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Journal of the American Society of... Aug 2021Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement...
BACKGROUND
Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts.
METHODS
We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network.
RESULTS
In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; =0.20; 95% CI, 0.14 to 0.25; =1.52x10) and chr.19p13.3 (C3 locus; rs11569470-G; =0.19; 95% CI, 0.13 to 0.24; =1.29x10). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; =0.40; 95% CI, 0.34 to 0.45; =4.58x10). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS (=-0.36; 95% CI, -0.42 to -0.30; =2.98x10) and C4-AL-BS (=0.25; 95% CI, 0.21 to 0.29; =8.11x10). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation.
CONCLUSIONS
We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans.
Topics: Adult; Aged; Alleles; Complement Activation; Complement C3; Complement C4; Databases, Genetic; Epidemiologic Studies; Female; Gene Dosage; Genetic Loci; Genetic Variation; Genome-Wide Association Study; Humans; Male; Medical Record Linkage; Medical Records; Middle Aged; Young Adult
PubMed: 33941608
DOI: 10.1681/ASN.2020091371 -
Orphanet Journal of Rare Diseases Jan 2020C3 hypocomplementemia and the presence of C3 nephritic factor (C3NeF), an autoantibody causing complement system over-activation, are common features among most patients...
BACKGROUND
C3 hypocomplementemia and the presence of C3 nephritic factor (C3NeF), an autoantibody causing complement system over-activation, are common features among most patients affected by Barraquer-Simons syndrome (BSS), an acquired form of partial lipodystrophy. Moreover, BSS is frequently associated with autoimmune diseases. However, the relationship between complement system dysregulation and BSS remains to be fully elucidated. The aim of this study was to provide a comprehensive immunological analysis of the complement system status, autoantibody signatures and HLA profile in BSS. Thirteen subjects with BSS were recruited for the study. The circulating levels of complement components, C3, C4, Factor B (FB) and Properdin (P), as well as an extended autoantibody profile including autoantibodies targeting complement components and regulators were assessed in serum. Additionally, HLA genotyping was carried out using DNA extracted from peripheral blood mononuclear cells.
RESULTS
C3, C4 and FB levels were significantly reduced in patients with BSS as compared with healthy subjects. C3NeF was the most frequently found autoantibody (69.2% of cases), followed by anti-C3 (38.5%), and anti-P and anti-FB (30.8% each). Clinical data showed high prevalence of autoimmune diseases (38.5%), the majority of patients (61.5%) being positive for at least one of the autoantibodies tested. The HLA allele DRB1*11 was present in 54% of BSS patients, and the majority of them (31%) were positive for *11:03 (vs 1.3% in the general population).
CONCLUSIONS
Our results confirmed the association between BSS, autoimmunity and C3 hypocomplementemia. Moreover, the finding of autoantibodies targeting complement system proteins points to complement dysregulation as a central pathological event in the development of BSS.
Topics: Adolescent; Adult; Aged; Autoimmunity; Child; Complement C3; Complement C3 Nephritic Factor; Complement C4; Complement Factor B; Female; Humans; Lipodystrophy; Male; Middle Aged; Properdin; Young Adult
PubMed: 31924231
DOI: 10.1186/s13023-019-1292-1 -
Brain, Behavior, and Immunity Mar 2024Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse...
Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications.
Topics: Humans; Schizophrenia; Complement C1q; Psychotic Disorders; Antipsychotic Agents; RNA, Messenger
PubMed: 38301948
DOI: 10.1016/j.bbi.2024.01.219 -
Journal of Clinical Laboratory Analysis May 2020The prognostic role of complement C3 and C4 in peripheral blood in early stage of acute pancreatitis (AP) is unknown. In this study, we aimed to evaluate the prognostic...
OBJECTIVE
The prognostic role of complement C3 and C4 in peripheral blood in early stage of acute pancreatitis (AP) is unknown. In this study, we aimed to evaluate the prognostic value of C3 and C4 in early stage of AP.
