HLA Haplotype Frequencies Research Articles

Single haplotype admixture models using large scale HLA genotype frequencies to reproduce human admixture.

The human leukocyte antigen (HLA) is the most polymorphic region in humans. Anthropologists use HLA to trace populations' migration and evolution. However, recent admixture between populations can mask the ancestral haplotype frequency distribution. We present a statistical method based on high-resolution HLA haplotype frequencies to resolve population admixture using a non-negative matrix factorization formalism and validated using haplotype frequencies from 56 world populations. The result is a minimal set of source components (SCs) decoding roughly 90% of the total variance in the studied admixtures. These SCs agree with the geographical distribution, phylogenies, and recent admixture events of the studied groups. With the growing population of multi-ethnic individuals, or individuals that do not report race/ethnic information, the HLA matching process for stem-cell and solid organ transplants is becoming more challenging. The presented algorithm provides a framework that facilitates the breakdown of highly admixed populations into SCs, which can be used to better match the rapidly growing population of multi-ethnic individuals worldwide.

HLA-A, -B, -C, -DRB1, and -DQB1 allele and haplotype frequencies: An analysis of umbilical cord blood units at the Barcelona Cord Blood Bank.

Allele-level HLA compatibility in cord blood transplantation has been associated with better transplant outcomes and is recommended as a selection criterion. It is also a crucial aspect for other therapeutic applications involving cord blood-derived cells. Determination of high-resolution HLA frequencies is an important step towards improving the quality of cord blood banks. We analyzed HLA-A, -B, -C, -DRB1, and -DQB1 allele frequencies in 5458 high-quality cord blood units from the Barcelona Cord Blood Bank and identified 275 class I and 121 class II HLA alleles. A*02:01, B*44:03, C*07:01, DRB1*07:01 and DQB1*03:01 were the most frequent alleles at each locus. We detected 26 novel alleles and were able to determine the presence or absence of some null alleles, including C*04:09N, in a large number of units. We also analyzed maternal HLA typing information for 1877 units to determine real haplotype frequencies and linkage disequilibrium. A*29:02-B*44:03-C*16:01-DRB1*07:01-DQB1*02:02 was the most frequent HLA haplotype and the DRB1-DQB1 gene pair contained the two-locus haplotypes with the strongest linkage disequilibrium values. Four of the 11 unique haplotypes identified in the HLA-homozygous cord blood units were the top-ranking haplotypes identified and were present in 18% of the cohort. This is the first study to report on HLA allele and haplotype frequencies for umbilical cord blood units from the Barcelona Cord Blood Bank and the largest study to date involving two fields of HLA resolution typing of Spanish registry data.

HLA profile of the Macedonian, Albanian and Macedonian Muslim donors in the Macedonian Bone Marrow Donor Registry

The aim of this study was to determine the HLA allele and haplotype frequencies of the volunteer donors from the Macedonian Bone Marrow Donor Registry (MBMDR). We analyzed 1541 donors, from different nationalities and presented the HLA allele and haplotype frequencies for Macedonian, Albanian and Macedonian Muslims, most numerous nationalities in MBMDR. Difference between the three groups was observed for allele frequencies in HLA-C and HLA-DRB1 loci. The most common haplotype in Macedonian was HLA-A*01-B*08-C*07-DRB1*03, while in Albanian and Macedonian Muslims HLA-A*02-B*18-C*07-DRB1*11. This study confirmed the close relationship between the populations that live in the Balkan Peninsula.

Multiplicative fitness, rapid haplotype discovery, and fitness decay explain evolution of human MHC

The major histocompatibility complex (MHC) is a central component of the vertebrate immune system and hence evolves in the regime of a host-pathogen evolutionary race. The MHC is associated with quantitative traits which directly affect fitness and are subject to selection pressure. The evolution of haplotypes at the MHC HLA (HLA) locus is generally thought to be governed by selection for increased diversity that is manifested in overdominance and/or negative frequency-dependent selection (FDS). However, recently, a model combining purifying selection on haplotypes and balancing selection on alleles has been proposed. We compare the predictions of several population dynamics models of haplotype frequency evolution to the distributions derived from 6.59-million-donor HLA typings from the National Marrow Donor Program registry. We show that models that combine a multiplicative fitness function, extremely high haplotype discovery rates, and exponential fitness decay over time produce the best fit to the data for most of the analyzed populations. In contrast, overdominance is not supported, and population substructure does not explain the observed haplotype frequencies. Furthermore, there is no evidence of negative FDS. Thus, multiplicative fitness, rapid haplotype discovery, and rapid fitness decay appear to be the major factors shaping the HLA haplotype frequency distribution in the human population.

