HLA typing in patients with chronic adenopathies in a population at risk for AIDS

HLA-A B and DR typing were performed in 77 patients with AIDS related complex (ARC)--69 lymphadenopathy associated syndrome and 8 thrombocytopenic purpura LAV/HTLV III related--and 21 symptom free homosexual males. A significant increase in the frequency of HLA DR5 antigen was observed in patients with ARC mainly in purpura thrombocytopenic patients. We suggest that increase of HLA DR5 antigen support the view that DR5 antigen could be one of the factors necessary at the spreading out clinical symptoms.     

An eight-year study of HLA typing proficiency in Eurotransplant

The main purpose of Eurotransplant, an international organ exchange organisation, is to maximize the survival time of transplanted organs through tissue typing and matching. Regular proficiency testings are necessary to assess the reproducibility and the reliability of the HLA typings performed by the individual typing centres. Two different protocols have been used: 1) since 1978, 35 samples of blood and donor spleen were used for cell exchanges (CE) and typed by all participating laboratories; 2) since 1977 samples of donor spleen have been shipped to the reference laboratory in Leiden for retyping (RD) resulting in over 2600 comparable HLA typings. The discrepancy rates of the HLA-A, B, C and DR specificities were analysed over the years. A large number of discrepancies was due to false negative assignments which led to assumed homozygosity at one or more HLA-loci. The recognition of HLA-DR has improved dramatically but with much variation per DR specificity. The concordancy rates for HLA-AB + DR have improved from 40% in 1981 to 91% for CE and 80% for RD typings in 1984. The reproducibility of DR typings in individual laboratories also has improved greatly but there is still considerable variation between the different laboratories.     

HLA antigens in ulcerative colitis: a study in the Sicilian population

HLA antigens were investigated in 41 Sicilian patients with ulcerative colitis and in 151 healthy controls. Frequencies of HLA-B5 and DR2 were increased in the group of patients with ulcerative colitis whereas the DR3 antigen frequency was decreased. However the corrected p values were not significant. Thus, present results indicate that in ulcerative colitis HLA linked genetic factors play a marginal role, if any.     

HLA typing in bartter syndrome

The mode of inheritance of Bartter syndrome is unclear; however, autosomal recessive inheritance seems likely. A consistent genetic marker of the carrier state likewise remains elusive. HLA typing was done in a family in whom six of 12 sibs have the syndrome. No significant HLA-syndrome linkage was found. This is in contrast to another familial hypokalemic syndrome in which a significant HLA association was found.     

人类白细胞抗原群体遗传学研究

人类白细胞抗原(human leukocyte antigen,HLA)系统是人类最复杂的遗传多态性系统。HLA群体遗传学的研究,一方面可揭示不同地区、不同民族的人群HLA分布情况,进行人群遗传学分析;另一方面有助于HLA与疾病相关性的研究以及为寻找HLA相合造血干细胞供者提供基础性资料。本文就HLA分子遗传基础、HLA群体遗传的内容及研究方法进展作一综述。     

Charting improvements in US registry HLA typing ambiguity using a typing resolution score

Unrelated stem cell registries have been collecting HLA typing of volunteer bone marrow donors for over 25 years. Donor selection for hematopoietic stem cell transplantation is based primarily on matching the alleles of donors and patients at five polymorphic HLA loci. As HLA typing technologies have continually advanced since the beginnings of stem cell transplantation, registries have accrued typings of varied HLA typing ambiguity. We present a new typing resolution score (TRS), based on the likelihood of self-match, that allows the systematic comparison of HLA typings across different methods, data sets and populations. We apply the TRS to chart improvement in HLA typing within the Be The Match Registry of the United States from the initiation of DNA-based HLA typing to the current state of high-resolution typing using next-generation sequencing technologies. In addition, we present a publicly available online tool for evaluation of any given HLA typing. This TRS objectively evaluates HLA typing methods and can help define standards for acceptable recruitment HLA typing.     

HLA and sporadic tuberculoid leprosy: a population study in Maharashtra, India

A population study to test whether associations between HLA and sporadic - i.e. non-familial - tuberculoid leprosy exist was undertaken in a hyperendemic area in India. Since previous family-studies in the same area had shown both non-random haplotype segregation in the family members affected with tuberculoid leprosy and the preferential segregation of HLA-DR2 into tuberculoid leprosy patients, an increased frequency of DR2 among the "sporadic" patients was expected. However, no heterogeneity for HLA was detected between patients and controls. These findings could indicate that tuberculoid leprosy is a heterogeneous disease with regard to genetic background.     

