The human leukocyte antigen (HLA) system, located on chromosome 6, is encoded by more than 200 highly polymorphic genes and functions to present antigenic peptides to the immune system. This system is divided into class I (HLA-A, -B, and -C) and class II (HLA-DR, -DQ, and -DP) loci. It plays a critical role in inducing and regulating both innate and adaptive immunity, and is consequently central to transfusion and transplantation compatibility, infectious disease responses, and pharmacogenomics (1).

In transfusion medicine, the absence of routinely HLA-matched blood products can lead to HLA sensitization, a condition associated with complications such as platelet refractoriness, transfusion-related acute lung injury (TRALI), and an increased risk of rejection in future transplants (2). Although leukoreduction and irradiation can mitigate these risks, their implementation is often inconsistent, particularly in developing countries like Colombia. There, leukoreduction remains limited, and irradiation is primarily reserved for preventing transfusion-associated graft-versus-host disease in high-risk patients (e.g., transfusion-associated graft-versus-host disease) (3). Avoiding HLA sensitization is crucial in multiple clinical settings including pregnancy, autoimmune diseases, and recurrent transfusions. Consequently, improving HLA compatibility represents an imperative goal for transfusion safety.

Advances in high-resolution HLA typing, now a gold standard in precision medicine, have revealed extensive allelic diversity, underscoring the need for population-specific genetic profiling. Latin American populations, particularly those with trihybrid ancestry (Indigenous, European, and African), such as found in Colombia, exhibit unique HLA diversity that remains markedly underrepresented in global databases (4, 5). This gap perpetuates healthcare disparities by limiting equitable access to safe transfusions, transplantation, and personalized therapies. Although a previous study demonstrated HLA genetic heterogeneity within Colombia (6), its findings were constrained by a limited sample size.

In this context, blood donors represent an ideal cohort for advancing such HLA studies. This population is typically large, ethnically diverse, and composed of essentially healthy volunteers, from whom biological samples and data can be ethically and readily obtained. The resulting high-resolution HLA data are of direct importance to transfusion medicine, as they can inform strategies to mitigate the risks of HLA sensitization and its associated complications, discussed above.

Establishing a local HLA databases is essential to enhance transfusion safety by minimizing alloimmunization risks in multi-transfused patients, improve transplant outcomes through better donor-recipient matching, especially for underrepresented groups, advance personalized medicine by enabling pharmacogenomics studies, and research on immune responses to endemic or emerging pathogens, and expand anthropogenetic knowledge of Colombia’s population history and its impact on immunogenetic variation.

Here, we present a high-resolution analysis of HLA diversity from over 11,500 Colombian blood donors across two distinct regions (Andean and Caribbean). This dataset provides a population-level characterization of HLA allele carrier status, genotype distributions and linkage disequilibrium measures in a Colombian cohort for HLA-A, -B, -DRB1, -DQB1, and -DPB1. These metrics collectively support clinical and immunogenetic applications such as donor–recipient matching feasibility, haplotype-based registry optimization, and regional benchmarking of immunogenetic diversity.

This resource is poised to bridge critical equity gaps in Latin-American genomic medicine and strengthen public health infrastructure. Furthermore, it establishes a foundational dataset for future research on Colombian HLA diversity, the interplay between genetic ancestry and immunogenetic variation, HLA-pathogen interactions in endemic infections, and HLA- disease associations.

It is well known that the HLA system plays a decisive role in clinical practice. Its extensive polymorphism and immunogenic poses significant challenges in transfusion and transplantation medicine. Currently, a high percentage of patients, including multi-transfused individuals, receive HLA-mismatched and even non-leukoreduced blood components, which can trigger the production of cytotoxic anti-HLA antibodies and, therefore, the alloimmunization of these patients (8). This alloimmunization can lead to serious complications such as platelet refractoriness, transfusion-related acute lung injury (TRALI), and in rare cases, non-hemolytic febrile transfusion reaction. Furthermore, immunocompetent cells in the blood component could recognize receptor cells’ histocompatibility antigens and generate a transfusion-associated graft-versus-host disease (8). The large, diverse, and readily accessible cohort of volunteer blood donors thus represents an invaluable resource for building the immunogenetic knowledge base needed to address these clinical challenges.

Colombia’s trihybrid ancestry (European, African, and Indigenous American) has generated a unique HLA landscape, one that remains poorly characterized at high resolution. Our study addresses this critical gap by presenting the first high-resolution of HLA allele and haplotype frequency analysis in a large-scale Colombian cohort (n = 11,576 blood donors), covering six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1). This represents one of the most comprehensive immunogenetic datasets for a Latin American population to date. By comparing two geographically and ancestrally distinct subpopulations: the high-altitude Andean region (predominantly Indigenous American/European ancestry, >2–000 meters above sea level) and the coastal Caribbean region (with stronger African admixture), we reveal a genetic complexity that directly reflects the nation’s rich demographic history, characterized by admixture among Indigenous, European, and African ancestral sources.

Our analysis identified 565 distinct allelic groups for HLA A*, B*, C*, DRB1*, DQB1* and DPB1* of the about 35,000 reported worldwide (9). The results reveal a high degree of genetic complexity shaped by the country’s rich demographic history, characterized by admixture among Indigenous, European, and African ancestral sources. Similar to high-resolution HLA studies in Latin America that have revealed high levels of diversity based on number of HLA alleles for each HLA loci, as well as high heterozygosity in Brazilian (10) and Mexican populations (11).

