The Role Of CRP And Its Genetic Polymorphisms And Arteritis And ¹⁸FDG-PET In The Assessment Of Aortic Disease Activity

Section 1. Insight into C-Reactive Protein and its Gene Polymorphisms in Takayasu ArteritisBackground and ObjectiveC-reactive protein (CRP) is an inflammatory factor which can bind to a variety of autologous and extrinsic ligands and plays an important role in inflammation. Recent studies showed that CRP associated with autoimmune diseases. Takayasu's arteritis (TA)is a chronic vasculitis,with aorta and its main branches predominantly involved,leads to arterial wall thickening, fibrosis, stenosis, and thrombus formation. Its pathogenesis is yet to be clarified. TA patients in active stage often have elevated serum CRP levels.CRP is usually used as a surrogate marker for estimating disease activity. In TA,remission usually correlated with decline of CRP levels. However, the role of CRP in TA pathogenesis has not been studied yet.MethodsA total of 178 TA patients and 229 healthy controls were included into the study. All patients fulfilled the American College of Rheumatology 1990 (ACR) criteria for the diognosis of TA. DNA was extracted from peripheral venous blood. Genotyping of CRP was performed using a polymerase chain reaction -ligase detection reaction (PCR-LDR)method. CRP concentrations were determined using a human turbidimetric immunoassay.Analyses between CRP and TA were evaluated using SPSS and SHEsis software.ResultsWe found no significant differences in the distribution of genotype (rs1800947,rs3093077, rs1205 and rs2808630) and allele frequencies between TA patients and healthy controls (p for genotype frequencies: 0.79,0.75, 0.98 and 0.19, respectively;p for allele frequencies : 0.79, 0.81, 0.99and 0.16, respectively). Five haplotypes with frequencies > 0.03 in both the patients and controls were listed. Haplotype G-T-T-T was the most common in TA with a frequency 51%. Haplotype frequencies were not significantly different in patients with TA compared with controls. The frequencies of TA in type ?,? and ? were56.7%. 14.6% and 28.7%. The percents of pulmonary involvement in Type ?, ? and ? were 11.8%, 3.8% and 19.8%. No association was found in CRP concentration (log(CRP+1)) between type ?,? and ? (0.84 ± 0.52 vs 0.58 ± 0.36 vs 0.77 ± 0.45,p=0.081). CRP concentration (log(CRP+l)) was not significantly different between patients with and without pulmonary involvement after adjusting for age sex and BMI (0.95 ? 0.45 vs 0.73 ? 0.46,p=0. 111). CRP concentration(log(CRP+1)) in severe group was significantly higher than in mild/moderate group (0.91± 0.46 vs 0.65 ± 0.43,p<0.01).ConclusionNo association was found between CRP genotype (rs1800947, rs3093077, rs1205 and rs2808630) and haplotype frequencies and TA susceptibility. Higher CRP concentrations in TA associated with pulmonary involvement and more serious disease status. CRP might contribute to the progression of TA.Section 2.18FDG -PET in assessing disease activity in Takayasu arteritis: a Meta-AnalysisBackground and ObjectiveTakayasu arteritis (TA) is a rare nonspecific inflammatory disease with unknown cause,predominantly affecting the aorta and its main branches, coronary arteries, and pulmonary arteries and. Further progression leads to stenoses and occlusions as well as to aneurysmatic dilatation. Early diagnosis is of great importance to the prognosis.Histopathology is gold standard in determining the activity of TA. However, it is impossible unless the surgery was carried out. TA activity assessment is of extreme importance and remains a difficulty in clinical. NIH criteria is usually adopted to assess the disease activity. 18F-fluorodeoxyglucose-positron emission tomography (18FDG -PET)scanning is a noninvasive metabolic imaging modality based on the regional distribution of 18FDG. Inflammatory cells usually have high metabolic rates and increased 1BFDG uptake can be detected. Now, it has become a potential examination assessing disease activity. However, the results concerning the efficacy in assessing TA activity were inconsistent. We assessed the diagnosis value of 18FDG-PET in estimating disease activity in Takayasu arteritis using meta-analysis.MethodsWe searched PubMed, EMBASE and The Cochrane Library. The search strategy was completed by searching words ('Takayasu arteritis' ) AND ('positron emission tomography/computed tomography' OR 'PET/CT' OR 'positron emission tomography-computed tomography' OR 'PET-CT' OR "fluorodeoxyglucose" OR"FDG") in July 25th 2012. The quality of the studies was assessed by QUAD AS standard and date was extracted by two authors, independently. We calculated pooled sensitivity(Se), specificity (Se), positive likelihood ratio (+LR), negative likelihood ratio (-LR) and diagnostic odds ratio (DOR) with