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3. Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder

Author

Dean, K. R., Hammamieh, R., Mellon, S. H., Abu-Amara, D., Flory, J. D., Guffanti, G., Wang, K., Daigle, B. J., Gautam, A., Lee, I., Yang, R., Almli, L. M., Bersani, F. S., Chakraborty, N., Donohue, D., Kerley, K., Kim, T. -K., Laska, E., Young Lee, M., Lindqvist, D., Lori, A., Lu, L., Misganaw, B., Muhie, S., Newman, J., Price, N. D., Qin, S., Reus, V. I., Siegel, C., Somvanshi, P. R., Thakur, G. S., Zhou, Y., Baxter, D., Bierer, L., Blessing, E., Cho, J. H., Coy, M., Desarnaud, F., Fossati, S., Hoke, A., Kumar, R., Li, M., Makotkine, I., Miller, S. -A., Petzold, L., Price, L., Qian, M., Scherler, K., Srinivasan, S., Suessbrick, A., Tang, L., Wu, X., Wu, G., Wu, C., Hood, L., Ressler, K. J., Wolkowitz, O. M., Yehuda, R., Jett, M., Doyle, F. J., and Marmar, C.

Subjects
0301 basic medicine, Biomarker identification, Oncology, Male, medicine.medical_specialty, post-traumatic, stress, disorder, MEDLINE, Disease, Stress Disorders, Post-Traumatic, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, Diagnostic biomarker, Medicine, Humans, Molecular Biology, Veterans, business.industry, Traumatic stress, Brain, Integrated approach, Omics, Psychiatry and Mental health, 030104 developmental biology, Military Personnel, Cohort, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

Published
2018

4. A DNA methylation biomarker of alcohol consumption

Author

Liu, C, Marioni, R E, Hedman, Åsa K, Pfeiffer, L, Tsai, P-C, Reynolds, L M, Just, A C, Duan, Q, Boer, C G, Tanaka, T, Elks, C E, Aslibekyan, S, Brody, J A, Kühnel, B, Herder, C, Almli, L M, Zhi, D, Wang, Y, Huan, T, Yao, C, Mendelson, M M, Joehanes, R, Liang, L, Love, S-A, Guan, W, Shah, S, McRae, A F, Kretschmer, A, Prokisch, H, Strauch, K, Peters, A, Visscher, P M, Wray, N R, Guo, X, Wiggins, K L, Smith, A K, Binder, E B, Ressler, K J, Irvin, M R, Absher, D M, Hernandez, D, Ferrucci, L, Bandinelli, S, Lohman, K, Ding, J, Trevisi, L, Gustafsson, Stefan, Sandling, Johanna K., Stolk, L, Uitterlinden, A G, Yet, I, Castillo-Fernandez, J E, Spector, T D, Schwartz, J D, Vokonas, P, Lind, Lars, Li, Y, Fornage, M, Arnett, D K, Wareham, N J, Sotoodehnia, N, Ong, K K, van Meurs, J B J, Conneely, K N, Baccarelli, A A, Deary, I J, Bell, J T, North, K E, Liu, Y, Waldenberger, M, London, S J, Ingelsson, Erik, Levy, D, Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Erasmus MC other, Internal Medicine, and Epidemiology

Subjects
Adult, Male, Alcohol Drinking, Ethanol, Black People, DNA Methylation, Middle Aged, White People, Epigenesis, Genetic, Annan medicinsk grundvetenskap, Genetics, Humans, CpG Islands, Female, Other Basic Medicine, Alcohol-Related Disorders, Biomarkers, Aged, Genome-Wide Association Study
Abstract

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted PDe tio första författarna delar på förstaförfattarskapet. De sex sista författarna delar på sistaförfattarskapet.

