DOCSLIB.ORG

Acute-Phase Serum Amyloid a Protein and Its Implication in the Development of Type 2 Diabetes in the KORA S4/F4 Study

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Acute-Phase Serum Amyloid a Protein and Its Implication in the Development of Type 2 Diabetes in the KORA S4/F4 Study Cardiovascular and Metabolic Risk ORIGINAL ARTICLE Acute-Phase Serum Amyloid A Protein and Its Implication in the Development of Type 2 Diabetes in the KORA S4/F4 Study 1,2 6 CAROLA MARZI, MPH H.-ERICH WICHMANN, MD, PHD ype 2 diabetes is preceded by a 2,3 4,7 CORNELIA HUTH, PHD MICHAEL RODEN, MD 4 2,3 differential activation of compo- CHRISTIAN HERDER, PHD ANNETTE PETERS, PHD T 2,3 1,2 nents of the innate immune system JENS BAUMERT, PHD HARALD GRALLERT, PHD 2,3 8 (1,2). Serum amyloid A (SAA) is a sensi- BARBARA THORAND, PHD WOLFGANG KOENIG, MD 5 1,9 tive marker of the acute inflammatory WOLFGANG RATHMANN, MD THOMAS ILLIG, PHD 2,3 CHRISTA MEISINGER, MD state. Its acute-phase isoform (A-SAA) is up-regulated up to 1,000-fold in response to inflammatory stimuli such as trauma, – OBJECTIVEdWe sought to investigate whether elevated levels of acute-phase serum amyloid infection, injury, and stress (3 5). The A (A-SAA) protein precede the onset of type 2 diabetes independently of other risk factors, high inductive capacity, along with the including parameters of glucose metabolism. fact that genes and proteins are highly conserved throughout the evolution of RESEARCH DESIGN AND METHODSd Within the population-based Cooperative vertebrates and invertebrates, suggests Health Research in the Region of Augsburg (KORA) S4 study, we measured A-SAA concentrations that A-SAA plays a key role in pathogen in 836 initially nondiabetic subjects (55–74 years of age) without clinically overt inflammation who participated in a 7-year follow-up examination including an oral glucose tolerance test. defense mechanisms and probably func- tions as an effector molecule of the im- RESULTSdA-SAA concentrations were significantly associated with incident type 2 diabetes mune system (3). (odds ratio [OR] for a one-SD increase of A-SAA adjusted for age and sex = 1.28 [95% CI 1.08– Cross-sectional data have demon- 1.53], P = 0.005), particularly in younger subjects (P value for interaction = 0.047). The asso- stratedanassociationbetweenelevated ciation attenuated when adjusting for parameters of glucose metabolism (fasting glucose, fasting systemic A-SAA concentrations and prev- insulin, HbA1c, and 2-h glucose; OR 1.16 [0.95–1.42], P = 0.15). Similar analyses for high- – alent type 2 diabetes (6,7) as well as the sensitive C-reactive protein (hs-CRP) yielded the following ORs: 1.39 (1.10 1.68, P = 0.0006) related metabolic parameters homeostatic and 1.13 (0.88–1.45, P = 0.34), respectively. In contrast, A-SAA concentrations were signifi- cantly associated with 2-h glucose levels at follow-up even after adjustment for parameters of model assessment for insulin resistance, glucose metabolism (P = 0.008, n = 803). fasting insulin, and HbA1c (8,9). In a sub- group of the current study population, we CONCLUSIONSdOur findings indicate similarly strong prospective associations with type 2 have previously shown that circulating diabetes for A-SAA and hs-CRP and suggest a potential causal link via postchallenge hypergly- levels of A-SAA were increased not only cemia. in prevalent type 2 diabetes subjects but also in individuals with impaired glucose Diabetes Care 36:1321–1326, 2013 tolerance (7). To our knowledge, up until now, only one prospective study con- ducted in 492 Aboriginal Canadian sub- ccccccccccccccccccccccccccccccccccccccccccccccccc jects has investigated the association between baseline levels of SAA and incident 1 From the Department of Molecular Epidemiology, Helmholtz Zentrum Munchen,€ German Research Center type 2 diabetes and did not find