GENETIC CONTRIBUTION TO COMPLICATIONS AFTER TRANSPLANTATION
Ken I Welsh, Sara E Marshall, Neil A Haldar, Andrew J McLaren, Charles G Mullighan, Mike Bunce, Tom G Bird, Eoin McKinney, Peter J Morris. Transplant Immunology, Radcliffe Hospital Trust & Nuffield Department of Surgery, Oxford, UK.
Identical twin recipients of allografts do not need immunosuppression whereas even fully class I and II MHC matched individuals do. This strongly implicates additional genes both in graft loss and other complications after transplantation. In order to test this hypothesis, we have, over the past 3 years, analysed a wide range of genetic variants postulated to be associated with specific clinical patterns after transplantation within a well characterised cohort. Patients were all recipients of cadaver kidneys and were immunosuppressed by a core triple therapy regimen. Polymorphisms were chosen on the basis of known product function and analysed using a unified PCR-SSP method. To address confounders a detailed clinical database was maintained and linked to the genetic database in order that stratified analyses could be made. To address Bonferroni all significant associations were confirmed on additional cohorts. To address bias DNA samples were blinded from clinical details.
Using this approach we have identified major genetic risk factors for the development of acute rejection, chronic rejection and skin tumours after transplantation: donor cytokine genotype influences the incidence of acute rejection (p rejection v no rejection <0.002), and provides a strong predictor of rejection severity (p severe rejection v no rejection <0.00002); genetically determined ability to oxidise plasma lipid influences susceptibility to biopsy proven chronic allograft failure in grafts surviving > one year (p < 0.001); glutathione S-transferase polymorphism is a strong predictor of skin cancer (p<0.001).
We conclude that a targeted multiple candidate gene approach is a powerful tool in identifying major risk factors for complications after transplantation. This may assist the development of algorithms by which therapy may be individualised.