Association of the Promoter Haplotype of IFN-γ-Inducible Protein 16 Gene with Schizophrenia in a Korean Population

Objective Viral infections play an important role in the development of schizophrenia, inducing the faulty immunological responses and aberrant inflammation. IFN-γ-inducible protein 16 (IFI16) is an immunological DNA sensor against viral infections, triggering the inflammatory responses. In this study, we investigated an association between putative promoter single nucleotide polymorphisms (SNPs) and haplotypes of IFI16 and schizophrenia.Methods A total of 280 schizophrenia patients and 427 control subjects were recruited in this study. We genotyped three promoter SNPs (rs1465175, rs3754464, rs1417806) using direct sequencing. Associations of SNPs and haplotypes of IFI16 with schizophrenia were analyzed. The promoter activities on the haplotypes of IFI16 were measured.Results The T allele of rs1465175 and the C allele of rs1417806 were protectively associated with schizophrenia (p=0.021 on rs1465175; p=0.016 on rs1417806), whereas the G allele of rs3754464 was associated with an increased risk of schizophrenia (p=0.019). In haplotype analysis, a significant association between the GGA haplotype and schizophrenia was shown (p=0.013). Moreover, we found that the GGA haplotype elevated the promoter activity compared to the GAA haplotype, whereas the TAC haplotype reduced that.Conclusion The promoter SNPs and haplotypes of IFI16 may contribute to the susceptibility of schizophrenia, affecting the promoter activity of IFI16.

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Human genetic deficiencies reveal the roles of complement in the inflammatory network: Lessons from nature

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0903613106 ◽

2009 ◽

Vol 106 (37) ◽

pp. 15861-15866 ◽

Cited By ~ 93

Author(s):

Knut Tore Lappegård ◽

Dorte Christiansen ◽

Anne Pharo ◽

Ebbe Billmann Thorgersen ◽

Bernt Christian Hellerud ◽

...

Keyword(s):

Inflammatory Responses ◽

Gram Negative Bacteria ◽

Enzyme Release ◽

Experimental Conditions ◽

Gram Negative ◽

Cytokines And Chemokines ◽

Ifn Γ ◽

Inducible Protein ◽

The Complement System

Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to Gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies—nature's own knockouts—including a previously undescribed C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1β and IL-8 were more dependent on complement than IFN-γ and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-γ inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on CD14. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to Gram-negative bacteria.

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Correlation between miRNA target site polymorphisms in the 3′ UTR of AVPR1A and the risk of hypertension in the Chinese Han population

Bioscience Reports ◽

10.1042/bsr20182232 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 1

Author(s):

Liuping Zhang ◽

Jinwei Liu ◽

Peng Cheng ◽

Fangchao Lv

Keyword(s):

Single Nucleotide Polymorphisms ◽

Mirna Target ◽

Direct Sequencing ◽

Chinese Han Population ◽

Control Group ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Single Nucleotide ◽

Han Population ◽

Increased Risk

Abstract We aimed to study the relationship between rs11174811 and rs3803107 single nucleotide polymorphisms (SNPs) in miRNA target sites of the 3′ UTR in the arginine vasopressin receptor 1a gene (AVPR1A) and the risk of hypertension in the Chinese Han population. The genotypes at rs11174811 and rs3803107 were analyzed by direct sequencing in 425 Chinese Han patients with hypertension and 425 healthy subjects. AVPR1A expression was investigated by transfecting miR-526b, miR-375, and miR-186 mimics into human umbilical vein endothelial cells (HUVECs) containing AVPR1A rs11174811 CC, CA/AA and AVPR1A rs3803107 GG, GA/AA genotypes. The A alleles of rs11174811 (adjusted OR = 1.424, 95% CI: 1.231–1.599, P<0.001) and rs3803107 (adjusted OR = 1.222, 95% CI: 1.092–1.355; P=0.001) were high risk factors for hypertension. Plasma levels of miR-526b, miR-375, and miR-186 were higher in the study group than in the control group (P<0.001). The expression levels of AVPR1A mRNA in AVPR1A rs11174811 and rs3803107 mutant HUVECs were higher than those in wild-type cells (t = 8.811, 4.068 and P=0.001, 0.015, respectively). The single nucleotide polymorphisms rs11174811 and rs3803107 in the AVPR1A gene are associated with an increased risk of hypertension in the Chinese Han population. This may be related to the effect of these variants on the regulation of AVPR1A expression by miRNAs.