the corresponding 95% confidence intervals (CI).I-squared (I2) statistic was calculated to measure the heterogeneity between studies. A study with I2>50% was considered to have substantial heterogeneity and random-effects model was applied. The receiver-operating-characteristics (sROC) curve and the area under the sROC curve (AUC) and specificity (Q* index) were estimated. Publication bias was examined by constructing a funnel plot using the Egger regression model. Analyses were performed with Meta-Disc 1.4 and STATA. All p values were two tailed and p <0.05 was considered statistically significant.ResultsThe latest literature search was finished in July 25 2012. Totally 191 articles were retrieved from PubMed, EMbase and the the Cochrane Library, of which 6 studies were finally included. The pooled Se, and Sp with 95% confidence interval were 70.1% (95%CI, 58.6-80.0) and 77.2% (95% CI, 64.2-87.3). The +LR and -LR were 2.313 (95% CI 1.108-4.829) and 0.341 (95% CI 0.142-0.824). The pooled DOR was 7.498 (95% CI 1.650-34.071). The AUC was 0.805(-0.084) and Q* index was 0.7402 (±0.0739). The heterogeneity among studies was as follow: for Se, I2 =77.6%, p = 0.000; for Sp, I2=36.4%, p = 0.164; for +LR,12 =48.7%, p = 0.083; for -LR, I2 =71.0%, p = 0.004; for DOR, I2 = 60.8%, p = 0.026). The heterogeneity was significant in Se, -LR and DOR,however, the number of the studies were too few to do regression analysis and subgroup analysis to explore the origin of heterogeneity. The plots showed symmetrical distribution, demonstrating no publication bias (egger's test: p = 0.280)Conclusion18FDG-PET had moderate sensitivity and specificity in assessing TA activity. It can provide important evidence for clinical judgment and guidance for patient's treatment.Section 3. Associations between Oxidized-Lipoprotein Receptor 1 G501C and 3'-UTR-C188T Polymorphisms and Coronary Artery Disease: A Meta-AnalysisBackground and ObjectiveAtherosclerosis of coronary artery is the pathogenesis basis of coronary artery disease(CAD). Oxidized low-density lipoprotein (Ox-LDL) plays a key role in the initiation and progression of atherosclerosis. Oxidized LDL receptor-1(OLR1) is the main receptor of Ox-LDL. LOX-1 on vascular endothelial cells can internalize and degrade Ox-LDL,which might contribute to the pathogenesis of CAD. The C-terminal domain is highly conserved and acts as a ligand-binding domain for Ox-LDL, Variations in OLR have been found to be associated with CAD. However, the results are not consistent. The objective of our study was to assess the relationship of OLR1 variations and CAD.MethodsWe systematically searched PubMed,EMbase, China National Knowledge Infrastructure(CNKI), and Chinese Biological Medical Literature Database (CBM) (all from 1990 to June 11, 2011) using key words'Oxidized-lipoprotein receptor 1','LOX1',or 'OLR1'paired with 'myocardial infarction','coronary artery disease', 'cardiovascular disease','coronary heart disease', 'unstable angina','acute coronary syndrome',and'polymorphism'. Seven polymorphisms (exon 4 501G>C; 3'-UTR-C188T; intron 4 IVS4+27 G>C, IVS4-73 C>T, IVS4-14 A>G; and intron 5 IVS5-70 A>G, IVS5-27 G>T)have been identified in the LOX-1 gene. Apart from G501C, the other six comprised a complete linkage disequilibrium block. So G501C and 3'-UTR-C188T were selected.Date was-extracted by two authors, independently. Pooled odds ratio (OR) with 95%confidence interval (CI) was calculated. Statistical heterogeneity between studies was formally testedwith Cochran's Q test. The I2 statistic was also examined. Publication bias was assessed with funnel plots and Egger's regression test. The data of meta-analysis were analyzed using Stata software and RevMan software.ResultsThe meta-analysis included eight studies with 4963 cases and 14864 controls for 3'-UTR-C188T and nine studies with 5660 cases and 15405 controls for G501C. The pooled OR of 3'-UTR-188T was 1.29 (95%CI: 1.05-1.58, p=0.02; heterogeneity:I2=88%,p < 0.00001)compared to C allele in dominant model, and was 1.38 (95%CI:1.09-1.74,p=0.007; heterogeneity: I2=72%, p=0.00004) in recessive model. The pooled OR of 501C was 0.79 (95%CI: 0.57-1.10,p=0.16; heterogeneity: I2=88%, p < 0.00001)compared to G allele in dominant model, and was 0.86 (95%CI: 0.71-1.04, p=0.12;heterogeneity: I2=3%, p= 0.41) in recessive model. No publication bias was found in present meta-analysis. Funnel plots of all enrolled studies suggested no publication bias(Egger's test: p= 0.095 for 3'-UTR-C188T in dominant model; p= 0.137 for 3'-UTR-C188T in recessive model; p=0.369 for G501C in dominant model; p=0.462 for G501C in recessive model)ConclusionThe synthesis of available evidence supports that the OLR1 3'-UTR-188T increases susceptibility for CAD. However, G501C is not associated with CAD.