HLA A*02 allele frequencies and B haplotype associations in Western Indians

The population of Western India is described as Australoid or Proto-Australoid elements with admixture from Caucasian, Mongoloid, and Aryan races. We investigated the frequencies of human leukocyte antigen (HLA) A*02 alleles and their B* allele haplotype associations among 664 healthy unrelated Western Indians. Fifty-one of 204 serologically typed A2 individuals were analyzed for 56 molecular A*02 subtypes using high resolution polymerase chain reaction-reverse line strip-sequence-specific oligonucleotide hybridization (PCR-RLS-SSOP). A total of seven different A*02 alleles were identified, A*02011 (16%), A*0203 (16%), A*0205 (2%), A*0206 (2%), A*0211 (52.9%), A*0222 (4%), and A*0236 (8%). The most common HLA B allele associated with A*02 was B*40. Among the 42 subtypes HLA B*4006 (37.22%) was the most frequent subtype. HLA A*0211 was highly frequent in this population, A*0206 and A*0203 are common alleles observed among Asian populations, whereas A*0205 occurs in Caucasians and Africans and A*0222 has been observed among Hispanics. A*0236 has been observed among the western Indians exclusively. Most of the HLA A*02 subtypes observed were associated with B*4006 haplotype, although A*0236 was with B*0702 or B*1302 among the western Indians. The prevalence of A*0211 at high frequencies, A*0222, A*0236 novel alleles along with A*02 related haplotypes, demonstrate a substantial heterogeneity, which may be a consequence of founder effect, racial admixture, or selection pressure due to environmental factors.     

African-American HLA class II allele and haplotype diversity

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African-American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRB1 allele frequencies (specifically DRB1*1501) and some haplotypes of DRB1-DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African-Americans. The high level of allele and haplotype diversity found in African-Americans has important implications for the construction of pools of unrelated potential donors for tissue transplantation.     

African-American HLA class II allele and haplotype diversity

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African-American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRB1 allele frequencies (specifically DRB 1*1501) and some haplotypes of DRB 1-DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African-Americans. The high level of allele and haplotype diversity found in African-Americans has important implications for the construction of pools of unrelated potential donors for tissue transplantation.     

Molecular diversity of HLA-A*02 in Asian Indians: predominance of A*0211

The North Indians are considered predominantly Caucasoid with an admixture of genes from the Mongoloid and Aryan races. The present study was undertaken to investigate the genetic diversity of HLA-A*02 in the North Indian population and determine the frequency distribution of its molecular subtypes at the population level. The study revealed a high occurrence of A*0211 (33.8%) in this population along with increased frequencies of the common Oriental alleles, A*0206 (7.5%) and A*0207 (32.5%) and also of HLA-A*0205 (15%) commonly observed in negroid populations. HLA-A*0211 has only been reported with very low frequencies among the Ticuna Jews, Thai population, and Colombian Blacks in the malaria endemic areas of Africa. Significantly, we observed an unexpectedly low frequency of A*0201 (3.8%) in contrast to its distribution in Western Caucasians in whom it constitutes 95% of the HLA-A2 repertoire. Prevalence of HLA-A*0211 at very high frequencies among North Indians may be a consequence of the founder effect, racial admixture or selection pressure due to environmental factors in this population.     

HLA allele and haplotype frequencies in the Panamanian population

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.     

Molecular aspects of a novel HLA-A*02 allele (A*0297): the first HLA class I allele mutated at codon 232

We describe a new HLA-A*02 allele, identified in a cord blood unit and in her mother. Nucleotide sequence analysis showed the presence of a new HLA-A*02 allele identical to HLA-A*02010101 except for a non-synonymous nucleotide exchange in exon 4 modifying codon 232 from GAG (Glu) to GAC (Asp). No other human leucocyte antigen class I allele sequenced so far shows this triplet at codon 232. The amino acid exchange affects a position that is part of the membrane proximal domain of class I major histocompatibility complex (MHC), designated alpha 3, and involved in the interaction with CD8 molecule. Using molecular modelling approach, the interactions between different subunits of the native and mutated forms of MHC-I resulted in relevant changes.     

Identification of a novel HLA-A*02 allele, A*027401*

A novel HLA-A*02 allele was detected in a Caucasian patient from central Italy, requiring a hematopoietic cell transplantation. Direct sequencing identified a variation in one nucleotide position, which was confirmed by cloning. The name A*027401 was officially assigned by the WHO Nomenclature Committee in November 2004. A*027401 differs from A*02010101 by a single G to A substitution at nucleotide position 595 in exon 3. The new variant would lead to a nonsynonymous nucleotide change (GGG to AGG) at codon 175, resulting in a basic Arg in the alpha-helix of the alpha2-domain, in place of a non-polar Gly. The presence of an uncommon variation at a highly conserved nucleotide position could have implications in unrelated hematopoietic cell transplantation.     