5-Locus high-resolution HLA allele and haplotype frequencies in Costa Ricans from the Central Valley

A total of 221 Costa Rican Mestizos from the Central Valley were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, -DRB1, and -DQB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*08:02:01-DQB1*04:02:01, with an estimated frequency of 2.04%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Costa Rica Central Valley Mestizo” and the identifier AFN3606.

4-Locus high-resolution HLA allele and haplotype frequencies in Costa Ricans from Guanacaste

A total of 110 Costa Rican Mestizos from the province of Guanacaste were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*35:12:01-C*04:01:01-DRB1*04:07:01G, with an estimated frequency of 2.73%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Costa Rica Guanacaste Mestizo” and the identifier AFN3609.

High resolution HLA allele and haplotype frequencies for Arab donors in the Hadassah bone marrow donor registry

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.

4-Locus high-resolution HLA allele and haplotype frequencies in Amerindians from Costa Rica

A total of 125 Costa Ricans of Amerindian descent were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*04:07:01G, with an estimated frequency of 8.26%. A deviation from Hardy-Weinberg Equilibrium was detected at the DRB1 locus (p = 0.099). The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Costa Rica Amerindians” and the identifier AFN3608.

4-Locus high-resolution HLA allele and haplotype frequencies in admixed population from Nicaragua

A total of 155 Nicaraguan Mestizos from across the country were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*04:07:01G, with an estimated frequency of 2.26%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Nicaragua Mestizo” and the identifier AFN3610.

4-Locus high-resolution HLA allele and haplotype frequencies in Costa Ricans from African-Caribbean descent

A total of 102 Costa Ricans of African-Caribbean descent were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*01:01:01-B*08:01:01-C*07:01:01-DRB1*03:01:01G, with an estimated frequency of 1.96%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Costa Rica African-Caribbeans” and the identifier AFN3607.

HLA‐A, B, C, DRB1 and DQB1 allele and haplotype frequencies in volunteer bone marrow donors from Eastern Region of Saudi Arabia

We analyzed HLA allele and haplotype frequencies from donors from the Eastern region of Saudi Arabia. A cross-sectional study was performed on 2405 bone marrow donors from the Eastern region. HLA typing was carried out by sequencing. The most common HLA allele groups were HLA-A*02:01:01G (11.08%), A*01:01:01G (10.40%), HLA-B*52:01:01G (8.79%), B*18:01:01G (8.07%), HLA-C*04:01:01G (17.88%), C*12:03:01G (10.23%), HLA-DRB1*10:01 (14.89%), DRB1*03:01:01G (14.10%), HLA-DQB1*02:01:01G (24.53%) and DQB1*05:01:01G (20.17%). The most frequent HLA-A~ C~ B~ DRB1~ DQB1 haplotypes were HLA-A*01:03~ C*15:05:01G~ B*73:01~ DRB1*10:01:01~ DQB1*05:01:01G (3.11%) and HLA-A*01:01:01G~ C*12:02:01G~ B*52:01:01G~ DRB1*15:02:01~ DQB1*06:01:01G (2.25%). When comparing the allele and haplotype frequencies of the Eastern regions' population to those from the Central region we found significant differences in several allele frequencies including A*01:01:01G (P ≤ 0.0001), B*52:01:01G (P ≤ 0.0001), B*18:01:01G (P = 0.0001), C*12:03:01G (P < 0.0001), DRB1*10:01:01 (P < 0.0001) and DQB1*05:01:01G (P < 0.0001). Our data confirms genetic heterogeneity among the Saudi population.