Published
2018
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5. A DNA methylation biomarker of alcohol consumption

Author

Liu, C, Marioni, R E, Hedman, Å K, Pfeiffer, L, Tsai, P-C, Reynolds, L M, Just, A C, Duan, Q, Boer, C G, Tanaka, T, Elks, C E, Aslibekyan, S, Brody, J A, Kühnel, B, Herder, C, Almli, L M, Zhi, D, Wang, Y, Huan, T, Yao, C, Mendelson, M M, Joehanes, R, Liang, L, Love, S-A, Guan, W, Shah, S, McRae, A F, Kretschmer, A, Prokisch, H, Strauch, K, Peters, A, Visscher, P M, Wray, N R, Guo, X, Wiggins, K L, Smith, A K, Binder, E B, Ressler, K J, Irvin, M R, Absher, D M, Hernandez, D, Ferrucci, L, Bandinelli, S, Lohman, K, Ding, J, Trevisi, L, Gustafsson, S, Sandling, J H, Stolk, L, Uitterlinden, A G, Yet, I, Castillo-Fernandez, J E, Spector, T D, Schwartz, J D, Vokonas, P, Lind, L, Li, Y, Fornage, M, Arnett, D K, Wareham, N J, Sotoodehnia, N, Ong, K K, van Meurs, J B J, Conneely, K N, Baccarelli, A A, Deary, I J, Bell, J T, North, K E, Liu, Y, Waldenberger, M, London, S J, Ingelsson, E, and Levy, D

Subjects
ddc
Published
2016

6. Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood

Author

Dedic, N, primary, Pöhlmann, M L, additional, Richter, J S, additional, Mehta, D, additional, Czamara, D, additional, Metzger, M W, additional, Dine, J, additional, Bedenk, B T, additional, Hartmann, J, additional, Wagner, K V, additional, Jurik, A, additional, Almli, L M, additional, Lori, A, additional, Moosmang, S, additional, Hofmann, F, additional, Wotjak, C T, additional, Rammes, G, additional, Eder, M, additional, Chen, A, additional, Ressler, K J, additional, Wurst, W, additional, Schmidt, M V, additional, Binder, E B, additional, and Deussing, J M, additional

Published
2017
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7. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

Author

Duncan, L E, primary, Ratanatharathorn, A, additional, Aiello, A E, additional, Almli, L M, additional, Amstadter, A B, additional, Ashley-Koch, A E, additional, Baker, D G, additional, Beckham, J C, additional, Bierut, L J, additional, Bisson, J, additional, Bradley, B, additional, Chen, C-Y, additional, Dalvie, S, additional, Farrer, L A, additional, Galea, S, additional, Garrett, M E, additional, Gelernter, J E, additional, Guffanti, G, additional, Hauser, M A, additional, Johnson, E O, additional, Kessler, R C, additional, Kimbrel, N A, additional, King, A, additional, Koen, N, additional, Kranzler, H R, additional, Logue, M W, additional, Maihofer, A X, additional, Martin, A R, additional, Miller, M W, additional, Morey, R A, additional, Nugent, N R, additional, Rice, J P, additional, Ripke, S, additional, Roberts, A L, additional, Saccone, N L, additional, Smoller, J W, additional, Stein, D J, additional, Stein, M B, additional, Sumner, J A, additional, Uddin, M, additional, Ursano, R J, additional, Wildman, D E, additional, Yehuda, R, additional, Zhao, H, additional, Daly, M J, additional, Liberzon, I, additional, Ressler, K J, additional, Nievergelt, C M, additional, and Koenen, K C, additional

Published
2017
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9. A DNA methylation biomarker of alcohol consumption

