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The primary goal of the unrelated population HLA diversity (UPHD) component of the 17th International HLA and Immunogenetics Workshop was to characterize HLA alleles at maximum allelic-resolution in worldwide populations and re-evaluate patterns of HLA diversity across populations. The UPHD project included HLA genotype and sequence data, generated by various next-generation sequencing methods, from 4,240 individuals collated from 12 different countries. Population data included well-defined large datasets from the USA and smaller samples from Europe, Australia, and Western Asia. Allele and haplotype frequencies varied across populations from distant geographical regions. HLA genetic diversity estimated at 2- and 4-field allelic resolution revealed that diversity at the majority of loci, particularly for European-descent populations, was lower at the 2-field resolution. Several common alleles with identical protein sequences differing only by intronic substitutions were found in distinct haplotypes, revealing a more detailed characterization of linkage between variants within the HLA region. The examination of coding and non-coding nucleotide variation revealed many examples in which almost complete biunivocal relations between common alleles at different loci were observed resulting in higher linkage disequilibrium. Our reference data of HLA profiles characterized at maximum resolution from many populations is useful for anthropological studies, unrelated donor searches, transplantation, and disease association studies.

The human leukocyte antigen (HLA) genes are extremely polymorphic and are useful molecular markers to make inferences about human population history. However, the accuracy of the estimation of genetic diversity at HLA loci very much depends on the technology used to characterize HLA alleles; high-resolution genotyping of long-range HLA gene products improves the assessment of HLA population diversity as well as other population parameters compared to lower resolution typing methods. In this study we examined allelic and haplotype HLA diversity in a large healthy European American population sourced from the UCSF-DNA bank. A high-resolution next-generation sequencing method was applied to define non-ambiguous 3- and 4-field alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1 loci in samples provided by 2248 unrelated individuals. A number of population parameters were examined including balancing selection and various measurements of linkage disequilibrium were calculated. There were no detectable deviations from Hardy-Weinberg proportions at HLA-A, HLA-DRB1, HLA-DQA1 and HLA-DQB1. For the remaining loci moderate and significant deviations were detected at HLA-C, HLA-B, HLA-DRB3/4/5, HLA-DPA1 and HLA-DPB1 loci mostly from population substructures. Unique 4-field associations were observed among alleles at 2 loci and haplotypes extending large intervals that were not apparent in results obtained using testing methodologies with limited sequence coverage and phasing. The high diversity at HLA-DPA1 results from detection of intron variants of otherwise well conserved protein sequences. It may be speculated that divergence in exon sequences may be negatively selected. Our data provides a valuable reference source for future population studies that may allow for precise fine mapping of coding and non-coding sequences determining disease susceptibility and allo-immunogenicity.

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.

The 17th International HLA and Immunogenetics Workshop (IHIW) conducted a project entitled "The Study of Haplotypes in Families by NGS HLA". We investigated the HLA haplotypes of 1017 subjects in 263 nuclear families sourced from five US clinical immunogenetics laboratories, primarily as part of the evaluation of related donor candidates for hematopoietic stem cell and solid organ transplantation. The parents in these families belonged to five broad groups - African (72 parents), Asian (115), European (210), Hispanic (118) and "Other" (11). High-resolution HLA genotypes were generated for each subject using next-generation sequencing (NGS) HLA typing systems. We identified the HLA haplotypes in each family using HaplObserve, software that builds haplotypes in families by reviewing HLA allele segregation from parents to children. We calculated haplotype frequencies within each broad group, by treating the parents in each family as unrelated individuals. We also calculated standard measures of global linkage disequilibrium (LD) and conditional asymmetric LD for each ethnic group, and used untruncated and two-field allele names to investigate LD patterns. Finally we demonstrated the utility of consensus DNA sequences in identifying novel variants, confirming them using HLA allele segregation at the DNA sequence level.

The highly polymorphic classical human leukocyte antigen (HLA) genes display strong linkage disequilibrium (LD) that results in conserved multi-locus haplotypes. For unrelated individuals in defined populations, HLA haplotype frequencies can be estimated using the expectation-maximization (EM) method. Haplotypes can also be constructed using HLA allele segregation from nuclear families. It is straightforward to identify many HLA genotyping inconsistencies by visually reviewing HLA allele segregation in family members. It is also possible to identify potential crossover events when two or more children are available in a nuclear family. This process of visual inspection can be unwieldy, and we developed the "HaplObserve" program to standardize the process and automatically build haplotypes using family-based HLA allele segregation. HaplObserve facilitates systematically building haplotypes, and reporting potential crossover events. HLA Haplotype Validator (HLAHapV) is a program originally developed to impute chromosomal phase from genotype data using reference haplotype data. We updated and adapted HLAHapV to systematically compare observed and estimated haplotypes. We also used HLAHapV to identify haplotypes when uninformative HLA genotypes are present in families. Finally, we developed "pould", an R package that calculates haplotype frequencies, and estimates standard measures of global (locus-level) LD from both observed and estimated haplotypes.

DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on 496 healthy adult donors from San Diego, California, to characterize allele frequencies in support of studies of T cell responses to common allergens. Deviations from Hardy Weinberg proportions were detected at each locus except A and C. Several alleles were found in more than 15% of individuals, including the class II alleles DPB1∗02:01, DPB1∗04:01, DQA1∗01:02, DQA1∗05:01, DQB1∗03:01, and the class I allele A∗02:01. Genotype data will be available in the Allele Frequencies Net Database (AFND 3562).