HLA Haplotype Frequencies and Genetic Profiles of the Kuwaiti Population

Objective: The aim of this study was to assess the HLA haplotype frequencies and genetic profiles of the Kuwaiti population. Materials and Methods: Whole venous blood was obtained from 595 healthy, unrelated Kuwaiti volunteers. The study population was genotyped for HLA class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1 and HLA-DQB1) loci using sequence-specific oligonucleotide (SSO) probe-based hybridization and high-resolution HLA genotyping. Haplotype frequencies were estimated using an implementation of the expectation maximization algorithm that resolves both phase and allelic ambiguity. The Kuwaiti population was compared with other populations from the US National Marrow Donor Program (NMDP), by running a principal component analysis (PCA) on the relevant haplotype frequencies. Results: The most common HLA class I alleles in Kuwait were HLA-A*02:01g, HLA-C*06:02g, and HLA-B*50:01g with frequencies of 16, 14, and 12%, respectively. The most common HLA class II alleles in Kuwait were HLA-DQB1*02:01g and HLA-DRB1*07:01 with frequencies of 29.7 and 16.5%, respectively. The most common Kuwaiti haplotype observed was HLA-A*02:01g∼HLA-C*06:02g∼HLA-B*50:01g∼HLA-DRB1*07:01∼HLA-DQB1*02:01g at a frequency of 2.3%. The PCA demonstrated close genetic proximity of the Kuwaiti population with Middle Eastern, Southeast Asian, and North African populations in the NMDP. Conclusion: Identifying the haplotype diversity in the Kuwaiti population will contribute to the selection of an HLA-match for HSCT, disease associations, pharmacogenomics, and knowledge of pop­ulation HLA diversity.

Tools for building, analyzing and evaluating HLA haplotypes from families

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.

HLA Antigens and Haplotype Frequencies among Renal Transplant Recipients and Donors Presenting to a Tertiary Care Hospital in Hyderabad, Telangana, South India

HLA Antigens and Haplotype Frequencies among Renal Transplant Recipients and Donors Presenting to a Tertiary Care Hospital in Hyderabad, Telangana, South India

The association of HLA/KIR genes with non-small cell lung cancer (adenocarcinoma) in a Han Chinese population.

The host immune system plays a crucial role in the surveillance, recognition and elimination of tumor cells. Recent studies found that Human lymphocyte antigen class I (HLA I) genes, Killer cell immunoglobulin-like receptor (KIR) genes and HLA/KIR combinations play a role in the defense against tumor cells. To evaluated the associations between HLA I genes, KIR genes and HLA/KIR combinations and non-small cell lung cancer (NSCLC) in a Chinese Han population, a total of 229 patients with NSCLC (adenocarcinoma) and 217 healthy individuals were studied. Our results showed that the HLA-C*08:01 allele occurred at a significantly higher frequency in the NSCLCs compared with the controls (P=0.034). The HLA haplotype frequencies bearing HLA-A, -B, and -C loci between the NSCLC and control groups were not different (P>0.05). And there were no differences in the KIR gene, genotype and haplotype frequencies between the NSCLC and control groups (P>0.05). Also, there were no differences between the HLA/KIR combinations in the KIR3D genes and HLA-A3/A11, HLA-Bw4 ligands and KIR2D genes and HLA-C1/C2 ligands between the NSCLC and control groups (P>0.05). Our results indicate that the HLA-C*08:01 allele could be a risk factor for NSCLC (adenocarcinoma) in the Chinese Han population (OR=2.395; 95% CI: 1.359-4.221).

6-Locus HLA allele and haplotype frequencies in a population of 1075 Russians from Karelia

A total of 1075 Russians from the Russian part of Karelia were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 using next generation sequencing methods. The haplotypic and allelic profiles as well as Hardy-Weinberg proportions of this population sample were evaluated. As the most frequent 6-locus haplotype, A*03:01 g ∼ B*07:02 g ∼ C*07:02 g ∼ DRB1*15:01 g ∼ DQB1*06:02 g ∼ DPB1*04:01 g was identified with an estimated frequency of 3.5%. No deviation from Hardy-Weinberg Equilibrium was detected at any of the loci studied. The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Russia Karelia” and the identifier AFN3430.

The Frequency of Human Leukocyte Antigen Class I and II Alleles and the Relationship Between Haplotypes in Gilaks Population of Iran

