Systematic assessment of the influence of complement gene polymorphisms on kidney transplant outcome

Abstract

The importance of the innate immune system, including complement, in causing transplant injury and augmenting adaptive immune responses is increasingly recognized. Therefore variability in graft outcome may in part be due to genetic polymorphism in genes encoding proteins of the immune system. This study assessed the relationship between single nucleotide polymorphisms (SNPs) in complement genes and outcome after transplantation. Analysis was performed on two patient cohorts of 650 and 520 transplant recipients. 505 tagged SNPs in 47 genes were typed in both donor and recipient. The relationships between SNPs and graft survival, serum creatinine, delayed graft function and acute rejection were analyzed. One recipient SNP in the gene encoding mannose binding lectin was associated with graft outcome after correction for analysis of multiple SNPs (p=6.41 × 10(-5)). When further correction was applied to account for analysis of the effect of SNPs in both donor and recipient this lost significance. Despite association p values of <0.001 no SNP was significantly associated with clinical phenotypes after Bonferroni correction. In conclusion, the variability seen in transplant outcome in this patient cohort cannot be explained by variation in complement genes. If causal genetic effects exist in these genes, they are too small to be detected by this study.

Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study

“…Study endpoints have most often been short‐term “surrogate” markers, such as how genetic variability in cytokine genes may influence the risk of acute rejection . However, a few candidate gene studies have also investigated gene variants in the context of longer‐term graft function .…”

Polymorphisms in genes related to the complement system and antibody-mediated cardiac allograft rejection

“…27 In the field of transplantation, most studies related to p.Gly54Asp have focused on renal transplant outcomes. The results were inconclusive because some studies failed to find an association between genetic profile of the lectin pathway of complement activation and allograft outcome in renal transplants, 19,21 whereas others showed a relationship with the incidence of acute rejection and graft outcome. 29,30 In HT, 2 studies described MBL deficiency related to development of CAV 31 and acute graft rejection.…”

“…[18][19][20] One limitation of these studies was that they analyzed o6 genes involved in the complement pathway. [13][14][15][16][17][18][19][20] Recently, Ermini et al 21 analyzed the relationship between single nucleotide polymorphisms (SNPs) in 47 complement genes and graft survival, serum creatinine, delayed graft function, and acute rejection in donors and recipients of renal transplants. They found 1 donor SNP, c.304þ363T4C (rs4935047), in the non-coding region of the mannose-binding lectin 2 gene (MBL2) associated with worse graft outcome.…”

Complement Polymorphisms in Kidney Transplantation: Critical in Graft Rejection?

“…Second, Ermini et al evaluated 1170 European donor–recipient pairs by a large multiplex polymerase chain reaction covering 505‐tagged SNPs in 47 complement genes. Although they identified several noncoding SNPs in the lectin pathway and C7 with low p‐values, these associations were not significant with graft survival after an extensive correction for multiple testing . Lastly, a SNP in the promoter region of CD46 (rs2796267) was significantly associated with acute rejection and late acute rejection, but not with allograft loss in 334 kidney transplant patients .…”