Next-generation sequencing reveals new information about HLA allele and haplotype diversity in a large European American population

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.     

HLA class I diversity among rural rainforest inhabitants in Cameroon: identification of A*2612-B*4407 haplotype

The population distribution of alleles of the classical HLA class I loci in Cameroon has not been well studied but is of particular interest given the AIDS and malarial epidemics afflicting this population. We investigated the genetic diversity of HLA-A, HLA-B and HLA-C alleles in remote populations of Cameroon. Subjects from seven small, isolated, indigenous populations (N = 274) in the rainforest of southern Cameroon were typed for HLA-A, HLA-B and HLA-C alleles using a polymerase chain reaction/sequence-specific oligonucleotide probe assay and sequence analysis. Multiple alleles of the HLA-A (N = 28), HLA-B (N = 41) and HLA-C (N = 21) loci were identified, of which A*2301[allele frequency (AF) = 12.8%], B*5802 (AF = 10.9%) and Cw*0401 (AF = 16.6%) were the most frequent individual alleles and A*02 (AF = 19.0%), B*58 (AF = 15.9%) and Cw*07 (AF = 22.4%) the most common serologically defined groups of alleles. Twenty-six (28.9%) alleles with a frequency of less than 1% (AF < 1%), 39 (43%) with a frequency of 2.0-15.0% (AF = 2.0-15.0%), three globally uncommon alleles [A*2612 (AF = 2.0%), B*4016 (AF = 0.7%) and B*4407 (AF = 1.4%)], and the A*2612-Cw*0701/06/18-B*4407 haplotype (haplotype frequency = 1.3%) were also identified. Heterozygosity values of 0.89, 0.92 and 0.89 were determined for HLA-A, HLA-B and HLA-C, respectively. The extensive allelic and haplotypic diversity observed in this population may have resulted from varied natural selective pressures on the population, as well as intermingling of peoples from multiple origins. Thus, from an anthropologic perspective, these data highlight the challenges in T-cell-based vaccine development, the identification of allogeneic transplant donors and the understanding of infectious disease patterns in different populations.     

Identification of the novel HLA‐B*13:02:13 allele in a Taiwanese haematopoietic stem cell donor and the probable HLA haplotype in association with B*13:02:13

Using sequence‐based typing method, we found a new HLA‐B*13:02 variant, B*13:02:13, in a Taiwanese haematopoietic stem cell donor. The DNA sequence of B*13:02:13 is identical to the sequence of B*13:02:01 in exons 2 and 3 except the nucleotide at position 588 where G is replaced by T (codon 172; CTG→CTT). The DNA sequence variation did not alter the amino acid sequence of B*13:02:01. The generation of B*13:02:13 is thought to derive from B*13:02:01 as a result of a silence mutation. The probable HLA‐A, HLA‐B and HLA‐DRB1 haplotype in association with B*13:02:1 may be deduced as HLA‐A*24‐B*13:02:13‐DRB1*07:01 or HLA‐A*02‐B*13:02:13‐DRB1*07:01. The discovery of B*13:02:13 furthers the polymorphism of HLA‐B*13 and HLA‐B*13:02.     

A new HLA-A*02 null allele, HLA-A*9213N

A novel HLA-A*02 null allele, differing from HLA-A*02010101 at codon 60 (TGG tryptophan-->TAG stop), is described.     

Identification of a novel HLA-C*02 allele, HLA-C*02:02:09

We report HLA-C*02:02:09 as a novel allele with a transition C->T at position 354.     

21-Hydroxylase gene mutant allele CYP21A215 strongly linked to the resistant HLA haplotype B14:02-DRB101:02 in chronic Chagas disease

We previously reported protective haplotype HLA-B^∗14:02-DRB1^∗01:02 against chronic Chagas disease in Bolivia. The V281L mutant allele of the 21-Hydroxylase gene, CYP21A2^∗15, is reported to be located in the Class III region of the Human leukocyte antigen region and linked to the haplotype HLA-B^∗14:02-DRB1^∗01:02. The mutant allele might play a primary role in the pathogenesis of chronic Chagas disease in the associated HLA region. We analyzed the frequency of this allele in the same subjects for the previous one. The statistical analysis showed a significant association of the CYP21A2^∗15 with resistance to severe chronic Chagas disease (OR = 0.207273; Pv = 0.0041). However, there is no significant tendency of the mutant gene contribution to the resistance after the elimination of the HLA-B^∗14:02-DRB1^∗01:02 linked mutants (OR = 0.38; Pv = 0.1533). Although the frequency of the CYP21A2^∗15 was small, we found no primary contribution of this mutation to the protection against chronic Chagas disease.     