evidence for Environmental Health, Neuherberg, Germany; the 2German Center for Diabetes Research (DZD), fi Neuherberg, Germany; the 3Institute of Epidemiology II, Helmholtz Zentrum Munchen,€ German Research for a signi cant association (10). Center for Environmental Health, Neuherberg, Germany; the 4Institute for Clinical Diabetology, German We set out to investigate whether el- Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Dusseldorf,€ Dusseldorf,€ evated levels of A-SAA precede the onset of Germany; the 5Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for type 2 diabetes during 7 years of follow-up € € 6 Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany; the Institute of Epi- in a large population-based study of ini- demiology I, Helmholtz Zentrum Munchen,€ German Research Center for Environmental Health, Neu- herberg, Germany; the 7Department of Metabolic Diseases, Heinrich Heine University Dusseldorf,€ tially nondiabetic, elderly Western Euro- Dusseldorf,€ Germany; the 8Department of Internal Medicine II-Cardiology, University of Ulm Medical pean subjects without clinically overt Center, Ulm, Germany; and the 9Hannover Medical School, Hannover Unified Biobank, Hannover, Ger- inflammation. Moreover, we assessed many. whether this association was independent Corresponding author: Wolfgang Koenig, [email protected]. Received 28 July 2012 and accepted 14 October 2012. of other risk factors, including parameters DOI: 10.2337/dc12-1514 of glucose metabolism (i.e., fasting glucose, This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 fasting insulin, HbA1c, and 2-h glucose), .2337/dc12-1514/-/DC1. which indicate early impairments of glu- W.K. and T.I. contributed equally to this study. © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cose homeostasis. Finally, the strength of cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ the association between A-SAA and inci- licenses/by-nc-nd/3.0/ for details. dent type 2 diabetes was compared with care.diabetesjournals.org DIABETES CARE, VOLUME 36, MAY 2013 1321 Acute-phase SAA and incident type 2 diabetes that of the most frequently used inflam- examination (n = 878) with missing data the Pearson coefficient of correlation for matory marker, circulating high-sensitive in type 2 diabetes status (n = 20) or in one normally distributed variables and the C-reactive protein (hs-CRP). of the covariables used in the different Spearman coefficient of correlation for models (n = 22) were also excluded. skewed distributed variables. Baseline RESEARCH DESIGN AND Thus, 836 subjects were included in the characteristics of subjects who developed METHODS present analyses. type 2 diabetes and those who remained diabetes free were compared using five Study population Ascertainment of type 2 diabetes different tests: 1) Pearson x2 test to test The current study included participants of and assessment of independent for independence of categorical variables the population-based Cooperative Health variables between groups, 2) Fisher exact test to Research in the Region of Augsburg Type 2 diabetes was defined on the basis of test for independence between groups (KORA) survey S4 (1999–2001; N = an OGTT according to the 1999 World with small sample sizes in categories, 3) 4,261) and its 7-year follow-up study F4 Health Organization diagnostic criteria two-sample Student t test for normally dis- (2006–2008; N = 3,080) and was conducted (11) or by a self-report, which was vali- tributed numerical variables with equal in the region of Augsburg, Southern dated using data on glucose-lowering med- variances, 4)Welcht test for normally dis- Germany. The study was approved by the ication or by questioning the attending tributed numerical variables with unequal ethics committee of the Bavarian Medical physician. At baseline, fasting EDTA variances, and 5) the Mann-Whitney