Next-Generation Sequencing of the HLA locus: Methods and impacts on HLA typing,population genetics and disease association studies

The human Major Histocompatibility Complex, known as the “Human Leukocyte Antigen (HLA)”, could be defined as a “super locus” (historically called “supergene”) governing the adaptive immune system in vertebrates. It also harbors genes involved in innate immunity. HLA is the most gene-dense, polymorphic and disease-associated region of the human genome. It is of critical medical relevance given its involvement in the fate of the transplanted organs/tissues and its association with more than 100 diseases. However, despite these important roles, comprehensive sequence analysis of the 4 megabase HLA locus has been limited due to technological challenges. Thanks to recent improvements in Next-Generation Sequencing (NGS) technologies however, one is now able to handle the peculiarities of the MHC notably the tight linkage disequilibrium between genes as well as their high degree of polymorphism (and hence heterozygosity). Increased read lengths, throughput, accuracy, as well as development of new bioinformatics tools now enable to efficiently generate complete and accurate full-length HLA haplotypes without phase ambiguities. The present report reviews current NGS approaches to capture, sequence and analyze HLA genes and loci. The impact of these new methodologies on various applications including HLA typing, population genetics and disease association studies are discussed.     

HLA typing in non-Hodgkin's lymphomas: Comparative study in Caucasoids, Mexican-Americans and Negroids

Over 200 cases of non-Hodgkin's lymphoma were typed for HLA-A, B, C and DR antigens, and typing was correlated with the morphologic diagnosis according to the Lukes-Collins classification system of non-Hodgkin's lymphomas. Three major racial groups were represented: Caucasoids, Mexican-Americans and Negroids. Significant associations were observed between HLA-AW33 and Caucasoid B-cell lymphomas, and for HLA AW24, HLA-B37 and HLA-B40 and B cell lymphomas in Negroids. No significant correlations were found within the Mexican-American patient population. The number of T cell lymphomas was insufficient to draw any conclusions. The DR antigens were not significantly associated with any of the diagnostic subgroups.     

HLA and multiple sclerosis: population and families study

Association between HLA and multiple sclerosis (MS) was investigated at the population level on 100 MS patients genotyped for HLA-A, B, C, DR and Bf, Glo, and on 155 patients phenotyped for the same HLA antigens. Association between MS and DR2 was clearly confirmed, although its strength is rather weak. No other genetic marker could be related to the disease, no haplotype nor any allelic combination could be recognized as MS specific, and antigen genotype frequencies among the diseased could not ascertain the mode of inheritance, although dominance is very likely. Computer analysis between HLA, Bf, Glo and age of the patient, sex, age of onset and evolution of MS, impairment indexes, titres of anti-DNA and anti-measles antibodies in CSF did not show any interaction. Twenty sib pairs and two trios of MS were also studied; they showed no significant distortion with the random distribution of haplotypes. DR2 gene frequency, however, was significantly higher in sib pairs showing one or two haplotypes than in HLA different affected siblings. Three crossing-overs were identified which suggest where the HLA-linked MS susceptibility (MSS) gene could be located within the HLA segment, while other epistatic MSS genes or environmental factors are likely to be important.     

HLA class I allele distribution of a Hong Kong Chinese population based on high-resolution PCR-SSOP typing

A stem cell registry population from Hong Kong, of Chinese ethnicity, was examined for HLA-A and HLA-B alleles using a two-stage sequence-specific oligonucleotide probe system. Comparison of the HLA-A and HLA-B frequencies with different populations showed a close relationship with a Chinese population from Singapore, although there were several differences in the presence/absence of alleles at the HLA-B locus. Having the data available on these registry donors will influence the search strategy and the ongoing compilation of new donors to the registry. In addition, knowing which alleles do/do not occur in this population will aid in the distinction of ambiguities which result from the use of many of the typing kits available.     

Study of HLA system in a Mataco population:

A search for antigens of the HLA system has been carried out in 53 Mataco Indians of Argentina living in a geographically isolated area in the northeast of the country. Samples were mostly collected from adults of both sexes who were not directly related.
Lymphocyte typing was performed using the microcytotoxicity technique of NIH. 118 sera specific for 15 antigens of the first HLA locus, 22 antigens of the second and 6 of the third were used.
The most frequently found alleles were HLA-A28, Aw31 and A2 for the first locus; B15 and B40 for the second; and Cw3 and Cw4 for the third.
In addition to previously published investigations on South American Indians, our typing work shows a remarkable homogeneous gene pool and a restricted range of polymorphism; therefore, a further set of haplotypes rendered us also restricted. The most frequent haplotypes that showed a significant statistical linkage desequilibrium were: A2-Cw4, A28-Bx, A2-Cw3, Aw31-Bw16, Aw24-Cw3, B15-Cw3, Bw16-Cw3 and A28-B5.
Some of these haplotypes have also been found in other indian populations.     

