Genetische Variabilität des Cytochrom P 450- Systems im Zusammenhang mit einem erhöhten Risiko für Rheumatoide Arthritis

• Main Author: Krause, Maren
• Other Authors: Universität Leipzig, Medizinische Fakultät
• Format: Doctoral Thesis
• Language: deu
• Published: Universitätsbibliothek Leipzig 2014
• Subjects: Cytochrom P 450; Cytochrome P 450; ddc:610
• Online Access: http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-143774; http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-143774; http://www.qucosa.de/fileadmin/data/qucosa/documents/14377/druckversion_vorpdf_06_13_2.pdf

Rheumatoid Arthritis is a chronic inflammatory systemic disease and is one of the autoimmune diseases. In this study, nine candidate genes of the cytochrome P450 system have been analyzed to determine their possible association with the formation of RA. These genes are: CYP1A1, CYP1B1, CYP2B6, CYP2E1, CYP2C9, CYP2D6, CYP2A6, CYP2C19 and CYP3A4.Within these genes, 21 single nucleotide polymorphism, SNPs, in 300 French Caucasian individuals (100 RA trio families) were genotyped using single-base-extensions, SBE, in a mass spectrometric analysis by MALDI-TOF-MS (matrix-assisted Laser Desorption/ Ionization-time-of-flight mass spectometry). The selection of the examined genes was carried out taking into account known associations with RA or other autoimmune disease, as well as known functional variants. Decisive were also the location of the gene and genetic variability. The results of genotyping were used to study polymorphisms on their association with Rheumatoid Arthritis. The statistical analyzes of CYP2C9 rs1799853 (3011) showed, in the family-based single-marker test, a lower transmission (TDT p-value 0.021) for the rare allele (3011-a). The case-control allelic based test shows, there is a protective effect (Odds Ratio 0.58). In the case-control-based genotypic test this issue could be reproduced (p-value 0.046). For the rare allele of the CYP2A6 rs1801272 (3022-a) the family-based single-marker test shows a lower transmittance (TDT p-value 0.037). The case-control allelic based test shows a protective effect of this allele (Odds Ratio 0.32). In the case-control-based genotypic test a statistical trend to protective behavior of this allele occurs. SNPs with predicted functional relevance showed no statistical abnormalities in the studied cohort. In genome-wide studies, the results could not be tracked, at least at the gene level weak associations could be detected. The results of this study should be to replicate in one second independent cohort. Care should be taken specifically to xenobiotic stress, such as job stress, smoking, and medication. In subsequent studies more SNPs of the candidate genes could also genotyped in order to verify the genetic variability with reference to of the haplotypes in more detail. Should the above-mentioned associations be confirmed, functional studies on different gene expression or altered metabolite spectrum are highly interesting.