U test Association, and informed written con- plasma samples were collected and A-SAA for skewed distributed numerical variables. sent was obtained from all participants. was analyzed by immunonephelometry Multivariable linear and logistic regression The selection process of study partici- on a BN II analyzer using an N Latex–en- analyses with various degrees of adjust- pants is displayed in Fig. 1. The sample hanced test (Siemens, Schwalbach, Ger- ment were performed. Interactions be- included all KORA S4 participants for many). The interassay coefficient of tween A-SAA and sex as well as A-SAA whom an oral glucose tolerance test variation was ,7% (7,12). and age were assessed by adding an inter- (OGTT) was performed at baseline (i.e., Information regarding the collection action term to the multivariable models. only the age-group between 55 and 74 of laboratory, anthropometric, and socio- Two-sided P values that were ,0.05 were years) and who were nondiabetic accord- economic variables is provided in detail considered to be statistically significant. All ing to the OGTT (n = 1,231). For the pres- elsewhere (13–16). statistical analyses were conducted using ent analyses, subjects with elevated levels SAS (version 9.2; SAS Institute, Cary, NC). of hs-CRP at baseline, which indicated an Statistical analyses acute proinflammatory state (hs-CRP A-SAA, hs-CRP, and covariables were RESULTSdBaseline characteristics .10 mg/L, n = 44), or with missing tested for normal distribution. Further- stratified by incident type 2 diabetes status A-SAA data (n = 16) were excluded. Fur- more, all numerical covariables were tested are provided in Table 1. thermore, participants in the follow-up for correlations between each other using Seven-year cumulative incidence of type 2 diabetes was 11.1% (n = 93) in our study. Circulating systemic A-SAA levels were significantly higher in 1) diabetic sub- jects (median of A-SAA levels = 4.0 mg/L [IQR 2.6–6.8 mg/L]) than in nondiabetic subjects (3.4 mg/L [2.2–5.4 mg/L], P = 0.009), 2) women (median = 3.9 mg/L [2.6–6.1 mg/L]) than in men (2.9 mg/L [2.0–4.7 mg/L], P , 0.0001), and 3)sub- jects between 65 and 74 years of age (me- dian = 3.6 mg/L [2.3–6.2 mg/L]) than in subjects between 55 and 64 years of age (3.3 mg/L [2.2–5.0 mg/L], P = 0.03).
Load more

Recommended publications
  • Influence of Serum Amyloid a (SAA1) And
    Influence of Serum Amyloid A (SAA1) and SAA2 Gene Polymorphisms on Renal Amyloidosis, and on SAA/ C-Reactive Protein Values in Patients with Familial Mediterranean Fever in the Turkish Population AYSIN BAKKALOGLU, ALI DUZOVA, SEZA OZEN, BANU BALCI, NESRIN BESBAS, REZAN TOPALOGLU, FATIH OZALTIN, and ENGIN YILMAZ ABSTRACT. Objective. To evaluate the effect of serum amyloid A (SAA) 1 and SAA2 gene polymorphisms on SAA levels and renal amyloidosis in Turkish patients with familial Mediterranean fever (FMF). Methods. SAA1 and SAA2 gene polymorphisms and SAA levels were determined in 74 patients with FMF (39 female, 35 male; median age 11.5 yrs, range 1.0–23.0). All patients were on colchicine therapy. SAA1 and SAA2 gene polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). SAA and C-reactive protein (CRP) values were measured and SAA/CRP values were calculated. Results. The median SAA level was 75 ng/ml (range 10.2–1500). SAA1 gene polymorphisms were: α/α genotype in 23 patients (31.1%), α/ß genotype in 30 patients (40.5%), α/γ genotype in one patient (1.4 %), ß/ß genotype in 14 patients (18.9%), ß/γ genotype in 5 patients (6.8 %), and γ/γ geno- type in one patient (1.4%). Of the 23 patients who had α/α genotype for the SAA1 polymorphism, 7 patients had developed renal amyloidosis (30.4%) compared to only one patient without this geno- type (1/51; 2.0%); p < 0.001. SAA2 had no effect on renal amyloidosis. SAA1 and SAA2 genotypes had no significant effect on SAA levels.