Author

Liu, C, primary, Marioni, R E, additional, Hedman, Å K, additional, Pfeiffer, L, additional, Tsai, P-C, additional, Reynolds, L M, additional, Just, A C, additional, Duan, Q, additional, Boer, C G, additional, Tanaka, T, additional, Elks, C E, additional, Aslibekyan, S, additional, Brody, J A, additional, Kühnel, B, additional, Herder, C, additional, Almli, L M, additional, Zhi, D, additional, Wang, Y, additional, Huan, T, additional, Yao, C, additional, Mendelson, M M, additional, Joehanes, R, additional, Liang, L, additional, Love, S-A, additional, Guan, W, additional, Shah, S, additional, McRae, A F, additional, Kretschmer, A, additional, Prokisch, H, additional, Strauch, K, additional, Peters, A, additional, Visscher, P M, additional, Wray, N R, additional, Guo, X, additional, Wiggins, K L, additional, Smith, A K, additional, Binder, E B, additional, Ressler, K J, additional, Irvin, M R, additional, Absher, D M, additional, Hernandez, D, additional, Ferrucci, L, additional, Bandinelli, S, additional, Lohman, K, additional, Ding, J, additional, Trevisi, L, additional, Gustafsson, S, additional, Sandling, J H, additional, Stolk, L, additional, Uitterlinden, A G, additional, Yet, I, additional, Castillo-Fernandez, J E, additional, Spector, T D, additional, Schwartz, J D, additional, Vokonas, P, additional, Lind, L, additional, Li, Y, additional, Fornage, M, additional, Arnett, D K, additional, Wareham, N J, additional, Sotoodehnia, N, additional, Ong, K K, additional, van Meurs, J B J, additional, Conneely, K N, additional, Baccarelli, A A, additional, Deary, I J, additional, Bell, J T, additional, North, K E, additional, Liu, Y, additional, Waldenberger, M, additional, London, S J, additional, Ingelsson, E, additional, and Levy, D, additional

Published
2016
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11. Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder

Author

Kilaru, V, primary, Iyer, S V, additional, Almli, L M, additional, Stevens, J S, additional, Lori, A, additional, Jovanovic, T, additional, Ely, T D, additional, Bradley, B, additional, Binder, E B, additional, Koen, N, additional, Stein, D J, additional, Conneely, K N, additional, Wingo, A P, additional, Smith, A K, additional, and Ressler, K J, additional

Published
2016
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12. The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription

Author

Donaldson, Z R, primary, le Francois, B, additional, Santos, T L, additional, Almli, L M, additional, Boldrini, M, additional, Champagne, F A, additional, Arango, V, additional, Mann, J J, additional, Stockmeier, C A, additional, Galfalvy, H, additional, Albert, P R, additional, Ressler, K J, additional, and Hen, R, additional

Published
2016
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14. Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood

Author

Dedic, N, Pöhlmann, M L, Richter, J S, Mehta, D, Czamara, D, Metzger, M W, Dine, J, Bedenk, B T, Hartmann, J, Wagner, K V, Jurik, A, Almli, L M, Lori, A, Moosmang, S, Hofmann, F, Wotjak, C T, Rammes, G, Eder, M, Chen, A, Ressler, K J, Wurst, W, Schmidt, M V, Binder, E B, and Deussing, J M

Abstract

Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Cav1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Cav1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Cav1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Cav1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.

Published
2018
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15. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

Author

Duncan, L E, Ratanatharathorn, A, Aiello, A E, Almli, L M, Amstadter, A B, Ashley-Koch, A E, Baker, D G, Beckham, J C, Bierut, L J, Bisson, J, Bradley, B, Chen, C-Y, Dalvie, S, Farrer, L A, Galea, S, Garrett, M E, Gelernter, J E, Guffanti, G, Hauser, M A, Johnson, E O, Kessler, R C, Kimbrel, N A, King, A, Koen, N, Kranzler, H R, Logue, M W, Maihofer, A X, Martin, A R, Miller, M W, Morey, R A, Nugent, N R, Rice, J P, Ripke, S, Roberts, A L, Saccone, N L, Smoller, J W, Stein, D J, Stein, M B, Sumner, J A, Uddin, M, Ursano, R J, Wildman, D E, Yehuda, R, Zhao, H, Daly, M J, Liberzon, I, Ressler, K J, Nievergelt, C M, and Koenen, K C

Abstract

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNPfor schizophrenia and is substantially higher than h2SNPin European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Published
2018
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16. Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD

Author

Maddox, S A, Kilaru, V, Shin, J, Jovanovic, T, Almli, L M, Dias, B G, Norrholm, S D, Fani, N, Michopoulos, V, Ding, Z, Conneely, K N, Binder, E B, Ressler, K J, and Smith, A K

Abstract

Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.

