Plasma C3 Research Articles

Uncovering the functions of plasma proteins in ulcerative colitis and identifying biomarkers for BPA-induced severe ulcerative colitis: A plasma proteome analysis

Ulcerative colitis (UC), a long-term inflammation of the colon, is a worldwide disease. Accumulating reports have suggested the contribution of environmental pollutants to UC development. As such, the identification of biomarkers to evaluate pollutant-induced UC could provide a better assessment on the world’s pollution problem. In the present study, we applied the plasma proteome to profile the plasma protein changes in three models: dextran sulfate sodium (DSS)-induced colitis, bisphenol A (BPA), and BPA-severe colitis. We aimed to investigate the functional roles of plasma proteins related to colitis development and further understand the synergistic effect of BPA on colitis. In addition, we aimed to identify novel biomarkers for UC non-invasive diagnosis and assessment of BPA-induced colitis. Our results showed a significant dysregulation of plasma proteins in these three models. Bioinformatics analysis, including gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and Ingenuity Pathway Analysis, highlighted the important effects of these dysregulated plasma proteins in immune and inflammatory responses through the regulation of CCR3 signaling in eosinophils, PI3K signaling in B lymphocytes, CD28 signaling in T helper cells, and leukocyte extravasation signaling in DSS-induced colitis model. Furthermore, our data suggested that BPA exposure altered the plasma proteins involved in lipid-related metabolic processes, leukocyte cell-cell adhesion and cytokine response. More importantly, we identified plasma proteins, ALB, APOA4, C3, CFB, DPEP1, HP, LTF, and Retnlg as biomarkers for assessing BPA-induced colitis.

A randomized diet-induced weight-loss intervention reduces plasma complement C3: Possible implication for endothelial dysfunction.

ObjectiveComplement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight‐loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction.MethodsThe study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8‐week dietary weight‐loss intervention.ResultsThe intervention significantly reduced C3 (−0.15 g/L [95% CI: −0.23 to −0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight‐loss‐induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule.ConclusionsDiet‐induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet‐induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity.

Plasma complement component 4 alterations in patients with schizophrenia before and after antipsychotic treatment.

This study was performed to investigate the plasma C4 level and the influence of antipsychotic medication in schizophrenic patients. Thirty-six schizophrenic patients were followed-up for a mean of four weeks. The plasma level of C4 in schizophrenia was significantly higher than that in healthy controls at baseline, and was significantly decreased after antipsychotic treatment. CRP at both baseline and follow-up in patients were comparable to that in healthy controls. Our findings indicate that the plasma level of C4 is increased in schizophrenia patients at the acute stage of illness and can be decreased by antipsychotic medication.

Plasma C4 level was associated with mortality, cardiovascular and cerebrovascular complications in hemodialysis patients

BackgroundPatients on maintenance hemodialysis (HD) exhibit a high risk of death, cardiovascular and cerebrovascular diseases (CCDs). Previous studies indicated complement activation associated with the increased risk of cardiovascular diseases in HD patients. This study aimed to explore whether the critical complement factors were associated with the adverse outcomes in HD patients.MethodsA total of 108 HD patients were included and followed up for 52 months. The baseline clinical characteristics and plasma C3c, C1q, CFH, CFB, C4, MAC, C5a, C3a and MBL were measured. The three endpoints were death, cardiovascular and cerebrovascular events (CCEs) and the composition of them. Univariate and multivariate Cox regression identified factors associated with the three endpoints respectively. X-tile analyses determined the optimal cut-off values for high risks. Restricted cubic spline plots illustrated the dose–response relationships. Correlations between the complement factors and risk factors for CCDs were analyzed.ResultsBaseline plasma C4 was finally selected by univariate and multivariate Cox regression analyses for three endpoints, including all-cause mortality, CCEs and the composition of them. When baseline plasma C4 exceeded 0.47 (P = 0.001) or 0.44 (P = 0.018) g/L respectively, the risks for death or achieving the composite endpoint enhanced significantly. The relationships of C4 and HR for the three endpoints showed a positive linear trend. Plasma C4 had prominent correlations with blood TG (r = 0.62, P < 0.001) and HDL (r = -0.38, P < 0.001).ConclusionsA higher baseline plasma C4 level was significantly associated with the future incidence of decease, CCEs and either of them. Plasma C4 level correlated with blood TG and HDL.

Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases.

ObjectiveCopy 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.MethodsUsing 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.ResultsA 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.ConclusionWe 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.

The clinical significance of low complement levels in patients with catastrophic antiphospholipid syndrome: A descriptive analysis of 73 patients from the "Catastrophic antiphospholipid syndrome registry".

To explore the prevalence and clinical significance of low complement levels in patients with catastrophic antiphospholipid syndrome (CAPS). We reviewed data from the "CAPS Registry" on C3 and/or C4 complement plasma protein levels during acute CAPS episodes. Patients were classified into those with low and normal complement levels. Data on clinical presentation, with special focus on thrombotic microangiopathy (TMA) features, diagnosis of systemic lupus erythematosus (SLE), and antiphospholipid antibody (aPL) profile were reviewed. The chi-square exact test was performed to evaluate differences between categorical data. The "CAPS Registry" includes 566 patients with a total of 578 episodes of CAPS. Data on complement plasma protein levels was available in 73 episodes from the same number of patients. Low levels of C3 and/or C4 complement plasma proteins were detected in 42 (58%) CAPS episodes. Low complement levels were more common in SLE patients (55% SLE vs. 19% No SLE; p<0.001). The frequencies of clinical TMA (72% vs. 80%; p=0.4) or TMA syndrome (86% vs. 84%, p=0.9), frequency of triple aPL triple positivity (67% vs 33%; p=0.3), or the mortality (35% vs. 31%; p=0.7) were similar between low and normal complement groups. In our study, low levels of C3 and C4 plasma proteins are detected in 58% episodes of CAPS, which were not associated with clinical presentation including TMA features, aPL triple positivity, or mortality.

Complement Activation Profile in Myasthenia Gravis Patients: Perspectives for Tailoring Anti-Complement Therapy.

The complement system plays a key role in myasthenia gravis (MG). Anti-complement drugs are emerging as effective therapies to treat anti-acetylcholine receptor (AChR) antibody-positive MG patients, though their usage is still limited by the high costs. Here, we searched for plasma complement proteins as indicators of complement activation status in AChR-MG patients, and potential biomarkers for tailoring anti-complement therapy in MG. Plasma was collected from AChR-MG and MuSK-MG patients, and healthy controls. Multiplex immunoassays and ELISA were used to quantify a panel of complement components (C1Q, C2, C3, C4, C5, Factor B, Factor H, MBL, and properdin) and activation products (C4b, C3b, C5a, and C5b-9), of classical, alternative and lectin pathways. C2 and C5 levels were significantly reduced, and C3, C3b, and C5a increased, in plasma of AChR-MG, but not MuSK-MG, patients compared to controls. This protein profile was indicative of complement activation. We obtained sensitivity and specificity performance results suggesting plasma C2, C3, C3b, and C5 as biomarkers for AChR-MG. Our findings reveal a plasma complement “C2, C3, C5, C3b, and C5a” profile associated with AChR-MG to be further investigated as a biomarker of complement activation status in AChR-MG patients, opening new perspectives for tailoring of anti-complement therapies to improve the disease treatment.