Background: The Human Leukocyte Antigen (HLA) is the most polymorphic region in human genome. Moreover, HLA haplotype frequencies are largely used in transplantation, the treatment of autoimmune diseases, and population-based studies. The present study aimed to determine HLA-A, -B, -DR alleles and haplotype frequencies in 88 unrelated donors of Iranian Gilak ethnic group, by Polymerase Chain Reaction with Sequence-Specific Primer (PCR-SSP) assay. The study findings were compared with previous reports on HLA alleles of different Iranian ethnics.Materials and Methods: The blood samples were collected from 88 donors of the Gilak ethnicity. Deoxyribonucleic Acid (DNA) of the samples were extracted. Then, we performed PCR and electrophoresis. The frequency of different alleles was analyzed using software.Results: Our obtained results suggested that the most frequent alleles for HLA-A were A*02 (24.4%), A*11 (17.6%), and A*03 (14.2%), and the same for HLA-B were B*35 (26.7%), B*51 (12.5%), and B*52 (11.4%), and for HLA-DRB1 were DRB1*11 (14.1%), DRB1*01 (13.5%), and DRB1*04 (11.8%). In addition, the most common three-locus haplotypes were A02:B35:DRB01 (9.1%), A68:B49:DRB14 (6.2%), and A11:B51:DRB04 (5.1%) among the studied group.Conclusion: Despite some differences, we found a strong relationship in the allelic variation between Gilak ethnicity and other Iranian and Caucasians ethnics.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1–associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

HLA profile of the donors in the Macedonian Bone Marrow Donor Registry.

The importance of HLA alleles in the process of haematopoietic stem cell transplantation, especially the process of unrelated donor search, is enormous. Macedonian Bone Marrow Donor Registry was established in 2010 and has registered volunteer donors from different nationalities that live in the Republic of Macedonia. The aim of this study was to determine the HLA allele and haplotype frequencies of the volunteer donors from the Macedonian Bone Marrow Donor Registry and to compare this results with the Macedonians from a family study. We analyzed 1,541 donors, with different nationalities, Macedonian, Albanian and Macedonian Muslims that were most numerous in MBMDR, and typed them for HLA-A, -B, -C, -DRB1, whereas Macedonian also for HLA-DQA1 and HLA-DQB1 by SSO method (One Lambda, CA, USA). The most frequent alleles in Macedonians were HLA-A*02, 01, 24; HLA-B*35, 18, 51; HLA-C*07, 04, 12; HLA-DRB1*11, 16, 13; HLA-DQA1*01, 05 and HLA-DQB1*05, 03, 06; in Albanians they were HLA-A*02, 24,01; HLA-B*51, 18, 35; HLA-C*07, 04, 12, HLA-DRB1*11, 13,16; and in Macedonian Muslims they were HLA-A*02, 01, 24; HLA-B*18, 51, 35, HLA-C*07, 04, 02 and HLA-DRB1*11, 16, 14. The most common haplotype in Macedonian was HLA-A*01-B*08-C*07-DRB1*03, whilst in Albanian and Macedonian Muslims HLA-A*02-B*18-C*07-DRB1*11. The comparison of the HLA allele groups between Macedonian from MBMDR and family study showed similar distribution. This study confirmed the close relationship between the populations that live in the Balkan Peninsula.

P075Extended HLA haplotypes in a greek population by NGS technology

Aim HLA alleles are observed in specific haplotypes due to Linkage Disequilibrium (LD) between certain alleles. Recent improvements in Next-Generation Sequencing (NGS) technologies accommodate the tight linkage disequilibrium between genes as well as the high degree of polymorphism of the MHC. In order to assign HLA haplotypes at allele level (4-fields) in a Greek population, in the context of 17th IHWS, 25 families including parents and siblings (95 subjects), all of Greek origin, were typed at 11 loci (HLA-A*, -B*, -C*, -DRB1*, DRB3/4/5*, -DQA1*, -DQB1*, -DPA1* and -DPB1*) by NGS technology. Methods Instrument and Chemistry: Illumina MiSeq, v2 chemistry, 300 cycles (2X150) and standard flow cell size. Illumina TruSight HLA v2.0 and Omixon Holotype HLA kits were used. HLA haplotype count and frequency (%) were estimated according to the number of parental haplotypes identified in the whole cohort. Additionally, haplotype count in families (N = 25) and subjects (N = 95) were calculated. Results HLA-A*01:01:01:01-C*07:01:01:01-B*08:01:01:01-DRB3*01:01:02:01-HLA-DRB1*03:01:01:01/02-DQA1*05:01:01:02-DQB1*02:01:01-DPA1*01:03:01:02-DPB1*04:01:01:01/02 haplotype was found in 3 members of 2 families (haplotype frequency 2%). All other haplotypes were observed once, giving haplotype frequency = 1%. Conclusions It is confirmed that the HLA-A*01-Cw*07-B*08-DRB1*03:01-DQB1*02 haplotype, defined by low-resolution molecular techniques, is the most common in Greeks, as in all Caucasians. These results are useful as reference data (controls) in disease association studies as well as in population genetics.