Investigating Effect of Genetic Admixture and Donor/Recipient Genetic Disparity on Transplant Outcomes

Aim

Survival after hematopoietic cell transplantation (HCT) is dependent on donor/recipient (D/R) HLA matching. However disparities in survival were reported for some ethnicities despite comparable HLA matching. Individual ethnicities/races, as reported through self-identification, can change over time. Most studies have shown that African-American recipients (AAFA race) experience worse survival. Another way to investigate ancestry is to use Ancestry Informative Marker SNPs (AIMs), providing ancestral admixture.  We hypothesized that information on donor and recipient genetic admixture may be used to evaluate D/R genetic disparity and that this may be associated with outcomes of HLA matched unrelated donor HCTs.

Methods

Study population included 1295 10/10 HLA matched D/R pairs receiving HCT for AML, ALL, CML and MDS between 1995 and 2011. Samples were genotyped for 500 AIMs.  We estimated African (AFR), European (EUR), Asian (ASI) and South European/Amerindian (SE/A) admixtures for donors and recipients using STRUCTURE at K=4 clusters. Tables 1 and 2 show the admixture distributions in each of the self-identified race groups.

To model D/R genetic disparity we ran principal components analysis (PCA) on the D/R genotypes, then calculated the pairwise Euclidean distance between a subset of PCA eigenvectors of each D/R duo.

Multivariate analyses were performed using Cox proportional hazards models for overall survival (OS), disease free survival (DFS), relapse, transplant related mortality (TRM), acute and chronic graft versus host disease (GVHD) for admixture and genetic disparity.

Results

For transplant recipients, increasing AFR admixture was associated with worse OS and TRM at p<0.01 and DFS at p=0.02 (Figure 1).  Recipient EUR and SE/A admixtures failed linearity test with p=0.04 and p<0.0001 respectively and were not further analyzed. For donors, increasing AFR admixture was associated with worse OS, DFS and TRM at p<0.01 (table 4).  No associations were noted for donor ASI, EUR and SE/A.

We tested for a cut point for AFR admixture that best associated with survival.  For recipients, the optimal cut point was > 14% AFR admixture. This only included 2.8% of the population (N=34 recipients) but 90% of the African-American self-identified recipients. For donors the cut point was > 23% AFR admixture which only included 1.9% of the population (N=24 donors) but 89% of African-American self-identified donors. Recipients and donors with high AFR admixture were highly confounded and numbers were too small to explore whether recipient or donor AFR admixture was more important.

No significant associations were observed for D/R pairwise genetic distance and clinical outcomes.

Conclusion

While no significant associations were found for the D/R genetic distance used here, increasing AFR admixture in recipient and donor associated with increased risk of overall mortality, TRM and decreased DFS.  The observed effect was attributed to 2.8% of the recipient and 1.9% of donor population with higher AFR admixture, groups that contained >89% of the self-identified African-Americans. Our findings are consistent with studies showing that self-identified African-Americans are associated with suboptimal HCT outcomes. It is still unclear whether the deleterious effect of AFR admixture is genetic in nature or due to other non-genetic factors such as access to healthcare or other socio-economic factors mostly pertinent to recipients.

Table1: Admix in recip race groups

Race	Admix
	AFR		EUR		SE/A		ASI
	Median	IQR	Med	IQR	Med	IQR	Med	IQR
AAFA N=26	0.81	0.7, 0.9	0.08	0.03, 0.1	0.06	0.02, 0.1	0.005	0.003, 0.008
CAU N=1113	0.004	0.002, 0.007	0.97	0.9, 0.98	0.015	0.007, 0.05	0.004	0.002, 0.007
HIS N= 63	0.005	0.003, 0.02	0.03	0.01, 0.14	0.764	0.5, 0.9	0.08	0.015, 0.2
API N= 20	0.005	0.002, 0.01	0.005	0.001, 0.01	0.008	0.002, 0.2	0.97	0.7, 0.99

Table2: Admix in donor race groups

Race	Admix
	AFR		EUR		SE/A		ASI
	Med	IQR	Med	IQR	Med	IQR	Med	IQR
AAFA N= 18	0.82	0.7, 0.9	0.1	0.03, 0.14	0.05	0.03, 0.06	0.004	0.002, 0.005
CAU N= 1077	0.004	0.002, 0.007	0.97	0.9, 0.98	0.014	0.007, 0.05	0.004	0.002, 0.008
HIS N= 60	0.006	0.003, 0.02	0.04	0.02, 0.48	0.7	0.3, 0.9	0.05	0.007, 0.2
API N=22	0.003	0.002, 0.005	0.003	0.002, 0.03	0.002	0.002, 0.03	0.98	0.8, 0.99

      Figure 1. Multivariate analysis evaluating the effects of recip AFR admix on outcomes.

Figure 2. Multivariate analysis evaluating the effects of donor AFR admix on outcomes.