Complement C3-α and C3-β Levels in Synovial Fluid But Not in Blood Correlate With the Severity of Osteoarthritis Research Society International Histopathological Grades in Primary Knee Osteoarthritis

BackgroundPrimary osteoarthritis (OA) is the most common cause of knee arthritis worldwide. The knee synovial fluid complement C3-β chain levels have been shown to correlate with clinical symptoms of knee OA. It is not known whether the complement C3 in the synovial fluid is derived from the circulation or is produced locally in the knee. MethodsFifty primary OA patients undergoing a total knee arthroplasty procedure were evaluated for biochemical analyses of C3-α and C3-β chains in the synovial fluid and blood plasma. These levels were corelated with the severity of corresponding knee OA based on the Osteoarthritis Research Society International (OARSI) grade. ResultsBoth synovial C3-α and C3-β levels correlated significantly with the severity of OA. Neither plasma C3-α levels nor C3-β levels significantly correlated with OARSI grading. Neither synovial C3-α levels nor C3-β correlated significantly with plasma C3-α or C3-β levels, respectively. Synovial C3-α chain and C3-β chain levels were significantly higher in the grade >6 group. In plasma, neither C3-α chain levels nor C3-β chain levels were significantly different between the groups. Neither synovial C3-α nor C3-β levels significantly correlated with plasma erythrocyte sedimentation rate or C-reactive protein levels. ConclusionIn knee primary OA, C3 seems to be produced and released locally into the synovial fluid instead of being derived from blood in the circulation. Synovial C3 levels, but not blood plasma C3, correlate with the histopathological severity of primary OA in the knee. Synovial C3 may be an important factor in the pathogenesis of primary OA clinical symptoms and a potential target for therapeutic intervention.

Zinc supplementation in practical diets for pond-raised hybrid snakehead (Channa maculate ♀ × Channa argus ♂) fingerlings: Effects on performance, mineral retention and health

Zinc (Zn) is an essential micromineral for fishes and is closely related to many biochemical processes. This study was designed to determine the effects of dietary Zn supplied in practical diets on the pond-raised hybrid snakehead (Channa maculate ♀ × C. argus ♂). Five extruded diets were supplemented with different Zn sulfate levels (analysed Zn values: 42.33, 65.79, 82.27, 100.41, and 120.18 mg kg-1). A total of 900 fish (initial weight 3.33 g) were divided into three net cages per treatment and fed twice daily to apparent satiety. The results indicated that dietary Zn influenced growth parameters, antioxidant capacity and innate immunity. The moisture and crude lipid contents of the whole body were significantly affected by dietary Zn concentration (P < 0.05). The whole-body, hepatic, and vertebral Zn concentrations were not significantly affected by dietary Zn level (P > 0.05). However, copper (Cu) content in the whole body, vertebrae, and liver increased and then decreased as dietary Zn increased (P < 0.05). The content of whole body Zn was significantly positively correlated with whole-body Fe, Mn (P < 0.01) and liver Cu (P < 0.05), and negatively correlated with whole-body Cu (P < 0.01). The content of liver Zn was positively correlated with liver Cu, Mn (P < 0.01), liver and whole body Fe (P < 0.05). Dietary Zn supplementation mitigated the generation of free radicals and improved the antioxidant capacity of hybrid snakehead. Plasma immune parameter activity and innate immune ability were both enhanced by appropriate dietary Zn levels. Liver Zn level was positively correlated with plasma C3 and TP (P < 0.05). Regression analysis of feed utilization, antioxidant and innate immunity parameters indicated that the optimum zinc concentration in a practical diet for fingerlings hybrid snakeheads ranged from 81.94 to 101.05 mg kg-1.

Elevated levels of C3, C4, and CH50 of the complement system in ICU and non-ICU patients with COVID-19.