    [Show full text]
  • Mass Spectrometric Determination of the Effect of Surface Deactivation on Membranes Used for In-Situ Sampling of Cerebrospinal Fluid (CSF)
    Supplementary Materials Mass Spectrometric Determination of the Effect of Surface Deactivation on Membranes Used for In-Situ Sampling of Cerebrospinal Fluid (CSF) Torgny Undin 1, Andreas P Dahlin 2, Jonas Bergquist 1, and Sara Bergström Lind 1,* 1 Department of Chemistry-BMC, Analytical Chemistry, Uppsala University, PO Box 599, SE-751 24 Uppsala, Sweden; [email protected] (T.U.); [email protected] (J.B.) 2 Department of Engineering Sciences, Uppsala University, PO Box 534, SE-751 21 Uppsala, Sweden; [email protected] * Correspondence: [email protected]; Tel.: +46-18-4713693 Supplementary Table Table A Heat map of identified adsorbed proteins on coated membranes in group A. A time resolved map of all identified proteins that adsorbs to the surface providing deeper information about the adsorption behavior of the individual proteins compared to the more schematic Fig. 2. The three colors in the heat map indicate zero (white), one (light green) or two or more (dark green) unique peptides identified for a particular protein. A protein must be identified by two peptides at least one time point to be considered identified. Protein 15 30 60 120 240 480 Complement C3 OS=Homo sapiens GN=C3 PE=1 SV=2 - [CO3_HUMAN] 2 2 2 2 2 2 Serum albumin OS=Homo sapiens GN=ALB PE=1 SV=2 - [ALBU_HUMAN] 2 2 2 2 2 2 Coagulation factor V OS=Homo sapiens GN=F5 PE=1 SV=4 - [FA5_HUMAN] 2 2 2 2 2 2 Complement C4-A OS=Homo sapiens GN=C4A PE=1 SV=2 - [CO4A_HUMAN] 2 2 2 2 2 2 Clusterin OS=Homo sapiens GN=CLU PE=1 SV=1 - [CLUS_HUMAN] 2 2 2 2 2 2 Fibulin-1
    [Show full text]
  • Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review
    Journal of Clinical Medicine Article Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review Hélène Vergneault 1 , Alexandre Terré 1, David Buob 2,†, Camille Buffet 3 , Anael Dumont 4, Samuel Ardois 5, Léa Savey 1, Agathe Pardon 6,‡, Pierre-Antoine Michel 7, Jean-Jacques Boffa 7,†, Gilles Grateau 1,† and Sophie Georgin-Lavialle 1,*,† 1 Internal Medicine Department and National Reference Center for Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA), APHP, Tenon Hospital, Sorbonne University, 4 rue de la Chine, 75020 Paris, France; [email protected] (H.V.); [email protected] (A.T.); [email protected] (L.S.); [email protected] (G.G.) 2 Department of Pathology, APHP, Tenon Hospital, Sorbonne University, 4 rue de la Chine, 75020 Paris, France; [email protected] 3 Thyroid Pathologies and Endocrine Tumor Department, APHP, Pitié-Salpêtrière Hospital, Sorbonne University, 47-83 Boulevard de l’Hôpital, 75013 Paris, France; [email protected] 4 Department of Internal Medicine, Caen University Hospital, Avenue de la Côte de Nacre, 14000 Caen, France; [email protected] 5 Department of Internal Medecine, Rennes Medical University, 2 rue Henri le Guilloux, 35000 Rennes, France; [email protected] 6 Dialysis Center, CH Sud Francilien, 40 Avenue Serge Dassault, 91100 Corbeil-Essonnes, France; [email protected] 7 Citation: Vergneault, H.; Terré, A.; Department of Nephrology, APHP, Tenon Hospital, 4 rue de la Chine, 75020 Paris, France; [email protected] (P.-A.M.); [email protected] (J.-J.B.) Buob, D.; Buffet, C.; Dumont, A.; * Correspondence: [email protected]; Tel.: +33-156016077 Ardois, S.; Savey, L.; Pardon, A.; † Groupe de Recherche Clinique amylose AA Sorbonne Université- GRAASU.