The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3 ∼ KIR3DL1/S1 ∼ KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

Differences in outcome to COVID-19 infection in different individuals is largely attributed to genetic heterogeneity leading to differential immune responses across individuals and populations. HLA is one such genetic factor that varies across individuals leading to differences in how T-cell responses are triggered against SARS-CoV-2, directly influencing disease susceptibility. HLA alleles that influence COVID-19 outcome, by virtue of epitope binding and presentation, have been identified in cohorts worldwide. However, the heterogeneity in HLA distribution across ethnic groups limits the generality of such association. In this study, we address this limitation by comparing the recognition of CTL epitopes across HLA genotypes and ethnic groups. Using HLA allele frequency data for ethnic groups from Allele Frequency Net Database (AFND), we construct synthetic populations for each ethnic group and show that CTL epitope strength varies across HLA genotypes and populations. We also observe that HLA genotypes, in certain cases, can have high CTL epitope strengths in the absence of top-responsive HLA alleles. Finally, we show that the theoretical estimate of responsiveness and hence protection offered by a HLA allele is bound to vary across ethnic groups, due to the influence of other HLA alleles within the HLA genotype on CTL epitope recognition. This emphasizes the need for studying HLA-disease associations at the genotype level rather than at a single allele level. [ABSTRACT FROM AUTHOR]

DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on 714 healthy adult blood bank donors from Colombo, Sri Lanka, to characterize allele frequencies in support of studies on T cell immunity against pathogens, including Dengue virus. Deviations from Hardy Weinberg proportions were not detected at any locus. Several alleles were found in >30% of individuals, including the class II alleles DPB1 * 04:01, DPB1 * 02:01, DQB1 * 06:01 and DRB1 * 07:01, and the class I alleles A * 33:03 and A * 24:02. Genotype data will be available in the Allele Frequencies Net Database.

DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on anonymized samples provided by 339 healthy adult blood bank donors in Managua, Nicaragua. The purpose of the study was to characterize allele frequencies in the local population to support studies of T cell immunity against pathogens, including Dengue virus. Deviations from Hardy Weinberg proportions were detected for all class II loci (HLA-DPB1, -DQA1, -DQB1 and -DRB1), and at the class I C locus, but not at the class I A and B loci. The genotype data will be available in the Allele Frequencies Net Database.

In this population-based case-control study conducted in the Chelyabinsk region of Russia, we examined the distribution of HLA - A, - B, - C, - DRB1, - DQB1 and - DPB1, in a group of 100 patients with confirmed COVID - 19 bilateral pneumonia. Typing was performed by NGS and statistical calculations were carried out with the Arlequin program. HLA - A, - B, - C, - DRB1, - DQB1 and - DPB1 alleles were compared between patients with COVID-19 and 99 healthy controls. We identified that COVID - 19 susceptibility is associated with alleles and genotypes rs9277534A (disequilibrium with HLA-DPB1*02:01, −02:02, −04:01, −04:02, −17:01 alleles) with low expression of protein products HLA-DPB1 (pc < 0.028) and homozygosity at HLA-C*04 (p = 0.024, pc = 0.312). Allele HLA-A*01:01 was decreased in a group of patients with severe forms of bilateral pneumonia, and therefore it may be considered as a protective factor for the development of severe symptoms of COVID - 19 (p = 0.009, pc = 0.225). Our studies provide further evidence for the functional association between HLA genes and COVID - 19. [ABSTRACT FROM AUTHOR]

Although human leukocyte antigen (HLA) gene polymorphism has been investigated in many populations around the world, the data on MHC class I chain-related (MIC) genes are still limited. The present study is aimed to analyze the allelic polymorphism of MICA and MICB genes and haplotype associations with HLA-B locus in 132 healthy, unrelated individuals from the Bulgarian population by next generation sequencing (NGS). A total of 36 MICA and 16 MICB alleles were observed with the highest frequency detected for MICA*008:01 (17.1%) and MICB*005:02 (32.4%). Further, two and three-loci haplotype frequencies and pairwise linkage disequilibrium were estimated. Highly significant global linkage disequilibrium was found between either HLA-B and MICA and MICB genes. This is the first study on MICA and MICB allelic polymorphism, linkage disequilibrium, and haplotype polymorphism in the Bulgarian population. These results will allow for better characterization of the genetic heterogeneity of the Bulgarian population and could contribute to further analyses on MICA and MICB clinical significance. [ABSTRACT FROM AUTHOR]

Next-generation DNA sequencing (NGS) technology advancements provide new insight into the level of variation in killer immunoglobulin-like receptor (KIR) genes. High resolution allele genotyping of seven KIR genes was conducted among 94 unrelated Malay and Orang Asli (OA) individuals of Peninsular Malaysia. A manual bioinformatics analysis is performed and optimised by Sanger sequencing method. The Malays expressed a total of 22 alleles, as compared to only 15 alleles in the OA population. In total, 12 centromeric and 9 telomeric allelic haplotypes were identified in the Malays, whereas 8 centromeric and 5 telomeric allelic haplotypes were identified in the OA. The KIR2DL1 , KIR2DL3 , and KIR2DS4 genes exhibited a high degree of variation and balanced distribution in the Malay and OA populations. On the other hand, KIR2DL4 , KIR3DL1, KIR3DL2 and KIR3DL3 genes exhibited a high degree of conservation, with less number of alleles identified and the dominance of a single allele at high frequency. High-resolution KIR allele genotyping has revealed unique sequence variations and allelic haplotypes between individuals and populations. The distributions of KIR alleles and haplotypes are useful for genetic population studies and serve as a baseline for future transplantation matching and disease association research. [ABSTRACT FROM AUTHOR]