PurposeSARS‐CoV‐2 infection has spread in each corner of the world. Many health systems have dealt with it intensively. The complement system is an instrumental component in the inflammatory immune response and plays a role in the activation of blood coagulation. Our understanding of the pathophysiology of SARS‐CoV‐2 is still limited but is constantly expanding. This study aimed to determine changes in the complement system in intensive care unit (ICU) and non‐ICU patients with COVID‐19.MethodsIn a cross‐sectional study, plasma levels of C3, C4, and CH50 were determined in two groups of ICU and non‐ICU patients with COVID‐19 to understand the potential effects of SARS‐CoV‐2 on the innate immune system. The assays of C3 and C4 were conducted using turbidimetry method. The CH50 test was conducted using the functional method.ResultsThe present study revealed that the C3, C4, and CH50 plasma levels were 142.48 ± 30.38 mg/dL, 32.58 ± 8.78 mg/dL, and 61.74 ± 19.54%, respectively. These results indicate high levels of complement components C3 and C4 and complement function (CH50) in patients with COVID‐19 than normal ranges. Plasma levels of C3, C4, and CH50 were higher in ICU patients than in non‐ICU COVID‐19 groups.ConclusionThese results indicate that the innate immune system was activated in both ICU and non‐ICU patients in response to SARS‐CoV‐2 infection. Further studies with a larger number of COVID‐19 patients and additional testing of complement components (C3a and C5a) may reveal the role of COVID‐19 infection in the activation of the complement system.

Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.

Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.

Complement Protein Levels Decrease with Tumour Severity in Pancreatic Ductal Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis and is resistant to various treatments including immunotherapy. The complement system is a major component of innate immunity and plays a major role in immunosurveillance and homeostasis although pancreatic cancer hijacks the innate immune response to evade detection. Despite advances, immunotherapy is still ineffective in PDAC treatment. This study aimed to elucidate the expression of complement proteins, C3 and C5, in South African PDAC patients. Methods: Following ethical approval (Ethics-M190734), twenty-five confirmed PDAC patients, 6 chronic pancreatitis, and 3 healthy controls were recruited and ELISA performed. Statistical analysis was conducted (Statistica V13.5), reported as mean±SEM, with p<0.05 considered as significant. Furthermore, we interrogated online databases (GENT2 & COSMIC V.92) to observe expression and mutation data of C3 and C5 for comparison purposes. Results: C3 plasma levels decreased in locally-advanced and metastatic disease 0.71±0.15μg/mL) compared to resectable cancer (0.97±0.09μg/mL;p<0.05). C5 was lower in healthy controls compared to patients with pancreatic cancer (p<0.05) and correlated with the inflammatory marker, C-reactive protein (CRP; p=0.0098). online databases showed both C3 and C5 were overexpressed in pancreatic tumours compared to normal tissues. Missense mutations were the most commonly occurring mutations in both C3 and C5 in PDAC. Conclusion: The decrease in C3 with disease severity in PDAC may indicate the loss of innate immune response and thus a compromised immunity. The correlation of C5 with CRP may imply potential roles in inflammation that might affect immune response, however, this needs to be further investigated.

Long‑term follow‑up of a case of recurrent angioedema due to acquired C1‑inhibitor deficiency – clinical and therapeutic aspects

Angioedema (AE) is a frequent pathology in medical practice, raising significant diagnostic and therapeutic problems. Angioedema due to acquired C1-inhibitor esterase (C1-INH) deficiency is a rare form of AE without urticaria, with life-threatening potential outcome, often associated with lymphoproliferative or autoimmune diseases. We report the long-term outcome of an 80-year-old female patient, diagnosed in 2014 with AE due to acquired C1-INH deficiency, with good response to attenuated androgens, who has been constantly monitored in our clinic for 12 years. The onset of AE attacks was six years before diagnosis confirmation, and was considered first induced by angiotensin-converting enzyme inhibitors (ACEIs) therapy, but she continued to have AE attacks after the discontinuation of ACEI. No underlying disease could be identified, despite extended medical evaluation. AE episodes stopped after the initiation of treatment with danazol in September 2014 and the C1-INH and C4 plasma levels became normal after one month. We have closely monitored the possible side effects of danazol and the occurrence of other clinical and laboratory manifestations. Danazol therapy was well tolerated and we could not find any causal disease for the C1-INH deficiency. During the last three years, moderate blood hypereosinophilia was recorded, with no clinical manifestations and clear cause, still under investigation.

Alterations of Plasma Galectin-3 and C3 Levels in Patients with Parkinson's Disease.