应用SBT直接测序分型法研究中国南方汉族人群HLA五个基因座单倍型

目的 研究中国南方汉族人群HLA-A、B、Cw、DRBl、DQBl等位基因多态性及单倍型的分布特征.方法 应用聚合酶链反应-直接测序分型(polymerase chain reaction sequence-based typing,PCR-SBT)法对186名中国南方汉族健康人群HLA-A、B、Cw、DRBl、DQBl进行基因分型.结果 检出的HLA-A、B、Cw、DRBl、DQBl等位基因分别有28、49、24、29、20种.经统计分析A*0207-B*4601(10.81%),A*3303-B*5801(6.14%),B*4601-DRBl*0901(6.22%),B*4001*DRBl*0901(3.78%),DRBl*0901-DQBl*0303(12.16%)和DRBl*1202-DQBl*0301(8.38%)单倍型呈强连锁不平衡单倍型(RLF≥0.5,X<'2>>3.84,P<0.05);A*0207-B*4601-Cw*0102(10.75%),A*3303-B*5801-Cw*0302(5.14%),A*0207-B*4601-DR*0901(5.07%),A*3303-B*5801-DRBl*0301(2.96%),A*0207-B*4601-Cw*0102-DRBl*0901-DQBl*0303(4.87%)和A*1101-B*1301-Cw*0304-DRBl*1501-DQBl*0601(2.43%)单倍型分别是中国南方汉族人群常见单倍型.结论 中国南方汉族人群HLA 5个基因座单倍型分布具有高度的遗传多态性且有其自身分布特点.本研究获得的较完整的HLA 5个基因座单倍型分布数据,将为人类学、HLA疾病相关性和器官移植等研究提供遗传学参考数据.     

Four-locus high-resolution HLA typing in a sample of Mexican Americans

Mexicans are the most common minority population of the United States. From a sample of 553 bone marrow donor registrants of self-described Mexican ancestry, human leukocyte antigen (HLA) loci A, C, B and DRB1 were typed by highresolution sequence based typing (SBT) methods. A total of 47, 34, 76 and 46 distinct alleles at A, C, B and DRB1 respectively were identified, including 3 new alleles. The four-locus haplotype frequency distribution was extremely skewed with only 53.9% of 1106 chromosomes present with more than one estimated copy. Haplotypes of Native American origin were identified. These data form an initial basis for determining the requirements for an adequate donor pool for stem cell transplantation in this population.     

Implications of HLA sequence-based typing in transplantation

Serology-based conventional microlymphocytotoxicity HLA typing method, which has been regarded as the gold standard in organ and hematopoietic stem cell transplantation, has been replaced now by DNA-based typing. Many laboratories all over the world have already switched over to molecular methods. Microlymphocytotoxicity-based tissue typing was done using commercial sera, while the molecular typing by genomic DNA based. DNA quality and its quantity obtained using various DNA extraction protocols was found to be an important factor in the molecular method of tissue typing in transplant outcome. Many polymerase chain reaction-based molecular techniques have been adopted with far reaching clinical outcome. The sequence-based typing (SBT) has been the ultimate technique, which has been of the highest reliability in defining the HLA alleles. The nonavailability of specific HLA antisera from native populations, large number of blank alleles yet to be defined and comparable low resolution of HLA alleles in SSP or SSOP technique, suggests that highly refined DNA-based methods like SBT should be used as an adjunct to HLA serology and/or low/intermediate/high resolution HLA typing in order to achieve a better transplant outcome.     

HLA polymorphisms in a Shanghai Chinese population

The frequencies of the HLA-A, B, C, D, DR and MB antigens have been determined in a homogeneous Shanghai Chinese population. Comparisons with the HLA-A and -B frequencies in other subsets of the Chinese population revealed some marked differences. No comparisons were possible for the D, DR and MB antigens since there were no previous studies of the antigens in those loci. We suggest that studies of the Chinese population should be confined to clearly defined homogeneous subsets. In this manner, the confounding effect of population heterogeneity may be avoided, and it is this heterogeneity which calls for extensive surveys of the huge Chinese population.     

HLA and narcolepsy in a German population

In this paper the first MHC data including HLA-A, B, C, DR, DQ and complement BF, C4A, C4B determinants in German narcoleptics are presented together with the first family studies in European Caucasoids. 57 out of 58 unrelated patients (98.3%) were positive for DR2 and DQw1, respectively. In contrast to all other reports, one patient with typical signs of narcolepsy was found to be DR2/DQw1 negative. Data showing significant increase in the frequency of B7, and normal frequencies of B35 were discordant with data from Japanese patients. Definition of the extended DR2 linked haplotypes, deduced from 6 families, revealed that 5 out of 12 were DQw1, DR2, BFS, C4B1, C4A3, B7 (Cw7), while 11/12 had DR2, DQw1, BFS, C4A3, C4B1 in common. In one multiple case family two genotypically different DR2 haplotypes were identified in affected siblings. Results from the family study were concordant with a dominant mode of inheritance with incomplete penetrance of a hypothetical disease susceptibility gene.