scholarly journals Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julia C. Stingl ◽  
Catharina Scholl ◽  
Julia E. Bosch ◽  
Roberto Viviani
Keyword(s):  
Genetic Polymorphism ◽  
Fetal Brain ◽  
Positive Association ◽  
Hippocampal Volume ◽  
Volume Estimation ◽  
Adult Brain ◽  
Brain Morphology ◽  
Cytochrome P450 Enzymes ◽  
Endogenous Substrates

AbstractPharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N = 608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.

scholarly journals Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain

2020 ◽  
Author(s):  
Julia C. Stingl ◽  
Catharina Scholl ◽  
Julia E. Bosch ◽  
Roberto Viviani
Keyword(s):  
Genetic Polymorphism ◽  
Fetal Brain ◽  
Positive Association ◽  
Hippocampal Volume ◽  
Volume Estimation ◽  
Adult Brain ◽  
Brain Morphology ◽  
Cytochrome P450 Enzymes ◽  
Endogenous Substrates

AbstractPharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N=608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.

scholarly journals Fetal brain sparing in a mouse model of chronic maternal hypoxia

2017 ◽  
Vol 39 (6) ◽  
pp. 1172-1184 ◽  
Author(s):  
Lindsay S Cahill ◽  
Johnathan Hoggarth ◽  
Jason P Lerch ◽  
Mike Seed ◽  
Christopher K Macgowan ◽  
...  
Keyword(s):  
Blood Flow ◽  
Mouse Model ◽  
Chronic Hypoxia ◽  
Fetal Brain ◽  
Adult Brain ◽  
Brain Morphology ◽  
Ductus Venosus ◽  
Experimental Mouse Model ◽  
Experimental Mouse ◽  
Maternal Hypoxia

Hypoxic stress is a common occurrence during human pregnancy, yet little is known about its effects on the fetal brain. This study examined the fetal hemodynamic responses to chronic hypoxia in an experimental mouse model of chronic maternal hypoxia (11% O2 from E14.5 to E17.5). Using high-frequency Doppler ultrasound, we found fetal cerebral and ductus venosus blood flow were both elevated by 69% and pulmonary blood flow was decreased by 62% in the fetuses exposed to chronic hypoxia compared to controls. This demonstrates that brain sparing persists during chronic fetal hypoxia and is mediated by “streaming,” where highly oxygenated blood preferentially flows through the ductus venosus towards the cerebral circulation, bypassing the liver and the lungs. Consistent with these changes in blood flow, the fetal brain volume measured by MRI is preserved, while the liver and lung volumes decreased compared to controls. However, hypoxia exposed fetuses were rendered vulnerable to an acute hypoxic challenge (8% O2 for 3 min), demonstrating global blood flow decreases consistent with imminent fetal demise rather than elevated cerebral blood flow. Despite this vulnerability, there were no differences in adult brain morphology in the mice exposed to chronic maternal hypoxia compared to controls.

scholarly journals The Role of Angiotensin Converting Enzyme 1 Insertion/Deletion Genetic Polymorphism in the Risk and Severity of COVID-19 Infection

2021 ◽  
Vol 8 ◽  
Author(s):  
Halim Saad ◽  
Karna Jabotian ◽  
Carine Sakr ◽  
Rami Mahfouz ◽  
Imad Bou Akl ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Polymorphism ◽  
Potential Role ◽  
Medical Center ◽  
Positive Association ◽  
American University ◽  
American University Of Beirut ◽  
Increased Risk ◽  
Study Population