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Impaired Hemostasis Leads To Alveolar Hemorrhages and Increased Mortality In Influenza A Infection

Blood ◽

10.1182/blood.v122.21.1095.1095 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1095-1095

Author(s):

Silvio Antoniak ◽

Kohei Tatsumi ◽

Justin Milner ◽

Melinda Beck ◽

Nigel Mackman

Keyword(s):

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Conflicts Of Interest ◽

Littermate Control ◽

Virus Challenge ◽

Protein Levels ◽

Increased Risk ◽

Influenza A H1n1 ◽

Body Weights

Abstract Objective Viral infections lead to activation of coagulation which enhances inflammatory responses. For instance, influenza A is associated with activation of coagulation and the increased risk for thrombotic events, such as myocardial infarction. Protease-activated receptor 4 (PAR-4) is the main functional receptor on mouse platelets. Here, we investigated the role of tissue factor (TF) and platelets in influenza A infection in mice. Methods We used male LowTF mice, which express 1% of normal TF levels, PAR-4 deficient mice and respective control mice. All mice were infected intranasal with influenza A H1N1/PR8. Changes in body weights and survival were analyzed up to 14 days after infection. In addition, bronchoalveolar lavage (BAL) was collected and analyzed 7 days after virus challenge. Results LowTF mice exhibited increased loss of body weights compared to littermate control mice between day 4 and 6 after infection (P<0.05). At day 7, BAL of LowTF had increased levels of free hemoglobin compared to infected control mice (2.60±0.39 g/dL vs. 0.05±0.02 g/dL, P<0.05). In addition, LowTF lungs exhibited increased protein levels in the BAL compared to controls (1.52±0.18 mg/mL vs. 0.70±0.26 mg/mL, P<0.05). Lung histology revealed that LowTF mice had extensive hemorrhages. The impaired hemostasis resulted in increased mortality in LowTF mice compared to control mice (90% vs 30%, P<0.004, N=9-10, Figure). Similarly, mice with defective thrombin signaling in platelets (PAR-4-/-) exhibited visible lung hemorrhages with increased hemoglobin levels in the BAL (P<0.05) at day 7 and increased mortality compared to controls (57% vs 10%, P<0.03, N=9-14, Figure). Conclusions TF mediated activation of coagulation and PAR-4 dependent platelet activation are essential for pulmonary hemostasis during influenza A infection. Disclosures: No relevant conflicts of interest to declare.

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Expansion of CD10neg neutrophils and HLA-DRneg/low monocytes driving inflammatory responses after myocardial infarction

eLife ◽

10.7554/elife.66808 ◽

2021 ◽

Vol 10 ◽

Author(s):

Daniela Fraccarollo ◽

Jonas Neuser ◽

Julian Möller ◽

Christian Riehle ◽

Paolo Galuppo ◽

...

Keyword(s):

Myocardial Infarction ◽

T Cells ◽

Viral Infections ◽

Inflammatory Responses ◽

Myeloid Cell ◽

Damage Function ◽

Cardiac Damage ◽

Bioinformatic Tools ◽

Hla Dr ◽

Ifn Γ

Background: Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored.Methods and Results: We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion.Conclusions: Immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.

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Intrauterine Viral Infections: Impact of Inflammation on Fetal Neurodevelopment

Frontiers in Neuroscience ◽

10.3389/fnins.2021.771557 ◽

2021 ◽

Vol 15 ◽

Author(s):

Sourav Ganguli ◽

Pavithra L. Chavali

Keyword(s):

Neurodevelopmental Disorders ◽

Viral Infections ◽

Inflammatory Responses ◽

Fetal Brain ◽

Preterm Births ◽

Autism Spectrum ◽

Future Research ◽

Increased Risk ◽

Mechanistic Basis ◽

Simplex Virus

Intrauterine viral infections during pregnancy by pathogens such as Zika virus, Cytomegalovirus, Rubella and Herpes Simplex virus can lead to prenatal as well as postnatal neurodevelopmental disorders. Although maternal viral infections are common during pregnancy, viruses rarely penetrate the trophoblast. When they do cross, viruses can cause adverse congenital health conditions for the fetus. In this context, maternal inflammatory responses to these neurotropic pathogens play a significant role in negatively affecting neurodevelopment. For instance, intrauterine inflammation poses an increased risk of neurodevelopmental disorders such as microcephaly, schizophrenia, autism spectrum disorder, cerebral palsy and epilepsy. Severe inflammatory responses have been linked to stillbirths, preterm births, abortions and microcephaly. In this review, we discuss the mechanistic basis of how immune system shapes the landscape of the brain and how different neurotropic viral pathogens evoke inflammatory responses. Finally, we list the consequences of neuroinflammation on fetal brain development and discuss directions for future research and intervention strategies.

