Disease relevance of SAA1

• A stepwise logistic-regression analysis showed that the SAA1alpha/alpha genotype was associated with a sevenfold increased risk for renal amyloidosis, compared with other SAA1 genotypes (odds ratio [OR] 6. 9; 95% confidence interval [CI] 2.5-19.0) [1].
• In particular, the amino acid substitution (Thr to Phe) at residue 69 of SAA1 may have an important role in this type of hereditary amyloidosis [2].
• Here, we establish that the qualitative and kinetic aspects of SAA1 and SAA2 transcription following treatment of HepG2 hepatoma cells and KB epithelial cells with glucocorticoids and cytokines are quite distinct [3].
• RT-PCR analysis confirmed the expression of the SAA1 and SAA4 genes in colon carcinomas, expression that was barely detectable in normal colon tissues [4].
• The cystic fibrosis AA protein represents a product of the SAA-specific cDNA clone now known to be the alpha-allelic form of SAA1 in which valine is present at position 52 and alanine is at position 57 [5].

Psychiatry related information on SAA1

• Among others, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, serum amyloid A (SAA), and white blood cells (WBC) were measured, and dietary habits (including fish consumption) were evaluated using a validated food frequency questionnaire [6].
• The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without posttraumatic stress disorder [7].
• We assessed the relationship between self-reported physical activity status and inflammatory, and coagulation markers [i.e., C-reactive protein (CRP), serum amyloid-A (SAA), interleukin (IL)-6, tumour necrosis factor (TNF)-alpha, white blood cell (WBC) counts, and fibrinogen (FIB)], after taking into account the effect of several confounders [8].
• Serum amyloid A protein, albumin and prealbumin in Alzheimer's disease and in demented patients with Down's syndrome [9].

High impact information on SAA1

• C-reactive protein and serum amyloid A protein in unstable angina [10].
• In contrast, no deaths or myocardial infarction occurred among the 11 patients with levels of C-reactive protein and serum amyloid A protein < 0.3 mg per deciliter, and only 2 of them required coronary revascularization [11].
• The amino-terminal sequences of the 14- and 12-kilodalton species were approximately 60 to 80 percent homologous with serum amyloid A and beta 2 microglobulin, respectively [12].
• Serum amyloid A is a chemoattractant: induction of migration, adhesion, and tissue infiltration of monocytes and polymorphonuclear leukocytes [13].
• The two major SAA polymorphs, designated SAA4 and SAA5 according to their order of elution from DEAE-cellulose, had different NH2-terminal sequences [14].

Chemical compound and disease context of SAA1

• METHODS: Serum amyloid A measurement and a rapid cTnT assay were performed on blood obtained at enrollment into Thrombolysis in Myocardial Infarction 11A, a dose-ranging trial of enoxaparin for unstable angina and NQMI [15].
• METHODS AND RESULTS: We measured plasma levels of CRP, serum amyloid A protein (SAA), fibrinogen, total cholesterol, and Helicobacter pylori and Chlamydia pneumoniae antibody titers in 53 patients admitted to our coronary care unit for Braunwald class IIIB unstable angina [16].
• Not only did MDL-A markedly inhibit IL-6- and IL-11-induced osteoclastogenesis in vitro, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis in vivo by a different mechanism from that of 17beta-estradiol [17].
• Amyloidosis and the serum amyloid A protein response to muramyl dipeptide analogs and different mycobacterial species [18].
• Serum amyloid A and high density lipoprotein (HDL) interrelationships were evaluated in 11 normal men during an acute phase response induced by the inflammatory steroid etiocholanolone [19].

Biological context of SAA1

• A comparison of the nucleotide and deduced amino acid sequences of SAA1 cDNA with that of SAA2 cDNA showed a high degree of homology: 95% nucleotide sequence homology in the coding region (91% amino acid sequence homology) and 90% homology in the 3' untranslated region [20].
• The SAA1 gamma [Ala52(GCC), Ala57(GCG)] differed from SAA1 alpha [Val52(GTC), Ala57(GCG)] only at one base, indicating a single point mutation [21].
• The finding of a NF kappa B binding site within the 66-bp cytokine-responsive fragment further suggests its functional importance in the regulation of SAA1 gene expression [22].
• Since the linkage disequilibrium relationship was reversed between the Japanese and Caucasoid populations, different exon 3 haplotypes of SAA1 are found to be associated with the risk of AA amyloidosis in different ethnic groups [23].
• RESULTS: We observed 3 novel single-nucleotide polymorphisms (SNPs) in the 5'-flanking region of SAA1: -61C/G, -13T/C, and -2G/A [23].

