scholarly journals Common Genetic Variants in the Complement System and their Potential Link with Disease Susceptibility and Outcome of Invasive Bacterial Infection

2019 ◽  
Vol 12 (2) ◽  
pp. 131-141 ◽  
Author(s):  
Bryan van den Broek ◽  
Michiel van der Flier ◽  
Ronald de Groot ◽  
Marien I. de Jonge ◽  
Jeroen D. Langereis
Keyword(s):  
Bacterial Infection ◽  
Complement System ◽  
Genetic Variants ◽  
Disease Susceptibility ◽  
Common Genetic Variants ◽  
Invasive Bacterial Infection ◽  
Potential Link ◽  
The Complement System

scholarly journals Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration

2021 ◽  
Vol 11 (12) ◽  
pp. 1256
Author(s):  
I. Erkin Acar ◽  
Esther Willems ◽  
Eveline Kersten ◽  
Jenneke Keizer-Garritsen ◽  
Else Kragt ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Genetic Variants ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Protein ◽  
Complement Proteins ◽  
New Associations ◽  
Age Related ◽  
The Complement System

Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The complement system has been identified as one of the main AMD disease pathways. We performed a comprehensive expression analysis of 32 complement proteins in plasma samples of 255 AMD patients and 221 control individuals using mass spectrometry-based semi-quantitative multiplex profiling. We detected significant associations of complement protein levels with age, sex and body-mass index (BMI), and potential associations of C-reactive protein, factor H related-2 (FHR-2) and collectin-11 with AMD. In addition, we confirmed previously described associations and identified new associations of AMD variants with complement levels. New associations include increased C4 levels for rs181705462 at the C2/CFB locus, decreased vitronectin (VTN) levels for rs11080055 at the TMEM97/VTN locus and decreased factor I levels for rs10033900 at the CFI locus. Finally, we detected significant associations between AMD-associated metabolites and complement proteins in plasma. The most significant complement-metabolite associations included increased high density lipoprotein (HDL) subparticle levels with decreased C3, factor H (FH) and VTN levels. The results of our study indicate that demographic factors, genetic variants and circulating metabolites are associated with complement protein components. We suggest that these factors should be considered to design personalized treatment approaches and to increase the success of clinical trials targeting the complement system.

scholarly journals Genetic variants in the complement system predisposing to age-related macular degeneration: A review

2014 ◽  
Vol 61 (2) ◽  
pp. 118-125 ◽  
Author(s):  
Elizabeth C. Schramm ◽  
Simon J. Clark ◽  
Michael P. Triebwasser ◽  
Soumya Raychaudhuri ◽  
Johanna M. Seddon ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Genetic Variants ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

Activation of the complement system is hampered in type 2 diabetes mellitus, during bacterial infection compared with controls

2018 ◽  
Vol 102 ◽  
pp. 141-142
Author(s):  
Dorottya Csuka ◽  
László Barkai ◽  
Katrine Pilely ◽  
Ráhel Dani ◽  
József Dobó ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Bacterial Infection ◽  
Complement System ◽  
The Complement System

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

Protein S and C4b-Binding Protein: Components Involved in the Regulation of the Protein C Anticoagulant System

1991 ◽  
Vol 66 (01) ◽  
pp. 049-061 ◽  
Author(s):  
Björn Dahlbäck
Keyword(s):  
Vitamin K ◽  
Complement System ◽  
Protein C ◽  
Protein S ◽  
High Affinity ◽  
Anticoagulant System ◽  
Dependent Protein ◽  
The Complement System ◽  
Β Chain ◽  
Dependent Domain