The risk of HIV-1 infection and the rate of disease progression vary considerably among individuals and the genetic makeup of the host may be one of the possible reasons for this. We aimed to determine association of functional single nucleotide polymorphism (SNPs), -1082A/G (rs1800896), -819C/T (rs1800871), and -592C/A (rs1800872) in IL-10 gene, with the susceptibility to HIV-1 infection and clinical parameters expressed as a baseline CD4 + T cell count, CD8 + T cell count, and viral load. Therapy naïve HIV-1 infected individuals and HIV-1 seronegative controls from Poland were recruited for this study. Genotyping results revealed significantly higher frequency of -1082G/G genotype (28.1 % vs 16.1 %; p = 0.0019, OR=0.49) and -1082G allele (47.6 % vs 38.8 %; p = 0.0028, OR = 0.70) as well as lower frequency of -592 and -819 heterozygosity (45.0 % vs 34.4 %; p = 0.0266, OR = 1.47) in controls compared to seropositive subjects. High producing haplotype GCC was associated with increased risk of HIV-1 infection (p = 0.0018, OR = 1.52). Individuals possessing -592 and -819 minor allele had significantly higher CD8 + T cell count compared to the wild type allele carriers (p = 0.0303). Moreover, presence of -1082G allele was related with lower viral load as well as CD4 + and CD8 + T cells counts among patients infected with R5 HIV-1 variant. Thus, IL-10 gene promoter variants may be a risk factor for HIV-1 transmission and may modulate disease progression in the Polish population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Punjabi population, constituting over 45 % of the country's total population, holds the highest prevalence in Pakistan. To understand their HLA genetics, we genotyped 389 Punjabi subjects for major Class-I loci using the PCR-SSO Luminex® method. Our study identified a total of 162 alleles, including 41 different HLA-A, 72 HLA-B, and 49 HLA-C alleles. The most common alleles included A*11:01 (14.6 %), A*01:01 (11.8 %), A*24:02 (11.3 %); B*40:06 (13.3 %), B*08:01 (10.9 %), B*51:01 (8.7 %); C*15:02 (15.5 %), C*07:02 (15.3 %), and C*04:01 (10.8 %). However, only locus B showed a significant deviation from HWE. The dominant Class I haplotype was A*24:02-B*40:06-C*15:02, followed by A*11:01-B*40:06-C*15:02, while significant LD was observed between all pairs of HLA loci. A distinct genetic makeup was observed in the Pakistani Punjabis as compared to Indian Punjabis, emphasizing the impact of the Indo-Pak partition and religious choices for marriage. In comparison to country's other ethnic groups, the Pakistani population exhibited 76 different alleles at a low field-resolution, with the Punjabi population having highest polymorphism. Phylogenetic analysis revealed that the Punjabi population is most closely related to the Sindhi population, while both populations sharing ancient connections with the Burusho population. These findings have significant implications for transplantation procedures, personalized medicine, disease susceptibility, and evolutionary studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Graft-versus-host disease (GVHD) is a potentially serious complication ofallogeneic hematopoietic stem cell transplantation (HSCT). Graft-contaminating T cells (donor T cells) arecrucial for the development ofGVHD since they are able to react against the recipient's antigens. In this study we aim toevaluatethepotentialassociation between the IVS3 + 17 T/C gene variation in the CD28 molecule, a T cells costimulatory factor, and the GVHD occurrence in a Tunisian group of recipients of allo-HSCTs. Results show that there is an association between the presence of this polymorphism and the occurrence of grades II-IV acute GVHD (OR: 2.470, I.C: 1.027-5.938, p = 0.043). As for the chronic GVHD, it seems that the studied gene variation has no impact on the occurrence of this complication, which appeared likely to be affected by the HSCT graft source (PBSC: peripheral blood stem cells) (OR: 5.141, I.C: 1.590-16.620, p = 0.006). Based on these data, we believe that the CD28 IVS3 + 17 T/C polymorphism is a significant factor in the pathogenesis of acute GVHD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