METHODS
A total of 164 patients were enrolled in this study. The blood samples were collected within 24 hours after AP onset. We compared C3 and C4 levels in patients with different AP severity. The optimal cutoff value for them to predict severe AP (SAP) was determined by receiver operating characteristic (ROC) curve analysis.
RESULTS
The reduction of C3 and C4 levels was observed. For prediction of MSAP and SAP, the AUC of C3 and C4 levels was 0.695 (95% CI: 0.612-0.779) and 0.739 (95% CI: 0.657-0.821). The cutoff value of C3 and C4 levels was 0.705 and 0.145 g/L, with the sensitivity of 0.612 and 0.735, and the specificity of 0.735 and 0.710. For prediction of SAP, the AUC of C3 and C4 levels was 0.749 (95% CI: 0.607-0.891) and 0.766 (95% CI: 0.596-0.936). The cutoff value of C3 and C4 levels was 0.400 and 0.125 g/L, with the sensitivity of 0.859 and 0.767, and the specificity of 0.600 and 0.786.
CONCLUSIONS
A marked change of complement C3 and C4 was observed in peripheral blood of patients with AP, suggesting the participation of complement system in the early phase of AP. C3 and C4 levels were sensitive and accurate in judging the severity of AP.
Topics: Adult; Aged; Biomarkers; Complement C3; Complement C4; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Pancreatitis; ROC Curve
PubMed: 32187754
DOI: 10.1002/jcla.23205 -
Scientific Reports May 2023Triple-negative breast cancer (TNBC) subtype is characterized by aggressive clinical behavior and poor prognosis patient outcomes. Here, we show that ADAR1 is more...
Triple-negative breast cancer (TNBC) subtype is characterized by aggressive clinical behavior and poor prognosis patient outcomes. Here, we show that ADAR1 is more abundantly expressed in infiltrating breast cancer (BC) tumors than in benign tumors. Further, ADAR1 protein expression is higher in aggressive BC cells (MDA-MB-231). Moreover, we identify a novel interacting partners proteins list with ADAR1 in MDA-MB-231, using immunoprecipitation assay and mass spectrometry. Using iLoop, a protein-protein interaction prediction server based on structural features, five proteins with high iloop scores were discovered: Histone H2A.V, Kynureninase (KYNU), 40S ribosomal protein SA, Complement C4-A, and Nebulin (ranged between 0.6 and 0.8). In silico analysis showed that invasive ductal carcinomas had the highest level of KYNU gene expression than the other classifications (p < 0.0001). Moreover, KYNU mRNA expression was shown to be considerably higher in TNBC patients (p < 0.0001) and associated with poor patient outcomes with a high-risk value. Importantly, we found an interaction between ADAR1 and KYNU in the more aggressive BC cells. Altogether, these results propose a new ADAR-KYNU interaction as potential therapeutic targeted therapy in aggressive BC.
Topics: Humans; Aggression; Breast; Complement C4; Histones; Triple Negative Breast Neoplasms; Adenosine Deaminase; RNA-Binding Proteins
PubMed: 37221310
DOI: 10.1038/s41598-023-35517-6 -
Acta Neuropathologica Communications Jul 2021Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is...
Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.
Topics: Animals; Brain; Brain Injuries, Traumatic; Brain Injury, Chronic; Complement Activation; Complement C2; Complement C3; Complement C4; Complement Inactivating Agents; Gene Expression Profiling; Mice; Neuroinflammatory Diseases; Recombinant Fusion Proteins; Transcriptome
PubMed: 34281628
DOI: 10.1186/s40478-021-01226-2 -
Human Genomics Jun 2015Membrane cofactor protein (MCP; CD46) is an ubiquitously expressed complement regulatory protein that protects host cells from injury by complement. This type-I membrane... (Review)
Review
Membrane cofactor protein (MCP; CD46) is an ubiquitously expressed complement regulatory protein that protects host cells from injury by complement. This type-I membrane glycoprotein serves as a cofactor for the serine protease factor I to mediate inactivation of C3b and C4b deposited on host cells. More than 60 disease-associated mutations in MCP have now been identified. The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified. This review summarizes our current knowledge of disease-associated mutations in this complement inhibitor.