Background: Individuals infected with the COVID-19 virus present with different symptoms of varying severity. In addition, not all individuals are infected despite exposure. Risk factors such as age, sex, and comorbidities play a major role in this variability; however, genetics may also be important in driving the differences in the incidence and prognosis of the disease. An Insertion/Deletion (I/D) polymorphism in the ACE1 gene (rs1799752) may explain these genetic differences. The aims of this study were to determine the potential role of ACE1 I/D genetic polymorphism in the risk of contracting COVID-19 as well as predicting the severity of COVID-19 infection.Methods: Three-hundred and eighty-seven non-related Lebanese subjects, 155 controls and 232 cases, who presented to the American University of Beirut Medical Center (AUBMC) for COVID-19 PCR testing were recruited. Clinical data were collected via filling a questionnaire and accessing the medical records. Peripheral blood was withdrawn for DNA isolation, and genotyping performed with standard PCR followed by band visualization on agarose gel.Results: In our study population, previously described risk factors such as gender, age, and comorbidities were associated with increase in disease susceptibility and severity. ACE1 I was the least common allele, and there was a positive association between ACE1 I and the risk of contracting the COVID-19 disease. More specifically, the frequency of II genotype was significantly higher among cases when compared to controls (P = 0.035) with individuals with the II genotype having greater risk for contracting the COVID-19 disease: OR = 2.074, P = 0.048 in the multivariate analysis. As for disease severity, the DD genotype and D allele were associated with increased risk for developing severe symptoms (OR = 2.845, P = 0.026 and OR = 2.359, P = 0.014, respectively), and the DD genotype with necessitating hospitalization (OR = 2.307, P = 0.042). In parallel, D allele carriers showed a significantly increased risk for developing hypoxia: OR = 4.374, P = 0.045.Conclusion: We found a positive association between ACE1 I and the risk of contracting the COVID-19 disease, and between ACE1 D and a worse outcome of the COVID-19 infection. Therefore, genotyping for ACE1 I/D polymorphism could be used to assess risk and predict severity for better prognosis and management of the disease.

scholarly journals Shared loci of telomere length with brain morphology, and pleiotropy in transcriptomic and epigenomic profiles of brain

2020 ◽  
Author(s):  
Gita A Pathak ◽  
Frank Wendt ◽  
Daniel F Levey ◽  
Adam Mecca ◽  
Christopher van Dyck ◽  
...  
Keyword(s):  
Telomere Length ◽  
Fetal Brain ◽  
Neuropsychiatric Disorders ◽  
Adult Brain ◽  
Brain Morphology ◽  
M Cell ◽  
Total N ◽  
Cell Cycle Transition ◽  
Calcium Ion Transport ◽  
Shared Genetic

Premature shortening of telomere length is observed in neuropsychiatric disorders. We tested genetic colocalization of seven and nine leukocyte telomere length (LTL) loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively (total n=60,601) with brain morphology measures for 101 region-of-interests (ROI) (n=21,821). The posterior probability (>90%) was observed for fourth ventricle, gray matter and cerebellar vermal lobules I-IV volumes. We found regulatory genes (p ≤ 2.47 x10-6) by integrating transcriptomic (EAS=4;EUR=5) and methylation data (EUR=17; EAS=4) of brain tissues using Summary-based Mendelian Randomization (SMR). The LTL SNP associations were tested for brain-based chromatin profiles using H-MAGMA (EUR=50; EAS=97; p<= 1.02 x10-6). Pathway enrichment of tissue-specific genes highlighted calcium ion transport (fetal brain) and G2/M cell cycle transition (adult brain). This study provides evidence that previously reported LTL associations with neuropsychiatric disorders could be related to a shared genetic relationship between LTL and brain structural and regulatory traits.

Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

2020 ◽  
Vol 3 (2) ◽  
pp. 216-242 ◽  
Author(s):  
Mayuri Shukla ◽  
Areechun Sotthibundhu ◽  
Piyarat Govitrapong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Adult Brain ◽  
Therapeutic Approaches ◽  
Therapeutic Implications ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.   

The role of placental growth factor in regulating fetal brain vascular development

2014 ◽  
Author(s):  
Matthew T Ratsep ◽  
Bruno Zavan ◽  
Nicki Peterson ◽  
Leandra Tolusso ◽  
Vanessa Kay ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vascular Development ◽  
Fetal Brain ◽  
Placental Growth Factor

Association of genetic polymorphism of cytokines and antioxidant enzymes with the development of asbestosis

2020 ◽  
Vol 60 (12) ◽  
pp. 898-903
Author(s):  
Lyudmila P. Kuzmina ◽  
Anastasiya G. Khotuleva ◽  
Evgeniy V. Kovalevsky ◽  
Nikolay N. Anokhin ◽  
Iraklij M. Tskhomariya
Keyword(s):  
Antioxidant Enzymes ◽  
Genetic Polymorphism ◽  
Genetic Predisposition ◽  
Risk Groups ◽  
Dust Exposure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Gstp1 Gene ◽  
Polymorphic Variants