    [Show full text]
  • The Expression of Genes Contributing to Pancreatic Adenocarcinoma Progression Is Influenced by the Respective Environment – Sagini Et Al
    The expression of genes contributing to pancreatic adenocarcinoma progression is influenced by the respective environment – Sagini et al Supplementary Figure 1: Target genes regulated by TGM2. Figure represents 24 genes regulated by TGM2, which were obtained from Ingenuity Pathway Analysis. As indicated, 9 genes (marked red) are down-regulated by TGM2. On the contrary, 15 genes (marked red) are up-regulated by TGM2. Supplementary Table 1: Functional annotations of genes from Suit2-007 cells growing in pancreatic environment Categoriesa Diseases or p-Valuec Predicted Activation Number of genesf Functions activationd Z-scoree Annotationb Cell movement Cell movement 1,56E-11 increased 2,199 LAMB3, CEACAM6, CCL20, AGR2, MUC1, CXCL1, LAMA3, LCN2, COL17A1, CXCL8, AIF1, MMP7, CEMIP, JUP, SOD2, S100A4, PDGFA, NDRG1, SGK1, IGFBP3, DDR1, IL1A, CDKN1A, NREP, SEMA3E SERPINA3, SDC4, ALPP, CX3CL1, NFKBIA, ANXA3, CDH1, CDCP1, CRYAB, TUBB2B, FOXQ1, SLPI, F3, GRINA, ITGA2, ARPIN/C15orf38- AP3S2, SPTLC1, IL10, TSC22D3, LAMC2, TCAF1, CDH3, MX1, LEP, ZC3H12A, PMP22, IL32, FAM83H, EFNA1, PATJ, CEBPB, SERPINA5, PTK6, EPHB6, JUND, TNFSF14, ERBB3, TNFRSF25, FCAR, CXCL16, HLA-A, CEACAM1, FAT1, AHR, CSF2RA, CLDN7, MAPK13, FERMT1, TCAF2, MST1R, CD99, PTP4A2, PHLDA1, DEFB1, RHOB, TNFSF15, CD44, CSF2, SERPINB5, TGM2, SRC, ITGA6, TNC, HNRNPA2B1, RHOD, SKI, KISS1, TACSTD2, GNAI2, CXCL2, NFKB2, TAGLN2, TNF, CD74, PTPRK, STAT3, ARHGAP21, VEGFA, MYH9, SAA1, F11R, PDCD4, IQGAP1, DCN, MAPK8IP3, STC1, ADAM15, LTBP2, HOOK1, CST3, EPHA1, TIMP2, LPAR2, CORO1A, CLDN3, MYO1C,
    [Show full text]
  • Human Serum Amyloid a (SAA)
    Clinical and Inflammation Research Area Human serum amyloid A (SAA) erum amyloid A recombinant SAA as well as purified endogenous apolipoprotein SAA has a tendency to aggregate and form oligomers Sfamily consists of (4-6). Presumably, the association of SAA molecules three members that in is mediated by amino acid residues located within human beings are cod- α-helix regions 1 (residues 2-8) and 3 (residues ed by different genes: 52-59) (4). SAA1, SAA2, and SAA4 (reviewed in 1-3). SAA1 The biological function of SAA and SAA2 are so-called acute phase isoforms. The biological function of SAA in inflammation is Their expression is in- unclear. It has been suggested that SAA is involved creased in response to in the recycling of cholesterol from damaged tissues. inflammation. SAA4 is It might play the role of a signaling molecule that a constitutive isoform, redirects HDL particles to activated macrophages the expression of which does not change during an and mediates the removal of stored cholesterol from acute-phase response. In addition, one more related them. Released cholesterol is then transferred to HDL gene (SAA3) has been identified, although this gene to be used again in the membranes of new cells that are is not expressed in human beings. required during acute inflammation and tissue repair (7). Besides that, published studies demonstrate Biochemical properties of SAA that recombinant SAA exhibits significant proinflammatory activity by inducing the synthesis SAA1 and SAA2 are synthesized in the liver of several cytokines and promoting chemotaxis for and secreted to the blood. When in the blood, monocytes and neutrophils in vitro (1, 8).