Published
2018
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18. Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways

Author

Wildman, D E, Ratanatharathorn, A, Aiello, A E, Almli, L M, Ressler, K, Meyers, J L, Koenen, K C, Uddin, M, Galea, S, Salling, M C, and Bradley, B

Subjects
16. Peace & justice
Abstract

Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n=788; 83% African American), 206 genetic variants across the mGluR–eEF2–AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value

19. A DNA methylation biomarker of alcohol consumption.

Author

Liu C, Marioni RE, Hedman ÅK, Pfeiffer L, Tsai PC, Reynolds LM, Just AC, Duan Q, Boer CG, Tanaka T, Elks CE, Aslibekyan S, Brody JA, Kühnel B, Herder C, Almli LM, Zhi D, Wang Y, Huan T, Yao C, Mendelson MM, Joehanes R, Liang L, Love SA, Guan W, Shah S, McRae AF, Kretschmer A, Prokisch H, Strauch K, Peters A, Visscher PM, Wray NR, Guo X, Wiggins KL, Smith AK, Binder EB, Ressler KJ, Irvin MR, Absher DM, Hernandez D, Ferrucci L, Bandinelli S, Lohman K, Ding J, Trevisi L, Gustafsson S, Sandling JH, Stolk L, Uitterlinden AG, Yet I, Castillo-Fernandez JE, Spector TD, Schwartz JD, Vokonas P, Lind L, Li Y, Fornage M, Arnett DK, Wareham NJ, Sotoodehnia N, Ong KK, van Meurs JBJ, Conneely KN, Baccarelli AA, Deary IJ, Bell JT, North KE, Liu Y, Waldenberger M, London SJ, Ingelsson E, and Levy D

Subjects
Adult, Aged, Alcohol Drinking metabolism, Alcohol-Related Disorders metabolism, Biomarkers blood, Black People genetics, CpG Islands genetics, Epigenesis, Genetic, Ethanol blood, Ethanol metabolism, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, White People genetics, Alcohol Drinking genetics, Alcohol-Related Disorders genetics, DNA Methylation drug effects
Abstract

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (n total =13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10 -7 . Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10 -7 . In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Published
2018
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20. Dysregulated biomarkers induce distinct pathways in preterm birth.

Author

Brou L, Almli LM, Pearce BD, Bhat G, Drobek CO, Fortunato S, and Menon R

Subjects
Adolescent, Adult, Case-Control Studies, Female, Humans, Infant, Newborn, Pregnancy, Tennessee epidemiology, Black or African American statistics & numerical data, Amniotic Fluid metabolism, Biomarkers blood, Fetal Blood metabolism, Premature Birth blood, Premature Birth ethnology, White People statistics & numerical data
Abstract