Introduction. Various industries widely use chrysotile asbestos, which determines the relevance of research aimed at the prevention of asbestos-related diseases. It is promising to assess the role of specific genes, which products are potentially involved in the development and regulation of certain links in the pathogenesis of asbestosis, forming a genetic predisposition to the disease. The study aims to analyze the presence of associations of genetic polymorphism of cytokines and antioxidant enzymes with asbestosis development. Materials and methods. Groups were formed for examination among employees of OJSC "Uralasbest" with an established diagnosis of asbestosis and without lung diseases. For each person included in the study, dust exposure doses were calculated considering the percentage of time spent at the workplace during the shift for the entire work time. Genotyping of single nucleotide polymorphisms of cytokines IL1b (rs16944), IL4 (rs2243250), IL6 (rs1800795), TNFα (rs1800629) and antioxidant enzymes SOD2 (rs4880), GSTP1 (rs1610011), CAT (rs1001179) was carried out. Results. The authors revealed the associations of polymorphic variants A511G IL1b gene (OR=2.457, 95% CI=1.232-4.899) and C47T SOD2 gene (OR=1.705, 95% CI=1.055-2.756) with the development of asbestosis. There was an increase in the T allele IL4 gene (C589T) frequency in persons with asbestosis at lower values of dust exposure doses (OR=2.185, 95% CI=1.057-4.514). The study showed the associations of polymorphism C589T IL4 gene and C174G IL6 gene with more severe asbestosis, polymorphism A313G GSTP1 gene with pleural lesions in asbestosis. Conclusion. Polymorphic variants of the genes of cytokines and antioxidant enzymes, the protein products directly involved in the pathogenetic mechanisms of the formation of asbestosis, contribute to forming a genetic predisposition to the development and severe course of asbestosis. Using the identified genetic markers to identify risk groups for the development and intense period of asbestos-related pathology will optimize treatment and preventive measures, considering the organism's characteristics.

CEO and CFO Equity Incentives and the Pricing of Audit Services

2013 ◽  
Vol 33 (2) ◽  
pp. 1-25 ◽  
Author(s):  
B. Anthony Billings ◽  
Xinghua Gao ◽  
Yonghong Jia
Keyword(s):  
Positive Association ◽  
Audit Fees ◽  
Internal Controls ◽  
Audit Risk ◽  
Pricing Decisions ◽  
Equity Incentives ◽  
Accounting Scandals ◽  
Using Data ◽  
Distinctive Role

SUMMARY: The alleged perverse role of managerial incentives in accounting scandals, and the distinctive role of auditors in identifying and intervening in attempted earnings manipulation, highlight the importance of explicitly considering executive incentive plans by auditors in the auditing process. By empirically testing auditors' responses to CEO/CFO equity incentives in planning and pricing decisions using data from 2002 through 2009, we document compelling evidence that CFO equity incentives are positively associated with audit fees and CEO equity incentives are not statistically related to audit fees, suggesting that auditors perceive heightened audit risk associated with CFO equity incentives. Our further analyses reveal that the positive association between CFO equity incentives and audit fees is more pronounced in firms with weak internal controls, indicating heightened risk associated with CFO equity incentives in this setting perceived by auditors. JEL Classifications: G30, G34, M42, M52.

The Role of Race in Relations of Social Support to Hippocampal Volumes Among Older Adults

2021 ◽  
pp. 016402752110172
Author(s):  
Desirée C. Bygrave ◽  
Constance S. Gerassimakis ◽  
Denée T. Mwendwa ◽  
Guray Erus ◽  
Christos Davatzikos ◽  
...  
Keyword(s):  
Social Support ◽  
Older Adults ◽  
African American ◽  
Disease Risk ◽  
Total Sample ◽  
Hippocampal Volume ◽  
Brain Pathology ◽  
Resonance Imaging ◽  
African American Older Adults

Evidence suggests social support may buffer brain pathology. However, neither its association with hippocampal volume, a marker of Alzheimer’s disease risk, nor the role of race in this association has been fully investigated. Multiple regression analyses examined relations of total social support to magnetic resonance imaging-assessed gray matter (GM) hippocampal volumes in the total sample ( n = 165; mean age = 68.48 year), and in race-stratified models of African American and White older adults, adjusting for select covariates. Results showed greater social support was associated with greater GM hippocampal volumes among African American older adults only ( p < .01). Our findings suggest greater total social support may play a role in supporting the hippocampus, particularly among African American older adults, who had lower hippocampal volumes than their White counterparts. Further research is needed to test these questions longitudinally and examine which aspects of social support may promote hippocampal integrity, specifically.

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