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Differential admixture, human leukocyte antigen diversity, and hematopoietic cell transplantation in Latin America: challenges and opportunities

Introduction

Hematopoietic cell transplantation (HCT) is in many cases the only curative approach to treat patients with hematologic malignant diseases. In addition, it is used to treat nonmalignant disorders including hemoglobinopathies, inborn errors of metabolism, immune deficiencies, autoimmune diseases, and some solid tumors [1]. HCT use continues to increase [2], but due to variables such as its cost and the availability of donors it is still performed mainly in high-income countries [3, 4]. However, developing regions such as Latin America are also seeing an expansion in its use [5, 6].

Latin America is composed of 28 countries and territories spanning more than 20 million km2. Close to 700 million, it represents 10% of the world’s population. In addition, ~60 million people of Hispanic/Latino American descent live in the United States. Both the Hispanic population in the United States and populations in Latin American countries are expected to continue growing, with mortality associated with cancer also expected to increase significantly in the coming decades [7]. These demographic variables suggest a scenario of increasing need for cancer treatment strategies including HCT in the region.

Although commonly grouped together and sharing historical and cultural traits, Latin Americans represent a very diverse group. Due to the European colonization and subsequent African slave trade, most Latin American countries have majority populations of admixed origin. In addition, some countries still have large Native American populations, characterized by extreme ancestral population differentiation [8], as well as relative isolation and different degrees of gene flow from non-Native Americans. Moreover, Latin America also possesses some of the largest populations of African origin outside Africa, with high levels of intrinsic genetic diversity [9]. Finally, several large waves of more recent immigration from different parts of the world including Europe, the Middle East, and East Asia, have further increased population complexity and admixture in the region.

Genetic diversity, in particular of the human leukocyte antigens (HLA), relevant to patient-donor histocompatibility crucial for the success of allogeneic transplant [10], plays a central role in the feasibility and efficacy of allogeneic (allo)HCT. Here, we seek to illustrate how the differential admixture processes that took and continue to take place in Latin America impact the diversity of HLA in the region, and why this is a crucial factor to consider for the expansion of HCT. We also propose strategies and future perspectives to face the challenge of genetic diversity and the opportunities for future HCT development.

HCT activity and donor resources in Latin America

Although documented in Latin America since the 1980s, HCT activity in the region is still limited in comparison to North America or Europe [11]. Data on more than 13,000 transplants performed between 1981 and 2009 from the Centre for International Blood and Marrow Transplant Research showed that the activity during those years was concentrated by a few countries and limited to sibling donor and autologous transplants [12]. A more recent survey conducted by the Latin American Bone Marrow Transplant Group [5] on more than 11,000 transplants between 2009 and 2012 showed that only 12 of 28 countries had data on HCT activity, and only seven countries reported HCT using unrelated donors (UD). Of note, about 50% of all HCT performed in the region was done in Brazil. Moreover, while in Europe (56.5%) and North America (58.1%) UD are the primary source of hematopoietic cells for allogeneic (allo)HCT, they represent only 25.4% of all alloHCT in Latin America. Overall, a 20–40-fold reduction in transplant rates has been observed in Latin America when compared with Europe and North America [13], with <10% of the required ideal numbers of transplants being performed [14]. Although the data reported in these studies are likely incomplete due to underreporting, they suggest HCT activity in the region needs to be expanded.

The still limited use of HCT in Latin America can be partly attributed to financial costs, scarcity of transplant centers and specialists, but also to donor availability. Even if the chances of finding a matched sibling donor in Latin America are still in principle higher than in Europe and North America due to larger family sizes, falling fertility rates in the region will progressively reduce this probability [15]. Moreover, most Latin American countries lack donor resources such as volunteer UD registries and cord blood (CB) banks. The World Marrow Donor Association lists only five UD registries based in Latin America. Together, these registries currently amount for more than 5 million UD, but this number is heavily concentrated by the REDOME, the Brazilian registry with 4.9 million UD.