HLA class I allele and haplotype diversity in Ugandans supports the presence of a major east African genetic cluster

The objective of this study was to characterize the class I human leukocyte antigen (HLA) genetic composition of the Ugandan population to better define its relationship with other African groups. Samples from 175 individuals from Kampala (Uganda) were subjected to class I HLA-A, -B, and -C sequence-based typing. The high concordance between the major alleles and haplotypes found in the current and Kenyan populations and interpopulation genetic distance analysis strongly supported the presence of an East African cluster that contained the current Ugandan population along with Kenyan Luo and Nandi populations. The congruence of major alleles in different populations would permit consideration of East Africa as an integrated setting when designing and evaluating much needed malaria, tuberculosis, and AIDS vaccines.     

HLA-A*02 allele frequencies and haplotypic associations in Koreans

We have investigated the frequencies of HLA-A*02 alleles and their haplotypic associations with HLA-B and -DRB1 loci in 439 healthy unrelated Koreans, including 214 parents from 107 families. All of the 227 samples (51.7%) typed as A2 by serology were analyzed for A*02 alleles using polymerase chain reaction (PCR)-low ionic strength-single-strand conformation polymorphism (LIS-SSCP) method. A total of six different A*02 alleles were detected (A*02 allele frequency 29.6%): A*0201/9 (16.6%), *0203 (0.5%), *0206 (9.3%), *0207 (3.0%), and one each case of *0210 and *02 undetermined type. Two characteristic haplotypes showing the strongest linkage disequilibrium were A*0203-B38-DRB]*1502 and A*0207-B46-DRB1*0803. Besides these strong associations, significant two-locus associations (P<0.001) were observed for A*0201 with B61, DRB1*0901 and DRB1*1401, and for A*0206 with B48 and B61. HLA haplotypes carrying HLA-A2 showed a variable distribution of A*02 alleles, and all of the eight most common A2-B-DR haplotypes occurring at frequencies of > or =1% were variably associated with two different A*02 alleles. These results demonstrate that substantial heterogeneity is present in the distribution of HLA-A*02 alleles and related haplotypes in Koreans.     

A novel HLA-A*02 allele, A*02202, identified by nucleotide sequencing

In this paper we report the identification of a new HLA-A*02 allele in two members of an Afghan family. This novel allele, designed as A*02202, differs from A*02201 by a silent substitution at codon 66 (AAC-->AAT) in the alpha1 domain. A*02202 appears to be the result of a novel mutation (Note).     

HLA allele and haplotype frequencies in Algerians : Relatedness to Spaniards and Basques

The powerful genetic polymorphism of the HLA system has been used to identify individuals and populations. Ethnic groups may be characterized by specific HLA allele frequencies and particular extended HLA haplotypes; also, genetic relationships among these groups may be deduced. In the present study, serology and DNA typing were used to detect HLA-A, -B, -C, -DR, and -DQ alleles in each individual and to calculae characteristic haplotypes in Algerians. These results were compared to those previously obtained in other populations, particularly northern Mediterraneans; genetic distances and their respective dendrograms place Basques and Spaniards closer to Algerians than to other Europeans. Also, characteristic Basque and/or Spanish haplotypes are found in Algerians; i.e., A30-B18-Cw3-DR3-DQ2 and Al-B57-Ctv7-DR7-DQ2. This supports the evidence that the Algerian population, mainly its paleo-North African component (Berbers), has a common descent with Basques and Spaniards, probably reflecting a preneolithic relationship between Iberians and paleo-North Africans.     

HLA class II allele and haplotype frequencies in Ethiopian Amhara and Oromo populations

Abstract: HLA class II alleles were identified in 181 healthy unrelated Ethiopian children of both sexes and in 350 European controls from the South of France. The Ethiopian individuals belonged to the two major ethnic groups of the country: Oromo ( N =83) and Amhara ( N =98). In both panels, genetic polymorphism of HLA class II alleles was analysed for the first time by molecular typing of DRB1, DQA1 and DQB1 loci. Allelic and phenotypic frequencies were compared with those of European controls and other African populations. Construction of HLA class II three-locus haplo-types was also performed. The study revealed some differences between the two groups. Characteristic features of Central and North African populations appeared on the Ethiopian HLA genotypes. Surprisingly, DRB1*11 presented one of the lowest gene frequencies in both Ethiopian ethnic groups in contrast to Europeans and West Africans. Furthermore, this decrease was more marked than those observed using serological techniques in other geographically close East African countries. Oromo and Amhara only showed minor differences in spite of their different origins and histories. One significant difference consisted of a lower DRB1*01 gene frequency in Oromo as reported in most West African people. Some new or rare haplotypes were also observed in the Oromo group. Our results underline the distinctive features of the Ethiopian populations among the few HLA genotyping data available for East African groups and emphasise the major interest of such investigations in this region of Africa.