    [Show full text]
  • Serum Amyloid a Binds to Gibrin(Ogen), Promoting Fibrin Amyloid Formation Martin J
    University of Kentucky UKnowledge Physiology Faculty Publications Physiology 2-28-2019 Serum Amyloid A Binds to Gibrin(ogen), Promoting Fibrin Amyloid Formation Martin J. Page Stellenbosch University, South Africa Greig J. A. Thomson Stellenbosch University, South Africa J. Massimo Nunes Stellenbosch University, South Africa Anna-Mart Engelbrecht Stellenbosch University, South Africa Theo A. Nell Stellenbosch University, South Africa See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/physiology_facpub Part of the Cell and Developmental Biology Commons, and the Physiology Commons Repository Citation Page, Martin J.; Thomson, Greig J. A.; Nunes, J. Massimo; Engelbrecht, Anna-Mart; Nell, Theo A.; de Villiers, Willem J. S.; de Beer, Maria C.; Engelbrecht, Lize; Kell, Douglas B.; and Pretorius, Etheresia, "Serum Amyloid A Binds to Gibrin(ogen), Promoting Fibrin Amyloid Formation" (2019). Physiology Faculty Publications. 144. https://uknowledge.uky.edu/physiology_facpub/144 This Article is brought to you for free and open access by the Physiology at UKnowledge. It has been accepted for inclusion in Physiology Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Authors Martin J. Page, Greig J. A. Thomson, J. Massimo Nunes, Anna-Mart Engelbrecht, Theo A. Nell, Willem J. S. de Villiers, Maria C. de Beer, Lize Engelbrecht, Douglas B. Kell, and Etheresia Pretorius Serum Amyloid A Binds to Gibrin(ogen), Promoting Fibrin Amyloid Formation Notes/Citation Information Published in Scientific Reports, v. 9, article no.
    [Show full text]
  • Kidney Involvement in Systemic Calcitonin Amyloidosis Associated with Medullary Thyroid Carcinoma
    Case Report Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma Timco Koopman, MD,1 Cindy Niedlich-den Herder, MD,1 Coen A. Stegeman, MD, PhD,2 Thera P. Links, MD, PhD,3 Johan Bijzet, BSc,4 Bouke P.C. Hazenberg, MD, PhD,4 and Arjan Diepstra, MD, PhD1 A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy- associated membranous glomerulopathy and tyrosine kinase inhibitor–induced focal segmental glomerulo- sclerosis. Surprisingly, the biopsy specimen revealed diffuse glomerular deposition of amyloid that was proved to be derived from the calcitonin hormone (Acal), produced by the medullary thyroid carcinoma. This amyloid was also present in an abdominal fat pad biopsy. Although local ACal deposition is a characteristic feature of medullary thyroid carcinoma, the systemic amyloidosis involving the kidney that is presented in this case report has not to our knowledge been described previously and may be the result of long-term high plasma calcitonin levels. Our case illustrates that systemic calcitonin amyloidosis should be considered in the differential diagnosis of proteinuria in patients with medullary thyroid carcinoma. Am J Kidney Dis. -(-):---. ª 2016 by the National Kidney Foundation, Inc. INDEX WORDS: Calcitonin amyloid (ACal); medullary thyroid carcinoma; systemic amyloidosis; kidney amyloidosis; amyloid-associated glomerulopathy; nephrotic syndrome; proteinuria; decreased kidney function; renal biopsy; case report. n patients with malignant disease, the development 131iodine-metaiodobenzylguanidine, the patient was clinically I of nephrotic syndrome can be caused by mem- stable. On follow-up, clinical progression was initially slow, with branous glomerulopathy due to the deposition of an- calcitonin levels increasing steadily from 150,000 to 400,000 ng/L tibodies.