Donor availability and genetic diversity

Resources for unrelated HCT can provide an alternative for patients lacking a compatible sibling donor (i.e., ~70%). However, their effectiveness in providing donors for a majority of the patients in need depends on several variables including the size of the registry or CB bank, as well as the genetic diversity of the target population, which has to be represented in the HLA diversity of the relevant registry. The effect of genetic diversity is much stronger in emerging registries from countries where diversity is inherently higher (e.g., India or Sub-Saharan Africa) [16] or admixture dominates (e.g., Latin America) [17]. Overall, assessment of HLA genetic diversity in the target population and in the UD donor registries and CB banks is fundamental to determine the feasibility, development, and efficacy of such resources [18]. On the other hand, knowledge of the HLA haplotypic diversity of any population can inform clinical decision making, since the frequency of the patient’s HLA haplotypes will determine the chances of finding a compatible UD [19] and have an impact on the time to transplant and its outcome [20].

Patients of Hispanic/Latino American descent in the United States have reduced chances of finding an UD when compared with patients of European descent [21, 22]. The likelihood of having an HLA-matched (8/8) UD listed in the National Marrow Donor Program Be The Match® registry for patients of Hispanic Caribbean, Mexican, and Hispanic Central American ethnicity lay between 35 and 40% for 2017 [23]. These figures become even worse when patients of African descent are considered, with Black Caribbean and Black South or Central American ethnicities having only 10–15% chances of finding a matched UD [23]. Moreover, patients of Hispanic descent in the United States have been reported to have up to 15% chances of not finding neither a 7/8 UD nor a 4/6 CB (mis)matched donor [24]. The same study showed that the likelihood of Hispanic patients actually undergoing the optimal 8/8 matched UD HCT was 35%, only higher than that of patients of African American descent. In line with this, the availability of UD has been identified as a significant factor for the improvement of patient outcomes, especially for patients of ethnic minorities in the United States [25]. Although several factors including their representation in the UD registries as well as higher rates of donor attrition [26, 27] affect the likelihood of undergoing timely and optimally matched HCT for these populations, one central key aspect is their HLA genetic diversity and differential admixture.

Differential admixture and genetic diversity in Latin Americans

Genetic diversity in Latin Americans is heavily affected by extensive population structure, differential admixture across and within countries [28], and the coexistence of minority groups with continuing gene flow from and to majority populations [29]. Genetic epidemiology studies of Hispanic populations in the United States [30, 31] showed that the terms ‘Hispanic’ or ‘Latino’ masked extensive variation in admixture, and that this diversity was a major confounding factor that needed to be accounted for [32,33,34]. Thorough analysis of genetic variation in human groups in Latin America is thus fundamental for medical genetic studies in the region [35].

HLA diversity and differential admixture in Latin American countries: two case studies

The central role of the HLA system in determining both access to as well as the outcome of alloHCT [36,37,38], in addition to its extensive polymorphism [39] underscores the relevance of characterizing its genetic diversity. Importantly, HLA loci show allelic and haplotypic frequencies that vary drastically across human populations [40, 41], and many HLA alleles can be considered geographic region specific [42], especially in Sub-Saharan African and Native American populations, where they represent a high proportion of the total allele pools [42]. Consequently, the effect of differential admixture on HLA diversity is of special interest in Latin American populations. Indeed, we have shown that the HLA profiles of Latin American and Hispanic populations segregate across a wide range, scattering among clusters of their ancestral populations according to the specific admixture histories of each population [43]. More recently, we have been conducting studies aimed at performing thorough characterizations of HLA haplotypic diversity in Latin American countries and showing how differential admixture impacts this diversity (Fig. 1). We present here two examples that illustrate this interplay relevant to HCT development both in small as well as in large Latin American countries.