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SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties

Frontiers in Immunology ◽

10.3389/fimmu.2020.622598 ◽

2021 ◽

Vol 11 ◽

Author(s):

Alastair Watson ◽

Jens Madsen ◽

Howard William Clark

Keyword(s):

Viral Infection ◽

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Chronic Obstructive ◽

Cell Functions ◽

Increased Risk ◽

Syncytial Virus

Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.

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Genetic Predisposition to Cervical Cancer and the Association With XRCC1 and TGFB1 Polymorphisms

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000001103 ◽

2017 ◽

Vol 27 (9) ◽

pp. 1949-1956 ◽

Cited By ~ 4

Author(s):

Najla M. Al-Harbi ◽

Sara S. Bin Judia ◽

Krishna N. Mishra ◽

Mohamed M. Shoukri ◽

Ghazi A. Alsbeih

Keyword(s):

Confidence Interval ◽

Cancer Patients ◽

Genetic Predisposition ◽

Odds Ratio ◽

Direct Sequencing ◽

Trend Test ◽

Nucleotide Polymorphisms ◽

Control Subjects ◽

Allele Dosage ◽

Increased Risk

ObjectiveCervical carcinoma (CC), a multifactorial cancer, is assumed to have a host genetic predisposition component that modulates its susceptibility in various populations. We investigated the association between CC risk in Saudi women and 6 single-nucleotide polymorphisms (SNPs) in hypothesis-driven candidate genes.MethodsA total of 545 females were included, comprising 232 CC patients and 313 age-/sex-matched control subjects. Six SNPs (CDKN1A C31A, ATM G1853A, HDM2 T309G, TGFB1 T10C, XRCC1 G399A, and XRCC3 C241T) were genotyped by direct sequencing.ResultsOf the 6 SNPs studied, TGFB1 T10C (odds ratio, 0.74; 95% confidence interval, 0.57–0.94) and XRCC1 G399A (odds ratio, 1.45; 95% confidence interval, 1.11–1.90) displayed different frequencies in cancer patients and control subjects and showed statistically significant association in univariate (P = 0.017, P = 0.005, respectively) analysis. The Cochran-Armitage trend test had confirmed the results (P = 0.027 and P = 0.006, respectively), indicating an ordering in the effect of the risk alleles in CC patients. The 2 SNPs, TGFB1 T10C and XRCC1 G399A, showed also degrees of deviation from Hardy-Weinberg equilibrium in cancer patients (P = 0.001 and P = 0.083, respectively) but not in the control subjects. Furthermore, correction for multiple testing using multivariate logistic regression to assess the joint effect of all SNPs has sustained significant statistical association (P = 0.025 and P = 0.009, respectively).ConclusionsTGFB1 T10C and XRCC1 G399A SNPs were associated with CC risk in univariate and multivariate analysis and displayed allele-dosage effects and coselection in cancer patients. Patients harboring the majority allele TGFB1 T10 (Leu) or the variant allele XRCC1 399A (Gln) have approximately 1.5-fold increased risk to develop CC. Host SNPs genotyping may provide relevant biomarkers for CC risk assessment in personalized preventive medicine.

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Immunological response of the respiratory tract in the SARS-CoV-2 infection

Coronaviruses ◽

10.2174/2666796702666210216143545 ◽

2021 ◽

Vol 02 ◽

Author(s):

Sanjiv Singh ◽

Punita Aggarwal ◽

Velayutham Ravichandiran

Keyword(s):

Immune System ◽

Respiratory Tract ◽

Viral Infections ◽

Inflammatory Responses ◽

Virus Disease ◽

Adaptive Immune System ◽

Immunological Response ◽

Immunological Responses ◽

Corona Virus ◽

Maximum Protection

: Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) is a contagious pathogen responsible for the ongoing corona virus disease 2019 (COVID-19) pandemic. The pathogenesis and immunological response of SARS-CoV-2 infection is poorly understood until now. After a person is infected by SARS-COV-2 immunity is compromised as both innate and adaptive immunity is playing a major role in the same. The host innate immune system forms the first layer of defense for protection from viral infections and initiates activation of the adaptive immune system in order to give maximum protection. In order to protect from tissue damage and diseases, the respiratory tract maintains the balance of T cell, B cell pro- and anti-inflammatory responses. In this review, we discuss the current update in our understanding of the involvement of the immune system in the antiviral defense against SARS-CoV-2. These novel insights at the respiratory tract immunological responses may support the future development of vaccines and immunoregulatory therapy for SARS-CoV-2 infection.