Parkinson’s disease (PD) is characterized by progressive neurodegeneration of dopaminergic neurons in the ventral midbrain. The complement-phagosome pathway is involved in the pathogenesis of PD. Here we measured levels of complement-phagocytosis molecules, including galectin-3, C3, C4, and cathepsin D, in the plasma of 56 patients with PD, and 46 normal controls (NCs). Plasma levels of galectin-3 (9.93 ± 3.94 ng/mL) were significantly higher in PD patients compared with NCs (8.39 ± 1.95 ng/mL, p = 0.012), and demonstrated a positive correlation with Hoehn and Yahr stages in PD patients (R2 = 0.218, p < 0.001). On the other hand, plasma C3 levels were significantly lower in PD patients (305.27 ± 205.16 μg/mL) compared with NCs (444.34 ± 245.54 μg/mL, p = 0.002). However, the levels did not correlate with Hoehn and Yahr stages (R2 = 0.010, p = 0.469). Plasma levels of C4 and cathepsin D in PD patients were similar to those in NCs. Our results show possible altered complement-phagocytosis signals in the peripheral blood of PD patients, highlighting the potential of galectin-3 as a biomarker of PD.

Pantothenate kinase activation relieves coenzyme A sequestration and improves mitochondrial function in mice with propionic acidemia.

Propionic acidemia (PA) is a rare autosomal-recessive metabolic disease that arises from mutations in propionyl-CoA (C3-CoA) carboxylase. Reduced enzyme activity slows C3-CoA metabolism, leading to an elevated plasma C3:C2-carnitine ratio, the hallmark biomarker of PA. The metabolic imbalances experienced in PA are however poorly defined. Here, we used a hypomorphic PA mouse model to demonstrate that C3-CoA accumulation in liver reduced non-esterified CoA (CoASH) and acetyl-CoA (C2-CoA). Tricarboxylic acid (TCA) cycle intermediates that are normally metabolized instead accumulated in urine, providing direct evidence for compromised mitochondrial function in PA. Pantothenate kinase (PanK) is known to catalyze the rate-controlling step in CoA biosynthesis, and its inhibition by C3-CoA prevents an increase in CoA biosynthesis to alleviate CoASH sequestration. PZ-3022 is an allosteric PanK activator that counteracts C3-CoA inhibition. PZ-3022 therapy increased hepatic CoASH and C2-CoA and decreased C3-CoA in the PA mouse model, leading to improved intracellular C3:C2-CoA and plasma C3:C2-carnitine ratios. Elevated urinary malate is a major component of the metabolic signature for TCA cycle dysfunction in the PA mouse, and the 80% reduction in urine malate by PZ-3022 therapy indicates the restoration of mitochondrial function. Thus, CoASH sequestration in PA leads to reduced TCA cycle activity that is relieved by PZ-3022, providing preclinical proof of concept for PanK activators as a therapy to attenuate the underlying mitochondrial defect in PA.

A Conformational Change of Complement C5 Is Required for Thrombin-Mediated Cleavage, Revealed by a Novel Ex Vivo Human Whole Blood Model Preserving Full Thrombin Activity.

Thrombin activation of C5 connects thrombosis to inflammation. Complement research in whole blood ex vivo necessitates anticoagulation, which potentially interferes with the inflammatory modulation by thrombin. We challenged the concept of thrombin as an activator of native C5 by analyzing complement activation and C5 cleavage in human whole blood anticoagulated with Gly-Pro-Arg-Pro (GPRP), a peptide targeting fibrin polymerization downstream of thrombin, allowing complete endogenous thrombin generation. GPRP dose-dependently inhibited coagulation but allowed for platelet activation in accordance with thrombin generation. Spontaneous and bacterial-induced complement activation by Escherichia coli and Staphylococcus aureus, analyzed at the level of C3 and C5, were similar in blood anticoagulated with GPRP and the thrombin inhibitor lepirudin. In the GPRP model, endogenous thrombin, even at supra-physiologic concentrations, did not cleave native C5, despite efficiently cleaving commercially sourced purified C5 protein, both in buffer and when added to C5-deficient serum. In normal serum, only exogenously added, commercially sourced C5 was cleaved, whereas the native plasma C5 remained intact. Crucially, affinity-purified C5, eluted under mild conditions using an MgCl2 solution, was not cleaved by thrombin. Acidification of plasma to pH ≤ 6.8 by hydrochloric or lactic acid induced a C5 antigenic change, nonreversible by pH neutralization, that permitted cleavage by thrombin. Circular dichroism on purified C5 confirmed the structural change during acidification. Thus, we propose that pH-induced conformational change allows thrombin-mediated cleavage of C5 and that, contrary to previous reports, thrombin does not cleave plasma C5 in its native form, suggesting that thrombin cleavage of C5 may be restricted to certain pathophysiological conditions.