Fig. 1
figure1

Differential admixture in Latin American populations revealed by extended HLA haplotype analysis. Population samples with available HLA genotype data reported in the Allele Frequencies Net database (http://allelefrequencies.net) [62] or from previous studies (Mexicans from Los Angeles, LA, or Mexico City, CDMX; Puerto Ricans) [63, 64] were analyzed for HLA haplotypic diversity and putative continental origin as described previously [44]. HLA haplotypes of European, Native American, and African origin were quantified and their cumulative frequencies in the population samples are shown

Case 1: Costa Rica and Nicaragua

Costa Rica and Nicaragua are two small Central American countries with ~11 million inhabitants. Both neighboring countries have majority Mestizo populations, in addition to Native American and African-Caribbean minorities. Until more recent activity in Panama, Costa Rica was the only Central American country performing HCT. Panama has an incipient UD registry, and Costa Rica has recently opened its first public CB bank. However, alloHCT is still performed exclusively with related donors [5].

By analyzing high-resolution extended HLA haplotypic diversity, we were able to show that majority admixed populations had limited HLA haplotype sharing with minority Native American and African-Caribbean populations [44]. Strikingly, despite sharing a tri-ethnic admixed origin, the three Mestizo populations studied had low overlap of HLA haplotype distributions, with 72–83% of the haplotypes being found only in any single population (Fig. 2a). Haplotypes shared by Mestizo populations represented only 5–9% of their haplotype distributions [44]. Differences in HLA haplotypic distributions in these populations correlated with differential admixture proportions found by examining the putative continental origin of HLA haplotypes [44] (Fig. 2b).

Fig. 2
figure2

HLA haplotypic diversity and differential admixture in populations from Costa Rica and Nicaragua. Extended HLA haplotypes were determined for three admixed Mestizo (Costa Rica Central Valley, Costa Rica Guanacaste, and Nicaragua) and two minority populations (Costa Rica African-Caribbean, and Costa Rica Native American). Putative continental origin of extended haplotypes was assigned as previously described [44]. a Proportion of shared (i.e., found in at least two populations) and private (non-shared) HLA haplotypes in the five populations studied. b Cumulative frequency of haplotypes of European, Native American, and African origin determined in each population. Admixture proportions in Mestizo populations were significantly different [44]

Case 2: Mexico

With ~150 million people, Mexicans and individuals of Mexican ancestry represent the second largest group among Latin Americans. The vast majority of Mexicans are Mestizos, with mainly Native American and European ancestry [45]. Mexico performs ~10% of alloHCT in Latin America [5], with one in six transplants being from UD. Mexico has an UD registry (DONORMO) and several CB banks.

We recently analyzed HLA haplotypic diversity in more than 15,000 individuals from all 32 Mexican states [46]. We identified 4323 unique HLA extended haplotypes. Only 5 of these were found in all 32 states, whereas 56% of the haplotypes identified were only observed in one state. Consistent with previous observations [47], the HLA haplotypic distribution was dominated by HLA haplotypes of putative Native American origin (Fig. 3a). Importantly, only 500 of the 4323 unique haplotypes were of Native American origin, but they represented 54.2% of the haplotype distribution across the country. When we compared the haplotypic distributions in different Mexican states, we observed evidence of differential admixture, with states in the south and south-east having a strong Native American component, whereas states in the west and north having major European components (Fig. 3b). Interestingly, these differences correlated with genetic diversity: states with higher Native American components showed reduced diversity [46] and reduced numbers of unique HLA haplotypes (Fig. 3c).