One hundred healthy infants enrolled as controls in a tuberculosis vaccine study in Nyanza Province, Kenya provided anonymized samples for DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, -DRB1, and -DRB3/4/5 loci. The purpose of the study was to characterize allele frequencies in the local population, to support studies of T cell immunity against pathogens, including Mycobacterium tuberculosis. There are no detectable deviations from Hardy Weinberg proportions for the HLA-B, -C, -DRB1, -DPB1, -DQA1 and -DQB1 loci. A minor deviation was detected at the HLA-A locus due to an excess of HLA-A*02:02, 29:02, 30:02, and 68:02 homozygotes. The genotype data are available in the Allele Frequencies Net Database under identifier 3393.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that impacts connective tissue and can affect various organs and systems within the body. One important aspect of this disease is the role of the human leukocyte antigen (HLA) system, a protein complex that plays a role in the immune response. Specifically, the HLA-DRB1 and HLA-DQB1 genes have been implicated in the development of SLE. In order to better understand this relationship in the Guatemalan population, a study was conducted with the objective of characterizing the allelic and haplotype profiles of the HLA-DQB1 and HLA-DRB1 loci in 50 patients diagnosed with SLE who were receiving treatment at a hospital in Guatemala. Allele and haplotype frequencies were determined and compared to 127 healthy Guatemalan subjects as a control group. The results of the analysis showed a reduction in the frequencies of HLA-DQB1*03 and HLA-DRB1*14 in SLE patients, which could suggest a protective effect on the development of the disease. In contrast, a risk association was found between HLA-DRB1*07, HLA-DRB1*08, HLA-DQB1*02 and HLA-DQB1*06 in SLE patients. Finally, we observed an additional protective associated of haplotype HLA-DRB1*04∼DQB1*03 with SLE patients, while haplotypes HLA-DRB1*07∼DQB1*02 and DRB1*08-DQB1*06 showed a risk association. [ABSTRACT FROM AUTHOR]

Currently, the genetic variants strongly associated with risk for Multiple Sclerosis (MS) are located in the Major Histocompatibility Complex. This includes DRB1*15:01 and DRB1*15:03 alleles at the HLA-DRB1 locus, the latter restricted to African populations; the DQB1*06:02 allele at the HLA-DQB1 locus which is in high linkage disequilibrium (LD) with DRB1*15:01 ; and protective allele A*02:01 at the HLA-A locus. HLA allele identification is facilitated by co-inherited ('tag') single nucleotide polymorphisms (SNPs); however, SNP validation is not typically done outside of the discovery population. We examined 19 SNPs reported to be in high LD with these alleles in 2,502 healthy subjects included in the 1000 Genomes panel having typed HLA data. Examination of 3 indices (LD R2 values, sensitivity and specificity, minor allele frequency) revealed few SNPs with high tagging performance. All SNPs examined that tag DRB1*15:01 were in perfect LD in the British population; three showed high tagging performance in 4 of the 5 European, and 2 of the 4 American populations. For DQB1*06:02 , with no previously validated tag SNPs, we show that rs3135388 has high tagging performance in one South Asian, one American, and one European population. We identify for the first time that rs2844821 has high tagging performance for A*02:01 in 5 of 7 African populations including African Americans, and 4 of the 5 European populations. These results provide a basis for selecting SNPs with high tagging performance to assess HLA alleles across diverse populations, for MS risk as well as for other diseases and conditions. [ABSTRACT FROM AUTHOR]

The heterogenous population of Malaysia includes more than 50 indigenous groups, and characterizing their HLA diversity would not only provide insights to their ancestry, but also on the effects of natural selection on their genome. We utilized hybridization-based sequence capture and short-read sequencing on the HLA region of 172 individuals representing seven indigenous groups in Malaysia (Jehai, Kintaq, Temiar, Mah Meri, Seletar, Temuan, Bidayuh). Allele and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, -DPA1 , and -DPB1 revealed several ancestry-informative markers. Using SNP-based heterozygosity and pairwise Fst, we observed signals of natural selection, particularly in HLA-A , -C and -DPB1 genes. Consequently, we showed the impact of natural selection on phylogenetic inference using HLA and non-HLA SNPs. We demonstrate the utility of Next Generation Sequencing for generating unambiguous, high-throughput, high-resolution HLA data that adds to our knowledge of HLA diversity and natural selection in indigenous minority groups. [ABSTRACT FROM AUTHOR]

The class I and class II Human Leucocyte Antigens (HLA) are an integral part of the host adaptive immune system against viral infections. The characterization of HLA allele frequency in the population can play an important role in determining whether HLA antigens contribute to viral susceptibility. In this regard, global efforts are currently underway to study possible correlations between HLA alleles with the occurrence and severity of SARS-CoV-2 infection. Specifically, this study examined the possible association between specific HLA alleles and susceptibility to SARS-CoV-2 in a population from the United Arab Emirates (UAE). The frequencies of HLA class I (HLA-A, -B , and -C) and HLA class II alleles (HLA-DRB1 and - DQB1); defined using Next Generation Sequencing (NGS); from 115 UAE nationals with mild, moderate, and severe SARS-CoV-2 infection are presented here. HLA alleles and supertypes were compared between hospitalized and non-hospitalized subjects. Statistical significance was observed between certain HLA alleles and supertypes and the severity of the infection. Specifically, alleles HLA-B*51:01 and HLA-A*26:01 showed a negative association (suggestive of protection), whilst genotypes HLA-A*03:01, HLA-DRB1*15:01, and supertype B44 showed a positive association (suggestive of predisposition) to COVID-19 severity. The results support the potential use of HLA testing to differentiate between patients who require specific clinical management strategies. [ABSTRACT FROM AUTHOR]

