Koster, A.L. (Anne Laura) (2012) The search for causal variants in the AOAH gene. thesis, Medicine.
Full text available on request.Abstract
Background: Ulcerative colitis is a chronic relapsing inflammation of the colon. Genetic and environmental factors play a role in the development and course of the disease. In Genome wide association studies (GWAS) a substantial amount of loci are discovered which are associated with UC, however they only explain ~28% of the total heritability of UC. In addition of the common variant found with GWAS there are the rare variants that could potentially explain a part of the “hidden heritability”. These variants could be found by fine mapping techniques and complete sequencing of biological and genetically relevant genes. Such a gene is AOAH, it encodes for an enzyme that detoxifies lipopolysaccharide, present on gram-negative bacterial cell walls. Deficiencies in response mechanisms against bacterial products like lipopolysaccharide play an important role in UC disease pathogenesis. Materials and methods: After isolation of the DNA from blood, we did a PCR to amplify the protein encoding regions of the AOAH gene. Thereafter we Sanger sequenced these regions, the obtained date was analyzed by the program Mutation surveyor. We selected 50 Dutch UC patients as our cases. We used two control groups, GoNL (n=769) a Dutch cohort and 1000genomes (n=500) a cohort of European ancestry. We did on both groups a chi2 Fisher exact test association analysis and a pooled analysis of both control groups compared to our cases. Results: We found 17 SNPs of which 13 were already included in de dbSNP database and 4 were novel. One of the found SNPs is probably damaging for the protein, this SNP is associated with UC compared to the GoNL data. Moreover, compared to this control group we found 8 other associated SNPs, these are all silent. Compared to 1000genomes we found 1 significant associated SNP(silent). In the pooled analysis 4 SNPs where associated with UC(all silent). Conclusion: Gene targeting for sequencing gives good results and multiple associated rare variants where found in our cohort. One of the associated SNPs found in AOAH is probably damaging the protein. Other identified SNPs are silent and also associated to UC. All indentified SNP are currently being genotypes in 1000 UC cases and 1000 controls.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Weersma, Dr. R.K. and MDL, UMCG |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 10:50 |
| Last Modified: | 25 Jun 2020 10:50 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/1149 |
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