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This dissertation, Association of DC-SIGN (CD209) Gene Polymorphisms With Severe Acute Respiratory Syndrome (SARS) by Meishu, Xu, 徐美術, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Association of DC-SIGN (CD209) gene polymorphisms with Severe Acute Respiratory Syndrome (SARS) Submitted by Xu Mei-Shu For the degree of Master of Philosophy at the University of Hong Kong in March, 2007 Severe acute respiratory syndrome (SARS), as a novel respiratory infectious disease, posed a major world-wide threat to health. Mounting evidence shows that DC-SIGN (CD209) plays an important role in pathogen recognition and immune regulation. DC-SIGN has been demonstrated to enhance the pseudo-typed SARS-CoV infection and facilitate viral transmission to susceptible cells. Although risk associations of DC-SIGN against HIV-1 infection and dengue disease have been demonstrated, there was no study to describe the association between DC-SIGN and susceptibility and severity of SARS. The aim of this study is to investigate the association between the DC-SIGN SNPs with susceptibility and prognosis of SARS in the Hong Kong Chinese population. We screened the promoter, coding region and flanking introns of DC-SIGN in 24 Hong Kong Chinese healthy individuals and identified eleven SNPs (-1466A>G, -1180T>A, -939G>A, -871A>G, -336A>G, -139A>G, IVS1-8G>C, IVS2+11G>C, IVS6-326G>C, IVS6-84A>C, IVS6-37G>C) by direct sequencing. Based on the allele frequencies, location of SNPs, linkage disequilibrium (LD) and different putative transcription factor binding scores of the SNPs, three SNPs (-336A>G, -871A>G and -939G>A) were selected for further genotyping in case-control study using RFLP and TaqMan assay.This case-control study included 829 SARS patients and 487 controls (178 healthcare worker controls and 300 general outpatient clinics controls). Risk association analysis for genotypes and alleles with disease, haplotypes construction and LD analysis were performed. Association between SNPs and clinico-pathological parameters in SARS patients was also investigated. We found no significant difference in the distribution of allele and genotype frequencies of the three SNPs between patients and controls (p>0.05). No difference in the LD and haplotype frequencies containing these three SNPs was found between patients and controls (p>0.05). In addition, -871A>G and -939G>A was not found to be associated with clinical features and laboratory parameters on admission (p>0.05). However, we observed a significant difference in normalized lactate dehydrogenase (LDH) level on admission between various genotypes of -336A>G. Previously, LDH-levels on admission have been suggested to be an independent prognostic indicator for severity of SARS. By independent-sample t-test, mean normalized LDH-level in the -336G-carrier group was significantly lower than that in non-G carrier group (p=0.019). To examine the risk level, patients were dichotomized using defined normalized LDH-level cutoff value. The G-carrier (GG and GA) was associated with lower LDH-level subgroup (p=0.014, OR: 2.491, 95%CI: 1.172-5.291); the -336G allele was associated with lower LDH-level when compared with -336A allele (p=0.015, OR=2.411, 95%CI: 1.156-5.025). In summary, -336A>G SNP was associated with LDH-levels on admission, suggesting that it was associated with severity of SARS. The G-allele carrier of this SNP might play a potential role in regulation of immune response to SARS. It will be helpful to investigate its relevance in rela

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