Introduction: The two subtypes of Antineutrophil Cytoplasmic autoantibody associated systemic vasculitis (AASV) cANCA and pANCA associated vasculitis are the commonest causes of rapidly progressive glomerulonephritis. In spite of recent advances in the pathogenesis and development of new therapeutic agents, long term outcomes are still poor with five year mortality of 25%. There are epidemiological, histological, clinical and outcome related differences between these two conditions. This strongly suggests that there must be differences between genetic factors and pathogenesis of these two conditions. There was also a perception amongst the clinicians that AASV is more common in the Greater Manchester area. Hence in this study I calculated the incidence of pauciimmune glomerulonephritis in Greater Manchester and analysed the genetic differences between cANCA and pANCA associated vasculitis. Methods: Five year incidence of pauciimmune glomerulonephritis was calculated in Greater Manchester between 1/1/1999 to 31/12/2003. I recruited 147 patients with ANCA associated vasculitis. Clinical data was collected. I studied single nucleotide polymorphisms (SNPs) of tumour necrosis factor alpha(TNFα), interleukin 8 (IL-8), transforming growth factor beta (TGFβ), platelet endothelial cell adhesion molecule 1 (PECAM-1), Chemokine (CC motif) ligand-5 C chemokine (CCL-5), interleukin 10 (IL-10) and interleukin 18 (IL-18) genes and compared the frequencies of genotypes and alleles in patients with cANCA and pANCA associated small vessel vasculitis and healthy volunteers. I also studied circulating cytokine profiles of IL-10 and IL-18. Results of IL-18 SNPs were validated in AASV cohort from South-East USA. Further I studied the gene expression patterns of active and remission state of AASV and metabolomics profile of cANCA and pANCA positive patients during active and remission state of vasculitis. Clinical outcomes (relapses and renal survival) were correlated with the genotypes. Results: I found a significantly higher incidence (9.8/million population) of pauciimmune glomerulonephritis in Greater Manchester compared to the previously published data from UK and USA (2.73 to 4.6/million). Renal function at the time of diagnosis predicted the long term renal survival. I also found a novel genetic association of increased frequency of high producer IL-18 SNPs 113T, 127C and 137G in pANCA positive patients compared to normal volunteers (p=0.04) and cANCA positive patients (trend- p=0.08). This was associated with increased levels of circulating IL-18 levels in these patients. This association was further confirmed in an independent cohort of AASV from USA. I also found a lower frequency of low producer GG genotype of IL-10 -1082 SNP (p=0.05) and this was associated with lower levels of circulating IL-10 in these patients compared to pANCA positive patients. I found significant difference in the metabolomics profiles of cANCA andpANCA positive patients. In paired plasma samples, levels of some metabolites were high during remission state compared to active vasculitis. Conclusions: These findings strongly support the hypothesis that there is an increased incidence of pauciimmune glomerulonephritis in Greater Manchester. There are genetic differences in cANCA and pANCA positive patients which may explain the different observed outcomes. Genome wide association study would strengthen these findings and should guide the vasculitis community to reclassify, assess and perhaps treat these two conditions separately.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:549027 |
| Date | January 2012 |
| Creators | Dhaygude, Ajay |
| Contributors | Brenchley, Paul ; Kalra, Philip ; Venning, Michael |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/epidemiology-genetic-differencesand-clinical-outcomes-ofantineutrophil-cytoplasmicautoantibody-associated-systemicvasculitis(1d4bf70b-3046-4997-9bdb-82206b6a8264).html |
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