"POLYCIS", polymorphisms of immunosuppressant proteic targets and implication in the drug response in transplantation
Zusammenfassung der Projektergebnisse
The project goal was to study selected genetic polymorphisms in kidney transplant patients in terms of specific clinical outcomes, i.e. rejection, nephropathy, and nephrotoxicity, representing the main challenges in kidney transplantation. We identified proteins involved in the intracellular pathway of T cell activation, which are targeted by cyclosporine A, a calcineurin inhibitor and widely-used immunosuppressive drug. Unfortunately, the initially intended broad range of proteins could not be studied due to technical restrictions. Therefore, only a consolidated list of 29 SNPs was finally genotyped by the TaqMan® standard assay in a total of 213 patients with European origin. The SNP rs2069763 in the IL2 gene, coding for the cytokine interleukin-2, was found significantly associated with rejection, which was in accordance with higher immunoglobulin levels reported by others. The SNP rs11938975 in the same gene had a significant effect on nephropathy, similar to that shown for Crohn’s disease, suggesting (auto-) immunological processes in nephropathy. Surprisingly to us, this SNP had the opposite effect on nephrotoxicity. Similarly, the risk-raising variant for autoimmune diseases was protective for nephrotoxicity concerning the following SNPs: rs6822844 (IL2), rs706778 (IL2RA, coding for the interleukin-2 receptor α chain), rs4749955 (IL2RA), rs3118470 (IL2RA), rs2104286 (IL2RA). Therefore, different pathomechanisms were assumed for nephropathy and autoimmune diseases on the one hand and nephrotoxicity on the other. One SNP, rs10795791 (IL2RA), stepped out of line because the protective variant was the same for both situations, possibly due to its additional transcriptional property. The SNP rs3039851 in the PPP3R1 gene, coding for calcineurin B1, additionally pointed in the direction of nephrotoxicity being an immunological process. For all the SNPs, intra- and intergenetic interactions with other SNPs, referred to as haplotypes, are very likely and should be studied in detail, especially in terms of functional consequences, as these could unfortunately not be covered within our project. By this pharmacogenetic – pharmacodynamic approach, it is very promising to find patients at risk for the major challenges in renal transplantation. More complete in vitro studies as well as large, prospective clinical validation trials will help stratify patients into risk groups and will eventually improve graft survival. In the future, we indeed hope that transplant patients will benefit from “personalized medicine” by early genetic testing.
Projektbezogene Publikationen (Auswahl)
- Exploring different DNA extraction and genotyping techniques in medium scale pharmacogenetic research, 6ème Congrès de Physiologie, Pharmacologie et Thérapeutique in Grenoble (France), March 22nd – 24th, 2011, and 4th Paris Workshop on Genomic Epidemiology in Paris (France), May 30th – June 1st,2011
M. Koitka, J. Abraham, P. Marquet, N. Picard
- Some lessons learned from using medium scale genotyping techniques in pharmacogenetic research, Clinical Chemistry and Laboratory Medicine 2011;49(3):551–552
M. Koitka, N. Picard