In class I, the HLA-A, -B, and -C loci demonstrated considerable allelic diversity, particularly HLA-B, exhibited considerable polymorphism, with prevalent alleles such as A*24:02:01G (21.63%), B*35:43:01G (8.57%), and C*04:01:01G (15.63%), supporting findings from previous Colombian studies (6, 12) and other admixed populations (1), while also suggesting the persistence of conserved haplotypes. Among class II loci, DRB1 and DQB1 displayed moderate-to-high polymorphism, with DRB1*04:07:01G (12.25%) and DQB1*03:02:01G, being the most common, frequencies also similar to those reported in Colombian studies (6, 12). Interestingly, DPB1 displayed a more constrained diversity, with two alleles—DPB1*04:02:01G and DPB1*04:01:01G—accounting for nearly 44% of all observations. A pattern also noted in other global populations (Chinese, Caucasians and Saudi) (1). These results underscores the necessity for local genetic studies, as HLA frequencies can differ significantly, even among subgroups within an admixed nation like Colombia.

The extreme haplotype diversity we observed—17,317 distinct six-locus combinations— these results are aligned with prior studies in admixed Latin American populations, where high haplotype diversity and low frequency of top haplotypes (<5%) are consistently reported (13, 14). The top 20 haplotypes had a cumulative frequency of only 3.17%, a pattern mirroring findings in Mexican Mestizos and Brazilians (10, 15). This reflects a high degree of heterogeneity, with no single haplotype dominating the distribution, and evidence that Interbreeding increases rare haplotypes, underscoring the impact of trihybrid ancestry (Indigenous, European, African) on HLA architecture. This heterogeneity, driven by trihybrid ancestry, complicates donor-recipient matching but profoundly enriches the region-specific immunogenetic dataset, representing a critical step toward reducing disparities in genomic research coverage (16), thus our results represent meaningful progress in bridging population disparities in genomic research coverage.

In contrast, HLA profiles among Colombian Amerindian groups, show a very low allele diversity. Therefore, some alleles are in high frequency as observed in class II DRB1, where alleles *0403, 0407 and *0411 are common (17). Several alleles are shared with Asian and Pacific Islander populations (18). Additionally, research on Afro-American populations, such as those in San Basilio de Palenque, reveals a unique genetic heritage reflective of this community’s ancestry (19), highlight the distinct HLA gene frequencies in this semi-isolated population, emphasizing the need for population-specific HLA databases, particularly in admixed Latin American populations.

Our population genetics analyses provide further insights. The absence of significant deviation from Hardy-Weinberg equilibrium across all loci indicates a stable, randomly mating population sample (20, 21). Furthermore, we detected strong linkage disequilibrium (LD), not only within but also between class I and class II loci (e.g., HLA-A with DQB1). This points to the preservation of extended haplotypes, likely maintained by balancing selection (22). These findings are consistent with prior reports of conserved HLA haplotype blocks in other admixed populations (13, 14).

In addition to carrier and expanded haplotype frequency analyses, this study conducted a comprehensive evaluation of linkage disequilibrium (LD) across the six classical HLA loci. Strong LD signals were observed particularly between class II loci and between class I and class II regions, most notably between HLA-A and HLA-DQB1, as well as HLA-B and HLA-DPB1, suggesting the presence of extended haplotypes likely maintained by selective pressures. These non-random associations support the hypothesis of conserved haplotypic structures within the Colombian population. Furthermore, population-level comparisons performed using Euclidean distance matrices, principal component analysis (PCA), and UPGMA clustering, revealed close genetic affinities between Colombian samples and Indigenous Chilean populations such as the Mapuche and Northern Interior groups (7) (Figure 4). Shared haplotypes between Peruvian, Bolivian, and Chilean Indigenous groups point to a continuum genetic exchange extending northward to Colombia (23), indicating that there is an ancient population continuity and later divergence, thus this close genetic proximity suggesting pre-Columbian migrations along the Andes. These patterns are consistent with a shared Andean genetic background shaped by ancient population movements (24, 25) and reflect both ancient population movements and more recent admixture events (26). This admixed background creates population-specific disease risks and pharmacogenomic profiles (27–29), but at the same time, unique HLA haplotypes from admixture complicate, for example, efforts in transplant matching and other areas of precision medicine, thereby necessitating tailored clinical approaches.

One limitation of this study is that, although it provides a comprehensive characterization of known allelic variants in HLA class I and II genes, systematic discovery of novel alleles was not feasible. Genotyping was performed by a third-party service, and only final consensus calls—not raw sequencing data—were accessible, per contractual agreement, to the authors. Consequently, the absence of reported novel alleles reflects methodological constraints rather than definitive allelic exhaustiveness in the population. Future studies will be essential to identify rare or population-specific variants with potential functional relevance to immune response and disease susceptibility.

In summary, this high-resolution HLA characterization of the Colombian population, particularly in Bogotá, provides an essential foundation for advancing public health and serves as an essential resource for future clinical and anthropological research. The findings underscore the critical need for localized genomic research to capture the unique immunogenetic landscape of underrepresented populations. Genomic research is essential for optimizing diagnostics, therapeutics, and ultimately, for achieving health equity in transfusion medicine, transplantation, and beyond. This dataset constitutes a national immunogenetic reference for Colombia and key contribution to Latin American population genomics.