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TNFα–308G/A Polymorphism as a Risk Factor for HPV Associated Cervical Cancer in Indian Population

Analytical Cellular Pathology ◽

10.1155/2007/418247 ◽

2007 ◽

Vol 29 (3) ◽

pp. 249-256

Author(s):

Indu Kohaar ◽

Nisha Thakur ◽

Sudha Salhan ◽

Swaraj Batra ◽

Veena Singh ◽

...

Keyword(s):

Cervical Cancer ◽

Direct Sequencing ◽

Hpv Infection ◽

Genotype Distribution ◽

Nucleotide Polymorphisms ◽

Promoter Polymorphisms ◽

Hpv 16 ◽

Indian Women ◽

Control Subjects ◽

Increased Risk

Background: Investigation of the potential association of single nucleotide polymorphisms (SNPs) at –308 G/A and –238 G/A of Tumor necrosis factor α (TNFα) with susceptibility to HPV-16 associated cervical cancer in Indian women. Methods: The study included 165 histologically confirmed cases with 45 precancer and 120 cancer patients and an equal number (165) of healthy controls with normal cervical cytology. PCR-RFLP was employed to analyze TNFα promoter polymorphisms, which were confirmed by direct sequencing. Both patients and controls were screened for Human Papillomavirus (HPV) infection. Results: The frequency of –308 A allele in TNFα was significantly higher in cases compared with control subjects (21% in cases vs. 9% in controls; p < 0.01), with an odds ratio of 2.7 (95% CI = 1.41–5.15). Also, women carrying A allele for this locus presented 3 times increased susceptibility to HPV 16 infection as evident from carrier genotype distribution between HPV positive cases and control subjects (24% in HPV positive cases vs. 9% in controls; p < 0.01; OR = 3.1; 95% CI = 1.60–6.03). No such association was found for TNFα–238 (G/A) polymorphism with the risk of development of cervical cancer. Conclusion: It suggests that SNP at –308 (G/A) of TNFα promoter may represent an increased risk for HPV infection and development of cervical cancer in Indian women.

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Evaluation of the melanocortin-1-receptor gene in melanoma predisposition, progression, and recurrence

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.9018 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 9018-9018

Author(s):

S. Sidash ◽

H. Ostrer ◽

J. D. Goldberg ◽

I. Belitskaya-Levy ◽

I. V. Lobach ◽

...

Keyword(s):

Disease Progression ◽

Medical Center ◽

Direct Sequencing ◽

Receptor Gene ◽

Nucleotide Polymorphisms ◽

New York University ◽

Melanocortin 1 Receptor ◽

Increased Risk ◽

Melanoma Patients ◽

The Impact

9018 Background: The melanocortin-1-receptor (MC1R) gene is highly polymorphic in humans. Multiple studies have shown the association between MC1R allelic variants and increased risk of melanoma. Over seventy MC1R single nucleotide polymorphisms (SNPs) have been identified making MC1R a likely target for the development of genetic markers for melanoma predisposition and progression. Alleles described as R and r result in a protein with reduced function compared to wild type, with r alleles having the greatest effect. We sought to investigate the impact of MC1R genotype on risk of developing melanoma and will test for association with disease progression and recurrence in a cohort of melanoma patients enrolled in a prospective study. Methods: Our cohort includes 291 newly diagnosed melanoma patients seen at the New York University Langone Medical Center. The control cohort included 449 subjects. DNA was isolated from leukocytes and analyzed for MC1R SNP status by PCR and direct sequencing. Associations were tested for R-variant R151C and r-variants V60L and V92M. Fisher's Exact test was used to detect significant differences in allele frequency. Odds ratios and confidence intervals were computed for each SNP. Results: Allele frequencies were significantly different in cases and controls for each of the variants (p<0.01). The greatest effect was seen with V60L (Odds Ratio=6.281 95% Confidence Interval 1.77- 22.20). Conclusions: Variants that result in reduced MC1R function increase an individual's risk of developing melanoma. We will continue to test associations with additional variants and determine if these alleles also contribute to risk of disease progression and recurrence. In addition, these variants will be tested for utility as biomarkers for risk assessment of melanoma in a clinical setting. No significant financial relationships to disclose.

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