The fact that CD6, along with its ligand - ALCAM, plays a role in regulating T cell activation makes the genes encoding these molecules promising candidates for research in T cell-mediated diseases such as psoriasis vulgaris (PsV). Our study aimed to determine whether CD6 (rs17824933C>G, rs11230563C>T and rs12360861G>A) and ALCAM (rs6437585C>T, rs11559013G>A) polymorphisms may affect psoriasis susceptibility and severity (assessed by Psoriasis Area and Severity Index (PASI)). Moreover, the presence of HLA-C*06:02, the strongest psoriasis risk factor in the Caucasian population, was also investigated. 273 patients diagnosed with psoriasis vulgaris and 256 blood donors with no history of PsV or other dermatoses were included in this study. Genotyping of the investigated polymorphisms was carried out using the allelic discrimination method with the application of TaqMan SNP Genotyping Assays. We observed the association of rs17824933G allele with a higher psoriasis risk in HLA-C*06:02(+) individuals (CG + GG vs CC, OR = 1.87, CI95% = 1.03; 3.37, p = 0.0350). Furthermore, we found a difference in average PASI score among groups of patients divided according to the number of CD6 and ALCAM polymorphic sites with minor alleles (F 2,173  = 6.159, p = 0.0026). Collectively, our findings suggest that polymorphisms of CD6-ALCAM axis genes may modulate psoriasis risk and outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

HLA studies in Crete show that this population is related to North Africans and also Iberians. This may be a reflection of a common prehistoric first Europeans relationships with North Africans and drying Saharan emigration after 10,000 years BC; it may be specifically represented by a primitive and early cult to the bull in both Cretan (Minoan) and Iberian populations. In the present study, unrelated Cretans representing different Island parts have been studied for class II HLA-DRB1 and -DQB1 alleles. The most frequent ones were HLA-DRB1*11:01 and HLA-DRB1*07:01 and HLA-DQB1*03:01 and DQB1*05:01. Also, the Cretan HLA class II haplotype HLA-DBR1*11:01-DQB1*03:01 had the highest frequency and is also common to other Mediterraneans, including Iberians. In addition, DRB1*07:01-DQB1*02:01 and HLA-DRB1*04:02-DQB1*03:02 Cretan haplotypes are shared with North Africans (the latter with Algerians, Tunisians and Moroccans). In summary, Crete was one of the first European classic cultures (Minoan) which was probably an early link, like Iberia, between North Africa /Sahara and Europe,also supported by genetic results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Waorani, an isolated indigenous tribe in Ecuador, have long been characterized by limited genetic diversity, with few studies delving into their genetic background. Human Leukocyte Antigen (HLA) genes which are located in the human major histocompatibility complex (MHC) provides valuable insights into population evolution due to its highly polymorphic nature. However, little is known about the HLA diversity and ancestry of the Waorani population. In this study, we sequenced eight HLA genes using Next Generation Sequencing (NGS) from 134 Waorani individuals and obtained up to four-field HLA allele resolution. Cluster and phylogenetic analysis show that the Waorani are genetically distant from other Ecuador populations, but instead show genetic affinities with the Puyanawa and Terena tribes from Brazil, as well as the Mixe tribe from Mexico. The identification of alleles common within the Waorani population, previously linked to specific health conditions, notably paves the way for future association analyses. This extensive study, employing Next-Generation Sequencing (NGS) technology, significantly enriches the sparse and segmented understanding of HLA diversity in the South American region. Our findings enhance the global comprehension of human genetic diversity and underscore the value of studying indigenous populations. Such research is vital for deepening our insights into human migration patterns and evolutionary processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

The diversity of clinical manifestations in COVID-19 has been observed not only among individuals but also among various populations in globally. HLA molecules play a central role in physiology, protective immunity, and deleterious, disease-related autoimmune reactivity or overreaction. This study exploited the association between HLA frequencies and SARS-CoV-2 susceptibility and disease severity among the Vietnamese cohort (159 patients and 52 controls). A significant difference in frequency of both HLA class I and II in mild, moderate, and severe/fatal COVID-19 patients and negative exposure individuals - the controls were observed. Regarding SARS-CoV-2 sensitivity, HLA-A*03:01, 30:01, HLA-DQA1*01:02, DRB1*15:01, and DRB5*02:02 presented higher frequency in the control group compared with infected patients but DRB1 09:01 frequency was higher in infected patients. Regarding COVID-19 severity, HLA-F*01:01, 01:03 and DPA1*01:03 and 02:01, DPB1*04:01, DQA1*01:02, and DQB1*05:02 alleles were detected with higher frequency in severe patients but DOB*01:01, DRB1*05:01 and 09:01 had a significantly higher frequency in the mild group than remaining groups. Surprisingly, HLA-DQA1*01:02 and DRB1*09:01 alleles were identified with both inversely potential roles in protective function and severe risk. The obtained data herein will contribute to explore on the role of host genetic background in the pathology of COVID-19 disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

We developed a cost-efficient workflow for genotyping HLA-E by NGS and applied it for genotyping more than 2.5 million potential stem cell donors. The data obtained were used to determine HLA-E allele frequency distributions for 104 populations. Our results confirm the known dominance of the alleles E*01:01 and E*01:03, which have a combined frequency of more than 0.99 in 97 of the 104 populations. E*01:01 is more frequent in Africa and the western part of South America, E*01:03 in Southeast and East Asia. E*01:03 shows a pronounced regional substructure at the high-resolution level with E*01:03:01G being particularly common in a large connected region extending from Turkey to China, E*01:03:02G in Northwestern Europe and E*01:03:03 in Central and Eastern Europe as well as Central Asia. The presented results are relevant both as a basis for further population genetics studies and for optimizing stem cell donor searches. [ABSTRACT FROM AUTHOR]

