How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

Kelly Nunes,Bruce S Weir,Miriam V Flor-Park,Shannon Kelly,Alexandre C Sena,Danielli C M De Oliveira,Claudia Maximo,Eduardo Tarazona-Santos,Diogo Meyer,Anna Barbara F Carneiro-Proietti,Paula Loureiro,Carla L Dinardo,Ester C Sabino,Vanderson G Rocha,Vitor R C Aguiar,Luís Cristóvão Porto,Fernanda S G Kehdy,Márcio Silva,Brian Custer

doi:10.3389/fimmu.2020.584950

Abstract

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci – an outcome of millions of years of natural selection – reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with “ethnicity” or “race”) and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil’s Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as “Black” and “Mixed” on average have lower chances of finding matches than those who self-identify as “White” (up to 57% reduction). We next show that an individual’s African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual’s genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.

Highlights

Since the first allogeneic transplant in the late 1950s, there has been significant progress in the technical procedures and success rate of hematopoietic stem cell transplantation (HSCT)
Local ancestry was estimated for the whole of chromosome 6, but we subsequently focused on the ancestry of the subset of the MHC region encompassing the classical HLA loci, delimited by HLA-A and -DQB1, and spanning 2,724,220 bp
We have shown that among patients seeking HSCT, those with a higher African ancestry face greater difficulty in locating potential donors

Summary

Introduction

Since the first allogeneic transplant in the late 1950s, there has been significant progress in the technical procedures and success rate of hematopoietic stem cell transplantation (HSCT). The success of allogeneic HSCT (allo-HSCT) is in part due to a better understanding of the role of HLA genes in the immune response. When HLA molecules bind a non-self antigen, cellular and humoral immune responses are triggered. In allo-HSCT the match between patient and donor HLA is critical, since different HLA alleles can generate distinct antigens detected as non-self during cellular immunological inspection. The patient’s immune system sees the donor cells with incompatible HLA as foreign and mounts an immune response, leading to rejection of the HSCT, and/or to graft versus host disease after grafting. The gold standard for allo-HSCT is full compatibility between patient and potential donor at the 2 alleles of HLA-A, -B, -C, -DRB1, and -DQB1 (10/10 match) [see review in Tiercy, 2016 [3]]. In some cases mismatches may be allowed (9/10 match), especially at alleles which do not generate an antiHLA antibody [4, 5], or when new therapeutic protocols of haploidentical transplant are used, in which the donor and recipient share a common HLA haplotype [6]

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