Role of Donor Genetics and Recipient Genetics in Kidney Transplant Outcomes

Genetic variation in the region of MYH9 and APOL1, located on chromosome 22, is a major contributor to the increased risk for kidney disease that characterizes African descent populations, although the specific gene, causative mutations, and the molecular and cellular mechanisms remain to be determined. We propose to study the role of MYH9 and APOL1 genetic variation, as well as other genes, in renal transplant, including the effect of donor genotype on recipient outcomes and on donor outcomes. Additional exploratory studies will address 1) whether variation in other donor genes might contribute to donor and recipient outcomes, which we may address with candidate gene studies or a genome-wide association study and 2) whether recipient genotype contributes to recipient outcomes, which we will address in similar ways.

MULTICENTER STUDY. We will identify 300 kidney transplant dyads (donor/recipient pairs), in which both individuals were of African descent and the kidney transplants were performed between 1995 and 2006. We will include 150 living donor transplants (selected on the basis of the ability to locate the surviving living donor and their willingness to participate) and 150 deceased donor transplants (selected at random, to minimize survival bias of the allograft). All subjects sign consents that are identical or similar to the NIH consent.

RECIPIENT OUTCOMES. We hypothesize that genetic variants in the kidney donor genome and secondarily in recipient genome might contribute to kidney recipient outcomes. We will obtain kidney donor genotypes using blood from surviving living donors or using transplant kidney biopsy DNA from now-deceased living donors, and we will obtain deceased donor genotypes by using transplant kidney biopsies. We will obtain recipient DNA, when available, from surviving recipients or from tissues obtained from deceased recipients. We will carry out Cox proportional hazards analysis to test the primary hypothesis, that donor MYH9 and APOL1 genotype influences allograft survival. We will also develop a multivariable model to predict last follow-up glomerular filtration rate, incorporating factors known to influence transplant outcomes and examining the effect of donor MYH9 and APOL1 genotype. In exploratory studies, we determine whether recipient genetic variants influence recipient outcomes.

DONOR OUTCOMES. We hypothesize that genetic variants in the kidney donor affect kidney donor outcomes. While kidney donors do not have an increased risk of chronic kidney disease compared to the general population, they do have an increased prevalence of microalbuminuria. Furthermore, the extent of compensatory renal hypertrophy appears to differ among individuals. We wish to determine whether MYH9 and APOL1 genotype affects these outcomes, as well as the uncommon occurrence of overt kidney disease after kidney donation. CLINICAL IMPLICATIONS. We believe that that these studies will expand our knowledge of how donor genotypes influence kidney transplant outcomes for both donors and recipients.

COLLABORATIVE STUDY. In separate but related studies, we will work with various collaborators who pursuing similar question under research protocols that they have generated and for which they have local IRB approvals. We will receive from these collaborators materials for preparation of DNA, from which we will genotype APOL1 and other genes known or hypothesized to be related to donor and recipient transplant outcomes.