The extensive allelic variability observed in several genes related to the immune response and its significance in different areas including transplantation, disease association studies, diversity in human populations, among many others, has led the scientific community to analyse these variants among individuals. Serving as an electronic data warehouse, the Allele Frequency Net Database (AFND, http://www.allelefrequencies.net) contains data on the frequency of immune related genes and their corresponding alleles from more than 1700 worldwide population samples covering more than ten million unrelated individuals. The collection of population data sets available in AFND encompasses different polymorphic regions including the highly-polymorphic human leukocyte antigen (HLA) system for which more than 1200 populations are available. In this article, we provide an insight of the high diversity found in the HLA region by examining population data sets stored in AFND, as well as a description of the available data sets for further analyses. [ABSTRACT FROM AUTHOR]

The single-antigen bead assay (SABA) demonstrates high sensitivity and specificity for detecting anti-human leukocyte antigen (HLA) antibodies. However, SABA may produce false-positive results for anti-HLA antibodies. Herein, we analyzed the data of patients with complement-dependent cytotoxic crossmatch−/flow cytometric crossmatch−/SABA+/− results to determine false-positive results for anti-HLA antibodies. We also determined the prevalence of false-positive results by comparing false-positive data from our laboratory and national allele frequency data obtained with high-resolution HLA typing. For HLA-A, -B, -C, and -DR, a ratio of positive frequency to allele frequency of ≥3 in our laboratory was considered a false-positive result. For HLA-DQA1/DQB1 and HLA-DPA1/DPB1, we considered the positive frequency of ≥3 as a false positive result due to lack of haplotype frequency data. SABA results from 284 patients (78.0%) demonstrated false reactivity. The antibody against HLA-C*17:01 displayed the highest frequency ratio (298.3). If false-positive reactivity is suspected, results should be confirmed using different methods. If confirmation tests are unfeasible, comparing the allele frequency with the positive rate of detected anti-HLA antibodies and using a ratio ≥3 may facilitate the interpretation of SABA results. The positive rate of anti-HLA antibodies can be validated using the HLA allele frequency of the population to determine false-positive results. [ABSTRACT FROM AUTHOR]

Azeri people are at present day mainly living in an area which comprises North (Azerbaijan) and South (Azeri Iran provinces) parts, living the biggest population in Azeri Iran provinces with about 17–20 million people. They were studied HLA-A, -B, -DRB1 and -DQB1 allele and extended haplotype frequencies in unrelated Iranian Tabriz Azeris from a rural area close to Tabriz City. The HLA extended haplotypes with highest frequencies are: 1) HLA- A*24:02-B*35:01-DRB1*11:01-DQB1*03:01, shared with Mediterraneans and southern Russians (Chuvash, which also show Mediterranean characters); and 2) HLA-A*01:02-B*08:01-DRB1*03:01-DQB1*02:01, found also in Chuvash and other Azeri samples from Tabriz. Neí's DA HLA-DRB1 genetic distances, HLA-DRB1 Neighbour-Joining dendrogram and Vista analyses show that population with closest distance is Kurdish, followed by Iranian Gorgan and Southern Russia/ North Caucasus Chuvash; probably these latter groups and Azeris were populating North Mesopotamia/ Caucasus Mts. since prehistoric times. Kurds (in Iraq and Iran) do not speak Turk while Azeris do: they are both genetically close, but they are not genetically close to present day Anatolia (Turkey) Turks who also speak Turk language and show a typical Mediterranean HLA profile. In summary, Azeri population studies show examples that genes and languages do not correlate, contradicting the postulate asserted by others. [ABSTRACT FROM AUTHOR]

Genes encoding KIRs vary in frequency among different populations and ethnic groups. This study investigated the KIR gene frequency distribution in 148 healthy unrelated Saudi subjects and compared the results with other published findings. All inhibitory and activating KIR genes were present at variable frequencies, with A haplotype-associated genes (KIR2DL1, -2DL3, -3DL1, and KIR2DS4) being observed at higher frequencies (88.9-99.5%) than B haplotype-associated genes (KIR2DS1, -2DS2, -2DS3, -2DS5, -2DL5 and -2DL2) (31.1-70.1%). Thirty-one different KIR genotypes were observed, and AA genotypes displayed the highest frequency (18.2%). This Saudi population possesses similar KIR gene distributional characteristics to those reported in other neighboring populations (e.g., Lebanese) and shows disparities in certain genes and gene contents from other populations (e.g., Australian Aborigines). These findings can be used as a reference control in future studies evaluating the functional significance of the KIR genes and their associations with specific diseases.

