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.

- INCLUSION CRITERIA:

We will study 300 African American kidney transplant dyads.

INCLUSION CRITERIA FOR DYADS:

1. African descent donor and African descent recipient

2. Kidney transplant performed Jan 1995 - Dec 2006.

3. First kidney transplant

4. Kidney only transplant (excluding transplant of any other organ at any other time).

EXCLUSION CRITERIA:

1. We will exclude donors whose kidneys were used in transplants in which two organs were
transplanted, e.g. pancreas and kidney, either simultaneously or at separate times. We
will exclude donors whose kidneys were used in second or subsequent transplants.
Rationale: dual organ transplants and serial transplants are more complicated clinical
situations and renal allograft survival may be shorter and thus not comparable with
other kidney transplants.

2. We will exclude recipients who had HIV, hepatitis B or hepatitis C infection diagnosed
either before or after the kidney transplant.

3. Children

4. Pregnant women will be excluded but invited to participate after delivery. The
rationale is the renal function is altered during pregnancy