Objective: To document racial disparity in biomarker concentrations in maternal/fetal plasma and amniotic fluid between African Americans and European Americans with spontaneous preterm birth (PTB; cases) and normal term birth (controls), and their contribution to distinct pathophysiological pathways of PTB., Design: Nested case-control study., Setting: The Perinatal Research Center, Nashville, Tennessee, USA., Sample: Maternal and fetal plasma and amniotic fluid samples were collected from 105 cases (59 African American and 46 European American) and 86 controls (40 African American and 46 European American)., Methods: Thirty-six biomarkers were analysed using the protein microarray approach., Main Outcome Measures: Differences in biomarker concentrations between cases and controls of different races in maternal, fetal and intra-amniotic compartments, and the risk of PTB. Dysregulated biomarker-induced PTB pathways associated with PTB in each race were determined using ingenuity pathway analysis (IPA)., Results: Racial disparity was observed in biomarker concentrations in each compartment between cases and controls: amniotic fluid, IL8 and MIP1α differed between case and controls in European Americans, whereas ANGPT2, Eotaxin, ICAM-1, IL-1β, IL1RA, RANTES and TNFα differed between case and controls in African Americans. In both races the FAS ligand, MCP-3 and TNFR-I differed between cases and controls. For fetal plasma, ANGPT2, Eotaxin, FGF basic, ICAM-1, IGF-I, IL10, IL-1β, IL2, IP10 KGF, MCP-3, MIP1α, PDGF-BB, TGFα, TGFβ1, TIMP1, TNFα, TNFR-I, TNFR-II and VEGF differed between cases and controls in European Americans, whereas only MMP7 differed between cases and controls in African Americans. IL-8 differed between cases and controls in both races. For maternal plasma, IL1RA, MMP7 and VEGF differed between cases and controls in European Americans, whereas ANGPT2, FGF basic, IL-1β, IL5, IL6R, KGF, MCP-3, MIP1α, TIMP1 and TNFα differed between cases and controls in African Americans. ANG, IL8 and TNFR-I differed between cases and controls in both races., Conclusions: We conclude that: (1) biomarker concentrations in maternal, fetal and intra-amniotic compartments differ between cases and controls; (2) there is racial disparity in the biomarker profile in each of the compartments; (3) substantial numbers of dysregulated fetal plasma biomarkers contribute to PTB in European Americans, whereas maternal plasma biomarkers contribute to PTB in African Americans; and (4) both inflammation and haematological functions are associated with PTB in European Americans, but maternal proinflammatory changes dominate PTB in African Americans. Biomarker analyses document racial disparity and the distinct pathophysiological contributions from different compartments that can determine pregnancy outcome., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Published
2012
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21. Multiple pathways of neuroprotection against oxidative stress and excitotoxic injury in immature primary hippocampal neurons.

Author

Almli LM, Hamrick SE, Koshy AA, Täuber MG, and Ferriero DM

Subjects
Animals, Animals, Newborn, Cell Death drug effects, Cells, Cultured, Chelating Agents pharmacology, Cyclic N-Oxides, Deferoxamine pharmacology, Ethylenediamines pharmacology, Excitatory Amino Acid Agonists toxicity, Free Radical Scavengers pharmacology, Hydrogen Peroxide pharmacology, Iron metabolism, Iron Chelating Agents pharmacology, Mice, Mice, Inbred Strains, N-Methylaspartate toxicity, Neurons cytology, Neurons metabolism, Neuroprotective Agents pharmacology, Nitrogen Oxides pharmacology, Oxidants pharmacology, Oxidative Stress drug effects, Reactive Oxygen Species metabolism, Hippocampus cytology, Hippocampus growth & development, Neurons drug effects
Abstract

In the immature brain hydrogen peroxide accumulates after excitotoxic hypoxia-ischemia and is neurotoxic. Immature hippocampal neurons were exposed to N-methyl-D-aspartate (NMDA), a glutamate agonist, and hydrogen peroxide (H(2)O(2)) and the effects of free radical scavenging and transition metal chelation on neurotoxicity were studied. alpha-Phenyl-N-tert.-butylnitrone (PBN), a known superoxide scavenger, attenuated both H(2)O(2) and NMDA mediated toxicity. Treatment with desferrioxamine (DFX), an iron chelator, at the time of exposure to H(2)O(2) was ineffective, but pretreatment was protective. DFX also protected against NMDA toxicity. TPEN, a metal chelator with higher affinities for a broad spectrum of transition metal ions, also protected against H(2)O(2) toxicity but was ineffective against NMDA induced toxicity. These data suggest that during exposure to free radical and glutamate agonists, the presence of iron and other free metal ions contribute to neuronal cell death. In the immature nervous system this neuronal injury can be attenuated by free radical scavengers and metal chelators.

Published
2001
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