We estimated HLA allele and haplotype frequencies of the Saudi Arabian population from a sample of 45,457 registered stem cell donors. The most frequent HLA alleles were A*02:01g (18.5%), C*06:02g (16.1%), B*51:01g (14.1%), DRB1*07:01g (16.2%), DQB1*02:01g (30.5%), and DPB1*04:01g (33.6%). The most frequent 5-locus haplotypes were A*02:05g~C*06:02g~B*50:01g~DRB1*07:01g~DQB1*02:01g (1.73%), A*02:01g~C*06:02g~B*50:01g~DRB1*07:01g~DQB1*02:01g (1.66%), and A*26:01g~C*07:02g~B*08:01g~DRB1*03:01g~DQB1*02:01g (1.38%). Furthermore, we used the calculated haplotype frequencies to estimate stem cell donor matching probabilities for Saudi Arabian donor and patient populations under various matching requirements. These results are relevant for strategic donor registry planning in the Kingdom of Saudi Arabia. [ABSTRACT FROM AUTHOR]

The co-stimulatory molecule CD28 plays an important role in T-cell-mediated immune response like acute cellular liver transplant rejection. The aim of the retrospective case- control study was to examine whether the single nucleotide polymorphisms (SNPs) rs3116487, rs3116494, and rs3116496 of the CD28 gene are associated with acute cellular liver transplant rejection. The mentioned SNPs were genotyped in 147 liver transplant recipients without acute cellular rejection and 144 liver transplant recipients with acute cellular rejection by real-time endpoint genotyping. The genotype and allele frequencies of the SNPs did not show any significant differences between both groups. Haplotype analyzes of the SNPs also showed no association. Our data suggest that the analyzed SNPs are not major contributors to the susceptibility of acute cellular liver transplant rejection. [ABSTRACT FROM AUTHOR]

HLA genotyping by next-generation sequencing (NGS) has evolved with significant advancements in the last decade. Here we describe full-length HLA genotyping of 11 loci in 612 individuals comprising a dengue vaccine cohort from Cebu province in the Philippines. The multi-locus individual tagging NGS (MIT-NGS) method that we developed initially for genotyping 4–6 loci in one MiSeq run was expanded to 11 loci including HLA-A, B, C, DPA1, DPB1, DQA1, DQB1, DRB1, and DRB3/4/5. This change did not affect the overall coverage or depth of the sequencing reads. HLA alleles with frequencies greater than 10% were A*11:01:01, A*24:02:01, A*24:07:01, A*34:01:01, B*38:02:01, B*15:35, B*35:05:01, C*07:02:01, C*04:01:01, DPA1*02:02:02, DPB1*05:01:01, DPB1*01:01:01, DQA1*01:02:01, DQA1*06:01:01, DQB1*05:02:01, DQB1*03:01:01, DRB1*15:02:01, DRB1*12:02:01, DRB3*03:01:03, DRB4*01:03:01, and DRB5*01:01:01. Improvements in sequencing library preparation provide uniform and even coverage across all exons and introns. This has led to a marked reduction in allele imbalance and dropout. Furthermore, including more loci, such as DRB3/4/5, decreases cross-mapping and incorrect allele assignment at the DRB1 locus. The increased number of loci sequenced for each sample does not reduce the number of samples that can be multiplexed on a single MiSeq run and is therefore more cost-efficient. We believe that such improvements will help HLA genotyping by NGS to gain momentum over other conventional methods by increasing confidence in the calls. [ABSTRACT FROM AUTHOR]

Five locus allele-level HLA-A, -B, -C, -DRB1, -DQB1 allele and haplotype frequencies have been calculated for almost 29,000 people from three Arab populations that live in Israel and were recruited as donors to the Hadassah bone marrow donor registry. These groups are of Muslim, Christian and Bedouin Arab descent which represent more than 90% of the Arabs that live in Israel. The goal of the study was to describe the HLA genetic profiles of the Hadassah Arab registry donors and investigate the utility of these donors for the local and international hematopoietic stem-cell transplant community. The results demonstrate that the analyzed Arab populations share at least seven of the top ten most frequent alleles. Comparison with other populations confirmed the proximity of the three Arab populations to each other and to the Be The Match® Middle Eastern population. Despite these similarities, some alleles are private to each of the three groups, possibly because of historical, environmental or societal events. Clinical data showed that Arab donors were HLA matched with Arab and international patients. This analysis indicates the value added by the Hadassah Arab donors to the local and global transplant community. [ABSTRACT FROM AUTHOR]

Class II HLA loci DRB1, DQB1 and DPB1 were typed for a total of 939 Gambian participants by locus-specific amplicon sequencing. Participants were from multiple regions of The Gambia and drawn from two studies: a family study aiming to identify associations between host genotype and trachomatous scarring (N = 796) and a cohort study aiming to identify correlates of immunity to trachoma (N = 143). All loci deviated from Hardy-Weinberg equilibrium, likely due to the family-based nature of the study: 608 participants had at least one other family member included in the study population. The most common alleles for HLA-DRB1, DQB1 and DPB1 respectively were DRB1*13:04 (18.8 %), DQB1*03:19 (27.9 %) and DPB1*01:01 (25.4 %). Participants belonged to a variety of ethnicities, including the Mandinka, Fula, Wolof and Jola ethnic groups. [ABSTRACT FROM AUTHOR]