    [Show full text]
  • Serum Amyloid a Protein in Acute Viral Infections
    210 Archives ofDisease in Childhood 1993; 68: 210-214 Arch Dis Child: first published as 10.1136/adc.68.2.210 on 1 February 1993. Downloaded from Serum amyloid A protein in acute viral infections Hiroyuki Miwata, Toshiyuki Yamada, Masahiko Okada, Toyoichiro Kudo, Hiroshi Kimura, Tsuneo Morishima Abstract infections have been reported to cause weak Concentrations of serum amyloid A protein C reactive protein responses,'8 9 and increased (SAA) were measured in 254 children with C reactive protein concentrations have been viral diseases, including measles, varicella, used to distinguish bacterial from viral origins. rubella, mumps, echo-30 meningitis, chronic In this study we investigated the clinical signifi- hepatitis B and C, and in eight with Kawasaki cance of SAA in viral diseases based on the disease. following points: (1) kinetics of SAA in acute Latex agglutination nephelometric immuno- viral diseases, (2) comparisons of SAA between asay was used for assaying SAA. In 191 out of the acute and chronic viral diseases, (3) relation 195 patients (98%), SAA concentrations between SAA and C reactive protein, (4) relation became markedly raised in the acute phase of between SAA and other acute phase reactants. the viral disease: measles (97%), varicella We used the latex agglutination nephelometric (100%), mumps (95%), and echo-30 meningitis immunoassay to assay SAA as it is simple, fast, (99%) with mean titres of 82-4, 80-5, 60 2, and precise.20 We also measured SAA in patients 75-2, and 101-1 itg/mI respectively. This with Kawasaki disease, which is classified as a increase in SAA was followed by a rapid collagen vascular disease.
    [Show full text]
  • Updates in Cardiac Amyloidosis: a Review Sanjay M
    CONTEMPORARY REVIEWS Updates in Cardiac Amyloidosis: A Review Sanjay M. Banypersad, MRCP; James C. Moon, MD, MRCP; Carol Whelan, MD, MRCP; Philip N. Hawkins, PhD, FMedSci; Ashutosh D. Wechalekar, DM, MRCP, FRCPath ystemic amyloidosis is a relatively rare multisystem dis- Pathophysiology S ease caused by the deposition of misfolded protein in vari- Amyloidosis is caused by the extracellular deposition of au- ous tissues and organs. It may present to almost any specialty, tologous protein in an abnormal insoluble β-pleated sheet fib- and diagnosis is frequently delayed.1 Cardiac involvement is a rillary conformation—that is, as amyloid fibrils. More than 30 leading cause of morbidity and mortality, especially in primary proteins are known to be able to form amyloid fibrils in vivo, light chain (AL) amyloidosis and in both wild-type and hered- which cause disease by progressively damaging the structure itary transthyretin amyloidosis. The heart is also occasionally and function of affected tissues.4 Amyloid deposits also con- involved in acquired serum amyloid A type (AA) amyloidosis and tain minor nonfibrillary constituents, including serum amyloid other rare hereditary types. Clinical phenotype varies greatly P component (SAP), apolipoprotein E, connective tissue com- between different types of amyloidosis, and even the cardiac ponents (glycosaminoglycans, collagen), and basement mem- presentation has a great spectrum. The incidence of amyloi- brane components (fibronectin, laminin).3,5–8 Amyloid deposits dosis is uncertain, but it is thought that the most frequently can be massive, and cardiac or other tissues may become diagnosed AL amyloidosis has an annual incidence of 6 to 10 substantially replaced.
    [Show full text]
  • Serum Amyloid a – a Review George H
    Sack Molecular Medicine (2018) 24:46 Molecular Medicine https://doi.org/10.1186/s10020-018-0047-0 REVIEW Open Access Serum amyloid A – a review George H. Sack Jr Abstract Serum amyloid A (SAA) proteins were isolated and named over 50 years ago. They are small (104 amino acids) and have a striking relationship to the acute phase response with serum levels rising as much as 1000-fold in 24 hours. SAA proteins are encoded in a family of closely-related genes and have been remarkably conserved throughout vertebrate evolution. Amino-terminal fragments of SAA can form highly organized, insoluble fibrils that accumulate in “secondary” amyloid disease. Despite their evolutionary preservation and dynamic synthesis pattern SAA proteins have lacked well-defined physiologic roles. However, considering an array of many, often unrelated, reports now permits a more coordinated perspective. Protein studies have elucidated basic SAA structure and fibril formation. Appreciating SAA’s lipophilicity helps relate it to lipid transport and metabolism as well as atherosclerosis. SAA’s function as a cytokine-like protein has become recognized in cell-cell communicationaswellasfeedbackininflammatory, immunologic, neoplastic and protective pathways. SAA likely has a critical role in control and possibly propagation of the primordial acute phase response. Appreciating the many cellular and molecular interactions for SAA suggests possibilities for improved understanding of pathophysiology as well as treatment and disease prevention. Keywords: Serum amyloid A, SAA, inflammation, amyloidosis, acute phase response (APR), arthritis, apolipoprotein, liver, cytokine, lipopolysaccharide (LPS), myeloid-derived suppressor cells (MDSC), atherosclerosis Background Both CRP and SAA are present, but at generally quite Homeostasis is essential for most biological systems.