Fig. 3
figure3

Differential admixture in Mexican Mestizos manifests in HLA haplotypic diversity. Extended HLA haplotypes were determined for a sample of 15,318 Mexicans from all 32 states [46]. Putative continental origin of HLA haplotypes was determined as previously described [44]. a HLA haplotype frequency distribution in the whole of Mexico. The frequency of 4323 extended haplotypes is plotted against rank and symbols indicate continental origin. b Cumulative frequencies of Native American and European HLA haplotypes in each Mexican state (both Baja Californias, and the Federal District and State of Mexico, ZMVM, were grouped together for simplicity). States are ordered from north-west to south-east. c Unique HLA haplotypes were determined in random subsamples of 200 chromosomes for three north-western (Baja California, BC; Sonora, Son; Sinaloa, Sin) and three south-eastern (Yucatán, Yuc; Quintana Roo, QRoo; Campeche, Cam) states

HLA diversity and differential admixture in Latin American stem cell donor registries

As exposed above, sufficient size and HLA diversity of donor resources is crucial for their effectiveness in facilitating HCT with UD or CB. A few countries in Latin America possess UD registries and CB banks, and recent analyses provide insight into the role of genetic diversity and differential admixture in their development and usefulness. The two largest registries in the region, the Brazilian REDOME, and the Argentinian Incucai represent interesting examples of this interplay.

REDOME was founded in the 1990s and has seen a 100-fold increase in size in the last 15 years [48, 49], reaching ~5 million donors and making it currently the third largest registry in the world. Importantly, REDOME continues to add ~300,000 new donors every year, accounting for nearly 10% of all new donors worldwide. The heavily admixed population it draws upon makes it one of the most diverse registries.

Due to Brazil’s vast dimensions and regional variation in HLA diversity [50], a policy for optimized regional development has been followed since 2012. This has allowed for the inclusion of donors from the majority of Brazilian municipalities, with only 2.5% of Brazilian cities not having at least one donor registered at REDOME [51]. In addition to the impact on the international UD repertoire, this expansion has also contributed to consolidate alloHCT in Brazil, with the number of patients undergoing UD alloHCT doubling between 2008 and 2018, and 70% of these Brazilian patients having at least one available Brazilian donor.

Recent analyses of its allelic and haplotypic diversity [49, 52] show that donor self-reported ethnic categories Branca (European) and Parda (admixed) could be distinguished from the closely related Preta (African) and Indígena (Native American) groups, and the Amarela (East Asian) one based on their HLA haplotype repertoires [49]. We analyzed the putative continental origin of the 100 most common HLA haplotypes in the REDOME as reported previously [44] (Fig. 4a), and found that the unexpected similarity between Preta and Indígena groups could be explained by extensive admixture present in both groups and appreciable by the proportion of African HLA haplotypes in both categories (Fig. 4b). Overall, the extensive admixture present in the Brazilian population is reflected by the fact that 84 of the top 100 haplotypes including haplotypes of European (50/54), East Asian (2/9), African (21/25), and Native American (11/12) origin are present in all ethnic categories. Moreover, the top ten haplotypes of the whole registry [49] include haplotypes of European, African, and East Asian origin (Fig. 4c).

Fig. 4
figure4

Continental origin of the top 100 extended HLA haplotypes in the REDOME. a Putative continental origin of the top 100 extended HLA haplotypes among 2.9 million UD listed on the REDOME reported by Halagan et al. [49] was determined as previously described [44]. b Cumulative frequency of HLA haplotypes of African and Native American origin in UD of five groups of self-described ethnic categories (Amarela = Asian, Branca = European, Indígena = Native American, Parda = Admixed, Mulatto, Preta = African) and individuals with undeclared (Não Informado) category. c Frequencies of the top ten HLA haplotypes in the REDOME in each of the self-declared ethnic categories and in individuals with no declared category. Haplotypes of European, Asian, and African origin are indicated with black, light gray, and discontinuous lines, respectively

A different situation is present in the Argentinian registry. Founded in the early 2000s, Incucai currently registers over 160,000 UD and CB units. Although it includes donors from all regions of Argentina, the majority of them come from the country’s central provinces [53]. Data from a recent study of its HLA diversity [53] show that Incucai’s HLA haplotype distribution is dominated by haplotypes of European origin, with only 12 and four haplotypes of Native American and African origin, respectively, reaching the top 100 (Fig. 5a). Overall, out of 1954 unique haplotypes identified in the sample from Incucai, 1288 (66%) are of likely European origin and represent 72.5% of the haplotypic distribution (Fig. 5b). This might however change if focused recruitment is carried out in other regions of Argentina, where different admixture proportions have been reported [54,55,56,57]. These data on genetic diversity and its geographic distribution reinforce the complexity associated with the analysis of HLA heterogeneity in UD registries in the region.

