetically driven. These new findings pave the way for a better understanding on how phantom sensations are molecularly driven and call for international biobanking efforts.
Resource type:
Article
Affiliation Label Tesim:
Department of Genetics
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/84mx-mt84
Identifier:
PMID: 28928766, PMCID: PMC5591447, Onescience id: ee8268411250a8f50d0154bb6345f543121e261e, and Publisher DOI: https://doi.org/10.3389/fgene.2017.00110
ISSN:
1664-8021
Journal Title:
Frontiers in Genetics
Journal Volume:
8
Keyword:
Neuropsychiatry, GWAS (genome-wide association study), Tinnitus, tinnitus, heritability, whole exome sequencing, subtype, neuropsychiatry, genetics, and Genetics
Language Label:
English
ORCID:
Other Affiliation:
Department of Molecular Epidemiology and Biostatistics; Karolinska Institutet, Department of Psychiatry, Experimental Audiology; Department of Physiology and Pharmacology; Karolinska Institutet, Otology and Neurotology Group; Department of Genomic Medicine; Pfizer-Uni. de Granada-Junta de Andalucia Centre for Genomics and Oncology Research (GENyO), and Department of Otolaryngology; Instituto de Investigación Biosanitaria ibs.GRANADA; Hospital Virgen de las Nieves; Universidad de Granada
Person:
Kähler, Anna K., Sullivan, Patrick F., Cederroth, Christopher R., and Lopez-Escamez, Jose A.
Rights Statement Label:
In Copyright
Source:
wp988r007

750. Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response

Title Tesim:
Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response
Creator:
Marvel, Skylar W., Rotroff, Daniel M., Graham, Hillary T., Buse, John B., Motsinger-Reif, Alison A., Wagner, Michael J., Havener, Tammy M., and Wilson, Alyson G.
Date of publication:
2016
Abstract Tesim:
Given the high costs of conducting a drug-response trial, researchers are now aiming to use retrospective analyses to conduct genome-wide association studies (GWAS) to identify underlying genetic contributions to drug-response variation. To prevent confounding results from a GWAS to investigate drug response, it is necessary to account for concomitant medications, defined as any medication taken concurrently with the primary medication being investigated. We use data from the Action to Control Cardiovascular Disease (ACCORD) trial in order to implement a novel scoring procedure for incorporating concomitant medication information into a linear regression model in preparation for GWAS. In order to accomplish this, two primary medications were selected: thiazolidinediones and metformin because of the wide-spread use of these medications and large sample sizes available within the ACCORD trial. A third medication, fenofibrate, along with a known confounding medication, statin, were chosen as a proof-of-principle for the scoring procedure. Previous studies have identified SNP rs7412 as being associated with statin response. Here we hypothesize that including the score for statin as a covariate in the GWAS model will correct for confounding of statin and yield a change in association at rs7412. The response of the confounded signal was successfully diminished from p = 3.19 × 10−7 to p = 1.76 × 10−5, by accounting for statin using the scoring procedure presented here. This approach provides the ability for researchers to account for concomitant medications in complex trial designs where monotherapy treatment regimens are not available.
Resource type:
Article
Affiliation Label Tesim:
Department of Medicine and Center of Pharmacogenomics and Individualized Therapy
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/e2/82/bb/5c/e282bb5c-ecfc-4dd2-8603-2a46b5cc8e4b
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/4119-bx79
Identifier:
Publisher DOI: https://doi.org/10.3389/fgene.2016.00138, PMID: 27775101, Onescience id: 51fd70cc9648a508bcdab85b8003b0ea1ccac5f1, and PMCID: PMC5013254
ISSN:
1664-8021
Journal Title:
Frontiers in Genetics
Journal Volume:
7
Keyword:
Cardiovascular Diseases, Genome, Fenofibrate, Linear Models, Sample Size, Thiazolidinediones, Metformin, Therapeutics, and Genome-Wide Association Study
Language Label:
English
ORCID:
Other Affiliation:
Bioinformatics Research Center; North Carolina State University and Department of Statistics; North Carolina State University
Person:
Marvel, Skylar W., Rotroff, Daniel M., Graham, Hillary T., Buse, John B., Motsinger-Reif, Alison A., Wagner, Michael J., Havener, Tammy M., and Wilson, Alyson G.
Rights Statement Label:
In Copyright
Source:
b5644x67h