SummaryThe protein C anticoagulant system provides important control of the blood coagulation cascade. The key protein is protein C, a vitamin K-dependent zymogen which is activated to a serine protease by the thrombin-thrombomodulin complex on endothelial cells. Activated protein C functions by degrading the phospholipid-bound coagulation factors Va and VIIIa. Protein S is a cofactor in these reactions. It is a vitamin K-dependent protein with multiple domains. From the N-terminal it contains a vitamin K-dependent domain, a thrombin-sensitive region, four EGF)epidermal growth factor (EGF)-like domains and a C-terminal region homologous to the androgen binding proteins. Three different types of post-translationally modified amino acid residues are found in protein S, 11 γ-carboxy glutamic acid residues in the vitamin K-dependent domain, a β-hydroxylated aspartic acid in the first EGF-like domain and a β-hydroxylated asparagine in each of the other three EGF-like domains. The EGF-like domains contain very high affinity calcium binding sites, and calcium plays a structural and stabilising role. The importance of the anticoagulant properties of protein S is illustrated by the high incidence of thrombo-embolic events in individuals with heterozygous deficiency. Anticoagulation may not be the sole function of protein S, since both in vivo and in vitro, it forms a high affinity non-covalent complex with one of the regulatory proteins in the complement system, the C4b-binding protein (C4BP). The complexed form of protein S has no APC cofactor function. C4BP is a high molecular weight multimeric protein with a unique octopus-like structure. It is composed of seven identical α-chains and one β-chain. The α-and β-chains are linked by disulphide bridges. The cDNA cloning of the β-chain showed the α- and β-chains to be homologous and of common evolutionary origin. Both subunits are composed of multiple 60 amino acid long repeats (short complement or consensus repeats, SCR) and their genes are located in close proximity on chromosome 1, band 1q32. Available experimental data suggest the β-chain to contain the single protein S binding site on C4BP, whereas each of the α-chains contains a binding site for the complement protein, C4b. As C4BP lacking the β-chain is unable to bind protein S, the β-chain is required for protein S binding, but not for the assembly of the α-chains during biosynthesis. Protein S has a high affinity for negatively charged phospholipid membranes, and is instrumental in binding C4BP to negatively charged phospholipid. This constitutes a novel mechanism for control of the complement system on phospholipid surfaces. Recent findings have shown circulating C4BP to be involved in yet another calcium-dependent protein-protein interaction with a protein known as the serum amyloid P-component (SAP). The binding sites on C4BP for protein S and SAP are independent. SAP, which is a normal constituent in plasma and in tissue, is a so-called pentraxin being composed of 5 non-covalently bound 25 kDa subunits. It is homologous to C reactive protein (CRP) but its function is not yet known. The specific high affinity interactions between protein S, C4BP and SAP suggest the regulation of blood coagulation and that of the complement system to be closely linked.

Stimulated Glanzmann’s Thrombasthenia Platelets Produce Microvesicles

1995 ◽  
Vol 74 (06) ◽  
pp. 1533-1540 ◽  
Author(s):  
Pål André Holme ◽  
Nils Olav Solum ◽  
Frank Brosstad ◽  
Nils Egberg ◽  
Tomas L Lindahl
Keyword(s):  
Complement System ◽  
Shape Change ◽  
Annexin V ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Large Numbers ◽  
Glanzmann's Thrombasthenia ◽  
Series Of Experiments ◽  
The Complement System ◽  
Number Of Particles

SummaryThe mechanism of formation of platelet-derived microvesicles remains controversial.The aim of the present work was to study the formation of microvesicles in view of a possible involvement of the GPIIb-IIIa complex, and of exposure of negatively charged phospholipids as procoagulant material on the platelet surface. This was studied in blood from three Glanzmann’s thrombasthenia patients lacking GPIIb-IIIa and healthy blood donors. MAb FN52 against CD9 which activates the complement system and produces microvesicles due to a membrane permeabilization, ADP (9.37 μM), and the thrombin receptor agonist peptide SFLLRN (100 μM) that activates platelets via G-proteins were used as inducers. In a series of experiments platelets were also preincubated with PGE1 (20 μM). The number of liberated microvesicles, as per cent of the total number of particles (including platelets), was measured using flow cytometry with FITC conjugated antibodies against GPIIIa or GPIb. Activation of GPIIb-IIIa was detected as binding of PAC-1, and exposure of aminophospholipids as binding of annexin V. With normal donors, activation of the complement system induced a reversible PAC-1 binding during shape change. A massive binding of annexin V was seen during shape change as an irreversible process, as well as formation of large numbers of microvesicles (60.6 ±2.7%) which continued after reversal of the PAC-1 binding. Preincubation with PGE1 did not prevent binding of annexin V, nor formation of microvesicles (49.5 ± 2.7%), but abolished shape change and PAC-1 binding after complement activation. Thrombasthenic platelets behaved like normal platelets after activation of complement except for lack of PAC-1 binding (also with regard to the effect of PGE1 and microvesicle formation). Stimulation of normal platelets with 100 μM SFLLRN gave 16.3 ± 1.2% microvesicles, and strong PAC-1 and annexin V binding. After preincubation with PGE1 neither PAC-1 nor annexin V binding, nor any significant amount of microvesicles could be detected. SFLLRN activation of the thrombasthenic platelets produced a small but significant number of microvesicles (6.4 ± 0.8%). Incubation of thrombasthenic platelets with SFLLRN after preincubation with PGE1, gave results identical to those of normal platelets. ADP activation of normal platelets gave PAC-1 binding, but no significant annexin V labelling, nor production of microvesicles. Thus, different inducers of the shedding of microvesicles seem to act by different mechanisms. For all inducers there was a strong correlation between the exposure of procoagulant surface and formation of microvesicles, suggesting that the mechanism of microvesicle formation is linked to the exposure of aminophospholipids. The results also show that the GPIIb-IIIa complex is not required for formation of microvesicles after activation of the complement system, but seems to be of importance, but not absolutely required, after stimulation with SFLLRN.

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