C3 and C4 complement levels in AQP4-IgG-positive NMOSD and in MOGAD

While complement-dependent cytotoxicity (CDC) is a known effector mechanism in aquaporin-4-immunoglobulin (Ig)G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD), the role of CDC in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear. We determined complement C3 and C4 plasma concentrations in patients with clinically stable AQP4-IgG+ NMOSD (n = 16), MOGAD (n = 15), early multiple sclerosis (MS, n = 19) and in healthy controls (HC, n = 18). C4 was lower in AQP4-IgG+ NMOSD than in MOGAD, MS and HC (p < 0.05, pairwise comparisons). C3 was lower in AQP4-IgG+ NMOSD than in MS (p = 0.034). These findings suggest subtle complement consumption in clinically stable AQP4-IgG+ NMOSD, but not in MOGAD.

Elevated plasma concentration of complement factor C5 is associated with risk of future venous thromboembolism

AbstractThe role of complement in the pathogenesis of venous thromboembolism (VTE) is unclear. We wanted to investigate (1) whether plasma complement component C5 (C5) levels are influenced by genetic variants or chronic inflammation and (2) the association between plasma C5 and risk of future VTE in a nested case-control study of 415 patients with VTE and 848 age- and sex-matched controls derived from the Tromsø Study. Plasma C5 levels were measured at inclusion. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for provoked and unprovoked VTE across tertiles of C5 concentrations were estimated by logistic regression. Adjustment for C-reactive protein (CRP) served as a proxy for general inflammation. Whole-exome sequencing and protein quantitative trait loci analyses were performed to assess genetic influence on C5 concentrations. There was no association between genome-wide or C5-related gene variants and C5 levels. The association between plasma C5 levels and VTE risk displayed a threshold effect, where subjects with C5 levels above the lowest tertile had increased risk of VTE. Subjects in tertile 3 (highest C5 levels) had an age- and sex-adjusted OR of 1.45 (95% CI, 1.07-1.96) compared with tertile 1 (lowest). These statistics were more pronounced for unprovoked VTE (OR, 1.70; 95% CI, 1.11-2.60). Adjustments for body mass index and CRP had minor impact on risk estimates. The OR increased substantially with shorter time between blood sampling and VTE event. In conclusion, plasma C5 was associated with risk of future VTE. C5 levels were not genetically regulated and were only slightly influenced by chronic inflammation.

Medical Records-Based Genetic Studies of the Complement System.

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. 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. In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; β=0.20; 95% CI, 0.14 to 0.25; P=1.52x10-11) and chr.19p13.3 (C3 locus; rs11569470-G; β=0.19; 95% CI, 0.13 to 0.24; P=1.29x10-8). 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; β=0.40; 95% CI, 0.34 to 0.45; P=4.58x10-35). 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 (β=-0.36; 95% CI, -0.42 to -0.30; P=2.98x10-22) and C4-AL-BS (β=0.25; 95% CI, 0.21 to 0.29; P=8.11x10-23). 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. 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.

No Evident Systemic Terminal Complement Pathway Activation in Hidradenitis Suppurativa

No Evident Systemic Terminal Complement Pathway Activation in Hidradenitis Suppurativa