Fig. 5
figure5

HLA extended haplotype distribution and continental origin for the Argentinian UD registry. a Frequency distribution of 1954 unique HLA haplotypes determined in 1472 UD listed in the Incucai [53]. Haplotype frequency is plotted against haplotype rank and haplotype putative continental origin is indicated by the symbols. b Cumulative frequency of haplotypes of diverse continental origin in the Incucai

HLA diversity and HCT development in Latin America: challenges and opportunities

HCT activity in Latin America has to be expanded in order to cope with the needs of its population. As exposed above, one key aspect for this expansion will have to be the tailoring of donor resources to the great genetic diversity due to differential admixture processes across populations in the region. It is necessary that this genetic diversity, in particular that of the HLA system, be more thoroughly characterized in order to achieve the optimization of HCT donor resources through the identification of population similarities/dissimilarities and selected, targeted recruitment of volunteer UD and CB units [58], something particularly relevant for minority populations [59].

Although genetic diversity in Latin America represents a challenge for HCT development, there is also room for opportunity. The presence and continuous development of UD registries and CB banks in the region should help increase the chances of Latin American patients finding donors, and closer collaboration between countries should foster donor exchange. The presence of a very large and diverse UD registry such as REDOME is a major asset for the Latin American HCT community. In fact, using a strategy previously implemented by the National Marrow Donor Program [22], REDOME’s rates of donor identification for hypothetical patients are encouragingly high and comparable across ethnic categories (Fig. 6). Moreover, REDOME has also become an alternative for international patients, with 282 hematopoietic cell products obtained from Brazilian donors exported to Europe, the Unites States, and Asia between 2016 and 2018. In addition, interest in increasing diversity in registries from other regions is also driving the expansion of donor recruitment in Latin America (e.g., Be The Match® Mexico, DKMS Chile), something that should also be an opportunity for Latin American countries. These examples highlight the potential of genetic diversity in the region and its impact on the supply of UD at the global level.

Fig. 6
figure6

Matching probabilities for REDOME. 10/10 and 9/10 donor matching rates for simulated “pseudo” patients were determined using the approach by Dehn et al. [22] according donor self-described ethnic categories (Amarela = Asian, Branca = European, Indígena = Native American, Parda = Admixed, Mulatto, Preta = African) from REDOME’s 2015 database after preliminary search (no additional HLA typing performed)

One important aspect relevant to this discussion is the growing use of haploidentical transplantation [60] in Latin America. This revolutionary transplantation platform has attracted the attention of transplant teams in developing countries [6], especially those lacking UD resources, mainly because it ensures that virtually all patients have a readily available related donor. For instance, in Brazil this modality represented 16% of alloHCT performed in 2016, and this number continues to increase [61]. Moreover, it does away with the financial costs of storage of CB units and the recruitment of UD. However, haploidentical transplantation requires special expertise, and there will still be patients lacking a haploidentical donor for whom an UD may be needed. In any case, Latin American countries will have to weigh these financial and logistic variables to decide whether the investment favors haploidentical transplantation or a combination of donor sources. A regional strategy for UD recruitment and exchange combined with the expansion of related transplantation in countries currently without activity might be the key for HCT success in Latin America.

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Arrieta-Bolaños, E., Oliveira, D.C. & Barquera, R. Differential admixture, human leukocyte antigen diversity, and hematopoietic cell transplantation in Latin America: challenges and opportunities. Bone Marrow Transplant 55, 496–504 (2020). https://doi.org/10.1038/s41409-019-0737-4

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