The Influence of Race and Common Genetic Variations on Outcomes After Pediatric Heart Transplantation

Abstract

Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow-up was 6.25 years. Unadjusted 5-year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8-19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes.

Comparison of 10‐year graft failure rates after induction with basiliximab or anti‐thymocyte globulin in pediatric heart transplant recipients—The influence of race

“…The profound immunosuppressive action of ATG early post‐transplant may help achieve adequate immunosuppression in the face of rapid drug metabolism in black recipients, who furthermore present a challenging immunologic milieu . Green et al propose a similar hypothesis in their discussion. Also, black recipients have more HLA mismatching, which is associated with poorer long‐term outcomes, and the broad anti‐lymphocyte effect of ATG, but not BAS, may help prevent early B‐cell effects on the allograft that might otherwise have a detrimental long‐term effect.…”

“…Black recipients have increased risk of poor outcomes . Clinical, socioeconomic, immunologic, and genetic factors have all been implicated as contributing to this survival discrepancy .…”

“…Clinical, socioeconomic, immunologic, and genetic factors have all been implicated as contributing to this survival discrepancy . Green et al noted racial differences in utilization of induction therapy but did not find this as a risk factor in their multivariate models. Due to anecdotal concerns of poor outcome in BAS‐induced black pediatric recipients at the primary author's center, we analyzed a large multicenter registry to determine whether there was an association between BAS and graft loss in black and non‐black pediatric recipients.…”

Joint testing of donor and recipient genetic matching scores and recipient genotype has robust power for finding genes associated with transplant outcomes

“…Genetic association studies for transplant outcomes tend to look at the recipient genome only (Dorr, Oetting, Jacobson, & Israni, 2018). Individual recipient single nucleotide polymorphisms (SNPs) have been found to be associated with acute rejection outcomes for kidney, liver, and heart transplants (Almoguera et al, 2014; Green et al, 2017; Morris et al, 2015). Recipient's genes have also been found to affect pharmacogenetic outcomes, such as immunosuppressant concentration in transplant recipients (Almoguera et al, 2014; Dorr et al, 2018; Oetting et al, 2016).…”

“…Recipient's genes have also been found to affect pharmacogenetic outcomes, such as immunosuppressant concentration in transplant recipients (Almoguera et al, 2014; Dorr et al, 2018; Oetting et al, 2016). Multiple studies have examined how differences in transplant outcomes that seem to be based on self‐reported race may be because of underlying genetic differences between different ethnic groups (Green et al, 2017; Morris et al, 2015). Fewer studies have been carried out looking at the association between the donor genome and transplant outcomes, but polymorphisms in donor APOL1 and TLR4 genes have been found to be significantly associated with negative transplant outcomes in the kidney and liver respectively (Dorr et al, 2018; Julian et al, 2017; Oetting et al, 2012).…”