Topics: Complement C3b; Complement C4b; Female; Glomerulonephritis; Humans; Lupus Erythematosus, Systemic; Membrane Cofactor Protein; Mutation; Pregnancy; Pregnancy Complications
PubMed: 26054645
DOI: 10.1186/s40246-015-0029-z -
Clinical Proteomics Dec 2022Recurrent spontaneous abortion (RSA) is a common and complicated pregnancy-related disease that lacks a suitable biomarker to predict its recrudescence.
BACKGROUND
Recurrent spontaneous abortion (RSA) is a common and complicated pregnancy-related disease that lacks a suitable biomarker to predict its recrudescence.
METHODS
Tandem mass tag (TMT) analysis was conducted to obtain quantitative proteomic profiles in follicular fluid from patients with a history of RSA and from control group. ELISA validation of candidate differentially expressed proteins was conducted in a larger group of patients.
RESULTS
A total of 836 proteins were identified by TMT analysis; 51 were upregulated and 47 were downregulated in follicular fluid from cases of RSA versus control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed several important pathways were enriched, involving a dysregulated immunoglobulin Fc receptor signaling pathway and overactivated complement cascade pathways. ELISA validated the differential expression of two proteins, histidine-rich globulin (HRG) and complement C4-B (C4B), which were downregulated and upregulated, respectively, in follicular fluid of patients with RSA. We performed receiver operating characteristic curve analysis of the ELISA results with the outcomes of current IVF cycles as classification variables. The area under the curve results for HRG alone, C4B alone and HRG-C4B combined were 0.785, 0.710 and 0.895, respectively.
CONCLUSIONS
TMT analysis identified 98 differentially expressed proteins in follicular fluid from patients with RSA, indicating follicle factors that act as early warning factors for the occurrence of RSA. Among them, HRG and C4B provide candidate markers to predict the clinical outcomes of IVF/ICSI cycles, and the potential for modeling an early detection system for RSA.
PubMed: 36528562
DOI: 10.1186/s12014-022-09383-9 -
Arthritis & Rheumatology (Hoboken, N.J.) Aug 2022Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to...
OBJECTIVE
Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis.
METHODS
Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls.
RESULTS
A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes.
CONCLUSION
We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
Topics: Autoantibodies; Complement C4; Complement C4b; DNA Copy Number Variations; Humans; Lupus Erythematosus, Systemic; Myositis; Risk Factors
PubMed: 35315244
DOI: 10.1002/art.42122 -
Neurobiology of Disease Feb 2020The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of... (Review)
Review
The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of diseases. For complex brain disorders such as schizophrenia, understanding the cellular and molecular pathways that intersect the bidirectional gut-brain axis is anticipated to lead to new methods of treatment. The means by which the microbiome might differ across neuropsychiatric and neurological disorders are not known. Brain disorders as diverse as schizophrenia, major depression, Parkinson's disease and multiple sclerosis appear to share a common pathology of an imbalanced community of commensal microbiota, often measured in terms of a leaky gut phenotype accompanied by low level systemic inflammation. While environmental factors associated with these disease states might contribute to intestinal pathologies, products from a perturbed microbiome may also directly promote specific signs, symptoms and etiologies of individual disorders. We hypothesize that in schizophrenia, it is the putatively unique susceptibility related to genes that modulate the immune system and the gut-brain pleiotropy of these genes which leads to a particularly neuropathological response when challenged by a microbiome in dysbiosis. Consequences from exposure to this dysbiosis may occur during pre- or post-natal time periods and thus may interfere with normal neurodevelopment in those who are genetically predisposed. Here, we review the evidence from the literature which supports the idea that the intersection of the microbiome and immune gene susceptibility in schizophrenia is relevant etiologically and for disease progression. Figuring prominently at both ends of the gut-brain axis and at points in between are proteins encoded by genes found in the major histocompatibility complex (MHC), including select MHC as well as non-MHC complement pathway genes.
Topics: Brain; Dysbiosis; Humans; Inflammation; Microbiota; Nervous System Diseases; Schizophrenia
PubMed: 30471416
DOI: 10.1016/j.nbd.2018.11.016