Abstract T cell receptors (TCRs) are a class of T cell surface molecules that recognize the antigen-derived peptides presented by the major histocompatibility complex (MHC) and are able to trigger a series of immune responses. TCRs are important members of the adaptive immune system that arose in the jawed fish 500 million years ago. T cell receptor beta variable (TRBV) genes have been widely used to characterize TCR repertoires. Studying the evolution of TRBV may help us to better understand the adaptive immune system. To investigate TRBV evolution and its impacts on the usages of TRBV genes in human populations, we compared the TRBV genes and their homologous sequences among humans, mouse, rhesus and chimpanzee, analyzed the single-nucleotide polymorphisms (SNPs) located at TRBV loci, and sequenced TCR repertoires in the peripheral blood of 97 healthy donors. We found that functional TRBV s are more evolutionarily conserved but possess more SNPs in human populations than do nonfunctional (pseudo) TRBV s. Based on the conservation levels in the four species, we classified the functional TRBV s into 2 groups: old (conserved between mouse and humans) and new (conserved only in primates). The new TRBV s evolve faster and possess more SNPs than the old TRBV s. The variations in TRBV genes frequencies in the peripheral blood of healthy donors are negatively correlated with SNP density. These observations suggest that TRBV usages may be influenced by TCR-MHC co-evolution. [ABSTRACT FROM AUTHOR]

Abstract The five closely linked CD1A-E genes encode the human CD1 family of proteins. Few studies of the allele frequencies of these genes in African populations have been published so far. This study aimed to genotype CD1A and CD1E variants and to compare their frequencies in Sub-Saharan Africans from Gabon and Ivory Coast, and Non-Africans from Syria and France. A restriction analysis of DNA fragments generated by PCR was performed to detect CD1A and CD1E alleles in 105 subjects from Gabon, 169 subjects from Ivory Coast, 107 subjects from Syria and 181 subjects from France. The frequencies of the CD1E*02 allele were high among Sub-Saharan Africans (87%) and low in West Asians (44%) and Europeans (36%), whereas the contrary was obtained for the CD1E*01 allele (7%, 55% and 64% respectively). Frequencies of CD1A alleles were similar between all groups, the CD1A*02 allele was most prevalent (91%). The high frequency of the CD1E*02 allele in Sub-Saharan Africans suggest that future work should investigate the relationship between CD1 polymorphism and infectious diseases. [ABSTRACT FROM AUTHOR]

Abstract Our understanding of sequence variation in the HLA-DPB1 gene is largely restricted to the hypervariable antigen recognition domain (ARD) encoded by exon 2. Here, we employed a redundant sequencing strategy combining long-read and short-read data to accurately phase and characterise in full length the majority of common and well-documented (CWD) DPB1 alleles as well as alleles with an observed frequency of at least 0.0006% in our predominantly European sample set. We generated 664 DPB1 sequences, comprising 279 distinct allelic variants. This allows us to present the, to date, most comprehensive analysis of the nature and extent of DPB1 sequence variation. The full-length sequence analysis revealed the existence of two highly diverged allele clades. These clades correlate with the rs9277534 A → G variant, a known expression marker located in the 3 ′ -UTR. The two clades are fully differentiated by 174 fixed polymorphisms throughout a 3.6 kb stretch at the 3 ′ -end of DPB1. The region upstream of this differentiation zone is characterised by increasingly shared variation between the clades. The low-expression A clade comprises 59% of the distinct allelic sequences including the three by far most frequent DPB1 alleles, DPB1*04:01, DPB1*02:01 and DPB1*04:02. Alleles in the A clade show reduced nucleotide diversity with an excess of rare variants when compared to the high-expression G clade. This pattern is consistent with a scenario of recent proliferation of A-clade alleles. The full-length characterisation of all but the most rare DPB1 alleles will benefit the application of NGS for DPB1 genotyping and provides a helpful framework for a deeper understanding of high- and low-expression alleles and their implications in the context of unrelated haematopoietic stem-cell transplantation. [ABSTRACT FROM AUTHOR]

In this study, we report for the first time HLA allele and haplotype frequencies in the modern Panamanian population at a two-field (four digits) resolution level. Reported frequencies were calculated from genotype data for the HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 loci of 462 healthy unrelated Panamanian adults of Hispanic ethnicity. In addition to providing new insights on the allelic structure of the Panamanian population and its origin, these data are critical for better planning of healthcare strategies in the country and for future research exploring the association with certain chronic and infectious diseases. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) at the HLA-A , -B , -C , -DRB1, -DRB3/4/5, -DQA1, -DQB1 , -DPA1 , and -DPB1 loci was performed on 5,266 southern Chinese unrelated donors of the Hong Kong Bone Marrow Donor Registry. High-resolution HLA genotypes defined by full sequencing of class I loci and extended coverage of class II loci were attained to determine allele frequencies and estimate haplotype frequencies. This study provides allele and haplotype frequencies on 11 loci estimated for the first time in the Hong Kong Chinese population. These results describe extended haplotypes including the less frequently typed HLA-DPA1, -DPB1 and -DQA1 loci and distinctive haplotype associations. The present data are timely in that they allow the permissible matching in HLA-DPB1 for Chinese patients awaiting haematopoietic stem cell transplantation upon applying the latest requirement of NMDP matching guidelines. Overall, these results provide a useful reference source for population genetics studies, HLA-disease association studies and for improving donor recruitment and selection strategies of bone marrow registries. The allele and haplotype data are available in the Allele Frequencies Net Database under the population name "Hong Kong Chinese HKBMDR, HLA 11 loci" and the identifier (AFND3724) [1]. [ABSTRACT FROM AUTHOR]