Anatomical context of SAA1

• We have shown that when 304 bp of 5' flanking region of the rat SAA1 gene is fused to a reporter gene, the chloramphenicol acetyltransferase (CAT) gene, CAT activity is induced in a cell-specific manner in response to conditioned media prepared from activated mixed lymphocyte cultures and recombinant interleukin-1 [24].
• The effects of glucocorticoids on SAA1 in both cell lines is glucocorticoid receptor-dependent [3].
• In contrast, untreated KB cells constitutively express SAA1 mRNA [3].
• Here we report the identification of a 29-bp regulatory element that possesses inhibitory activities on SAA1 promoter in HeLa cells but has no such effects in liver cells [25].
• The expression of SAA1 and SAA2 was also detected in irradiated cells of human bone marrow stromal cell lines in vitro [26].

Associations of SAA1 with chemical compounds

• The application of the synthetic glucocorticoid dexamethasone in the context of cytokine stimulation enhanced the transcriptional activity of the SAA1, but not the SAA2, promoter such that readout from the former became equivalent to that from the latter [27].
• Mink SAA1 has alanine in position 10, isoleucine in positions 24, 67, and 71, lysine in position 27, and proline in position 105 [28].
• To study the cis- and trans-activating promoter element involved in the SAA1 gene expression by HASMCs and HepG2 cells, we constructed plasmid vectors for luciferase reporter gene assay with varying lengths of SAA1 upstream regulatory region (up to 1431 bp), and examined their response to proinflammatory cytokines and/or steroid hormones [29].
• Two of these, SAA1 and SAA4, have the same 20 NH2-terminal residues despite striking differences in electrophoretic mobility and solution properties [30].
• In addition, SAA protects RA FLS against the apoptotic death induced by serum starvation, anti-Fas IgM, and sodium nitroprusside [31].

Physical interactions of SAA1

• Serum amyloid A binds specific extracellular matrix glycoproteins and induces the adhesion of resting CD4+ T cells [32].
• Expression of recombinant human serum amyloid A in mammalian cells and demonstration of the region necessary for high-density lipoprotein binding and amyloid fibril formation by site-directed mutagenesis [33].

Regulatory relationships of SAA1

• Serum amyloid A (apoSAA) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases [34].
• A-SAA expression was regulated by proinflammatory cytokines and occurred in association with FPRL1 expression in FLS and endothelial cells, which is consistent with a biologic role at the sites of inflammation [35].
• Recombinant human A-SAA induced both MMP-1 and MMP-3 secretion by FLS [35].
• We established that the order in which either cell line was treated with TNF-alpha and IL-6 influenced A-SAA promoter transcriptional activation [36].
• mRNA expression and release of interleukin-8 induced by serum amyloid A in neutrophils and monocytes [37].
• Selective reduction of SAA-induced gene expression was observed in tlr2-/- mouse macrophages compared with wild-type cells [38].

Other interactions of SAA1

• Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus [39].
• CONCLUSION: The up-regulation of the A-SAA and FPRL1 genes in inflamed synovial tissue suggests an important role in the pathophysiology of inflammatory arthritis [35].
• OBJECTIVE: To evaluate the regulation of acute-phase serum amyloid A (A-SAA) production in inflamed synovial tissue, and to elucidate a possible pathophysiologic role in the induction of matrix metalloproteinase (MMP) release by fibroblast-like synoviocytes (FLS) [35].
• Immunohistochemical analysis demonstrated the expression of A-SAA protein production by several synovial cell populations, and immunofluorescence analysis confirmed A-SAA colocalization with the macrophage marker CD68 [35].
• The frequencies of the gamma/gamma genotype and gamma alleles at the SAA1 locus were significantly higher in the amyloidosis population than in the early RA population (34.9% versus 7.8%, and 58.1% versus 33.8%, chi2 test P=0.0001) [40].

Analytical, diagnostic and therapeutic context of SAA1

• Sequence analysis and quantification suggest that these isoforms are the result of the first confirmed allelic variation at the SAA1 locus [41].
• Fluorescence in situ hybridization analysis using a cosmid probe carrying the SAA2 and SAA4 genes refined the localization of these genes (and SAA1) to 11p15 [42].
• Isoelectric focusing has demonstrated that SAA1 and SAA2 alpha are expressed but not SAA2 beta [43].
• SAA1 and SAA2 gene polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) [44].
• In this study, using monoclonal antibodies specific for SAA1, we developed an enzyme-linked immunosorbent assay (ELISA) for SAA1 [45].

References