    [Show full text]
  • Inflammation-Dependent Cerebral Deposition of Serum Amyloid A
    The Journal of Neuroscience, July 15, 2002, 22(14):5900–5909 Inflammation-Dependent Cerebral Deposition of Serum Amyloid A Protein in a Mouse Model of Amyloidosis Jun-tao Guo,1 Jin Yu,1 David Grass,5 Frederick C. de Beer,2 and Mark S. Kindy1,3,4 Departments of 1Biochemistry and 2Internal Medicine, and 3Stroke Program of the Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, 4Veterans Affairs Medical Center, Lexington, Kentucky 40506, and 5Xenogen Corporation, Princeton, New Jersey 08540 The major pathological hallmark of amyloid diseases is the however, induction of a systemic acute-phase response in presence of extracellular amyloid deposits. Serum amyloid A transgenic mice enhanced amyloid deposition. This deposition (SAA) is an apolipoprotein primarily produced in the liver. Serum was preceded by an increase in cytokine levels in the brain, protein levels can increase one thousandfold after inflamma- suggesting that systemic inflammation may be a contributing tion. SAA is the precursor to the amyloid A protein found in factor to the development of cerebral amyloid. The nonsteroidal deposits of systemic amyloid A amyloid (AA or reactive amy- anti-inflammatory agent indomethacin reduced inflammation loid) in both mouse and human. To study the factors necessary and protected against the deposition of AA amyloid in the brain. for cerebral amyloid formation, we have created a transgenic These studies indicate that inflammation plays an important mouse that expresses the amyloidogenic mouse Saa1 protein role in the process of amyloid deposition, and inhibition of in the brain. Using the synapsin promoter to drive expression of inflammatory cascades may attenuate amyloidogenic pro- the Saa1 gene, the brains of transgenic mice expressed both cesses, such as Alzheimer’s disease.
    [Show full text]
  • Serum Amyloid a Forms Stable Oligomers That Disrupt Vesicles At
    Serum amyloid A forms stable oligomers that disrupt PNAS PLUS vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis Shobini Jayaramana,1, Donald L. Gantza, Christian Hauptb, and Olga Gurskya aDepartment of Physiology & Biophysics, Boston University School of Medicine, Boston, MA 02118; and bInstitute of Protein Biochemistry, University of Ulm, 89081 Ulm, Germany Edited by Susan Marqusee, University of California, Berkeley, CA, and approved June 29, 2017 (received for review April 28, 2017) Serum amyloid A (SAA) is an acute-phase plasma protein that functions prefibrillar oligomers with diverse structural and pathogenic fea- in innate immunity and lipid homeostasis. SAA is a protein precursor of tures (see refs. 13–15 and references therein). Such polymorphic reactive AA amyloidosis, the major complication of chronic inflamma- oligomers can exert toxicity through multiple mechanisms in- tion and one of the most common human systemic amyloid diseases cluding perforation of cell membranes (7, 13); in addition, mature worldwide. Most circulating SAA is protected from proteolysis and fibrils can mediate a range of pathological processes (16, 17). misfolding by binding to plasma high-density lipoproteins. However, Certain “on-path” oligomers can also trigger fibril formation via unbound soluble SAA is intrinsically disordered and is either rapidly the crystallization-like nucleation-growth mechanism (16, 18) in a degraded or forms amyloid in a lysosome-initiated process. Although process that can be affected by
    [Show full text]