Systemic Lupus Erythematosus is an autoimmune disease of complex aetiology. It presents several clinical and immunological features, amongst them the presence of autoantibodies and lymphopenia. It is known that genetic susceptibility plays a part in developing the diseases, although few specific genes have been identified. As disturbances of apoptosis play a part in the pathogenesis of SLE, genes that code for proteins leading to, or belonging to this pathway are good candidates for the polygenic background predisposing to the disease. Eight known genes were selected as candidates based on a literature review. Markers in the candidate genes were genotyped on 388 Caucasian trios, predominantly by mass spectroscopy with the Sequenom platform. Association was evaluated with the transmission disequilibrium test. A ninth gene was selected based on positional cloning ofthe SLE subphenotype ofB cell levels. Evidence for association to SLE was found for: a haplotype spanning the second and third exons ofFAS, a haplotype in the 3' end ofFASL, SNPs in the 5' region of TP53, a haplotype spanning PARP, SNPs in the promoter region of CRH, a 3' haplotype of PDCDl and a SNP in the 3' untranslated region of SMAC/DIABLO. Genotypes for the same SMAC marker also showed significant differences in B cell levels. No assoc~ation was found between BCL2 and SLE. Haplotype and linkage patterns were established for all the candidate genes in the UK Caucasian cohort used. This study strengthened the hypothesis of involvement ofapoptosis genes in lupus pathogenesis and delimited genomic regions ofinterest for further genetic screening.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:485723 |
| Date | January 2007 |
| Creators | Mendiratta, Maya Losa |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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