Distribution of HERV-LTR elements in the 5′-flanking region of HLA-DQB1 and association with autoimmunity

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTR5 showed identical distribution to LTR3, consistent with a previously suggested LTR3-LTR5 tandem arrangement. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DQB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DQB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.     

Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population

BACKGROUND: It has been reported that HLA class II haplotypes DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0901-DQA1*0302-DQB1*0303 are major susceptibility haplotypes for type 1 diabetes mellitus (DM) in Japanese population. However, little has been reported on the susceptibility HLA class II haplotypes in Japanese patients with autoimmune polyglandular syndrome type II and type III (APS III). PATIENTS AND METHODS: HLA class II haplotypes of DRB1-DQA1-DQB1 in 31 patients with APS III, 14 patients with Hashimoto's thyroiditis alone, and 15 patients with Graves' disease alone were examined in Japanese population. APS III patients were divided into three groups (A, B, and C) depending on the combination of autoimmune endocrine diseases. RESULTS: In 13 APS III patients with both Hashimoto's thyroiditis and type 1 DM (group A), the haplotype frequencies of the HLA DRB1*0802-DQA1*0401-DQB1*0402 and DRB1*0901-DQA1*0302-DQB1*0303 were significantly higher than in the controls. In patients with Hashimoto's thyroiditis alone, the haplotype frequency of DRB1*0901-DQA1*0302-DQB1*0303 was significantly higher than in controls, whereas the frequency of DRB1*0802-DQA1*0401-DQB1*0402 did not differ significantly from those in the controls. In 11 APS III patients with both Graves' disease and type 1 DM (group B), the haplotype frequencies of HLA DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0802-DQA1*0301-DQB1*0302 were significantly higher than in controls. In patients with Graves' disease alone, the haplotype frequency of DRB1*0803-DQA1*0103-DQB1*0601 were significantly higher than those in controls, suggesting that the susceptibility haplotypes for group B APS III differed from those for Graves' disease alone. In 7 APS III patients with both autoimmune thyroid diseases and pituitary disorders (group C), the haplotype frequency of HLA DRB1*0405-DQA1*0303-DQB1*0401 was significantly higher than in controls. CONCLUSIONS: Susceptible HLA class II haplotypes of DRB1-DQA1-DQB1 for APS III differ between the Japanese and Caucasian populations. More interestingly, the susceptible HLA class II haplotypes differ among the three types of Japanese APS III and are not merely a combination of susceptibility haplotypes of each endocrine disease.     

HLA polymorphism in type 1 diabetes Tunisians

Several studies of the association between HLA and type 1 diabetes have been carried out revealing differences between ethnic groups. Our study, as part of the studies that should be performed about this association in the rest of the word, aims at elucidating the HLA DRB1, DQB1 polymorphism in Tunisian type 1 diabetes. This study includes 43 unrelated type 1 diabetes patients, and their mean age at onset is less than 15 years. Analysis of the frequency of alleles and haplotypes in these subjects, compared to a reference group (n = 101) led to the following results. 1) The Tunisian insulin-dependent diabetics present similarities as well as differences with other ethnic groups (Caucasians, North Africans). 2) The haplotype DRB1*04 DQ*0302 and DRB1*03 DQB1*0201 is positively associated to type 1 diabetes. 3) The heterozygotic genotype DRB1*04 DQB1*0302 / DRB1*03 DQB1*0201 is strongly associated to type 1 diabetes. 4) The haplotypes DRB1*01501 DQB1*0602 and DRB1*11 DQB1*0301 proved to be protective. In addition, the study of the subtypes DRB1*04 showed that alleles DRB1*0405 predispose to type 1 diabetes, whereas the allele DRB1*0403, which is in linkage disequilibrium with the DQB1*0402 in the Tunisian population, has a protective effect.     

HLA class II DR and DQ genotypes and haplotypes associated with rheumatic fever among a clinically homogeneous patient population of Latvian children

The HLA system is being paid more and more attention because it is very significant in polymorphous immunological reactions. Several studies have suggested that genetic susceptibility to rheumatic fever (RF) and rheumatic heart disease (RHD) is linked to HLA class II alleles. We hypothesized that HLA class II associations within RHD may be more consistent if analysed amongst patients with a relatively homogeneous clinical outcome. A total of 70 RF patients under the age of 18 years were surveyed and analysed in Latvia. HLA genotyping of DQA1, DQB1 and DRB1 was performed using PCR with amplification with sequence-specific primers. We also used results from a previous study of DQB1 and DRB1 genotyping. In the RF patients, HLA class II DQA1*0401 was found more frequently compared to DQA1*0102. In the RF homogeneous patient groups, DQA1*0402 has the highest odds ratio. This is also the case in the multivalvular lesion (MVL) group, together with DQA1*0501 and DQA1*0301. In the chorea minor patients, DQA1*0201 was often found. Significant HLA DQA1 protective genotypes were not detected, although DQA1 genotypes *0103/*0201 and *0301/*0501 were found significantly and frequently. In the distribution of HLA DRB1/DQA1 genotypes, *07/*0201 and *01/*0501 were frequently detected; these also occurred significantly often in the MVL group. The genotype *07/*0201 was frequently found in Sydenhamn's chorea patients that had also acquired RHD, but DRB1*04/DQA1*0401 was often apparent in RF patients without RHD. In the distribution of HLA DQA1/DQB1 genotypes, both in RF patients and in the homogeneous patient groups, the least frequent were *0102/*0602-8. The genotype DQA1*0501 with the DQB1 risk allele *0301 was often found in the MVL group. The genotype *0301/*0401-2 was frequently found in the RF and Sydenhamn's chorea patient groups. The haplotype *07-*0201-*0302 was frequently found in RF and homogeneous patient groups, including the MVL group. In addition, haplotypes *04-*0401-*0301 and *04-*0301-*0401-2 were frequent amongst patients with Sydenhamn's chorea. The protective alleles DQA1*0102 and DQB1*0602-8 in the haplotype DRB1*15 were less frequently found in RF patients. The results of the present study support our hypothesis and indicate that certain HLA class II haplotypes are associated with risk for or protection against RHD and that these associations are more evident in patients in clinically homogeneous groups.     

Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus

Human leukocyte antigen (HLA) class I and class II alleles are implicated as genetic risk factors for many autoimmune diseases. However, the role of the HLA loci in human systemic lupus erythematosus (SLE) remains unclear. Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, we identified three distinct haplotypes that encompassed the class II region and exhibited transmission distortion. DRB1 and DQB1 typing of founders showed that the three haplotypes contained DRB1*1501/ DQB1*0602, DRB1*0801/ DQB1*0402, and DRB1*0301/DQB1*0201 alleles, respectively. By visualizing ancestral recombinants, we narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to an approximately 500-kb region. We conclude that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.     

HLA-A, -B, -C, -DRB1 and -DQB1 alleles associated with different hematological diseases in Chinese population

The purpose of this study was to explore the association between human leukocyte antigens (HLA)-A, -B, -C, -DRB1 and -DQB1 allele polymorphisms and different hematological diseases in Chinese groups. Retrospective analyses of HLA genotyping data in high-resolution for patients with acute myeloid leukemia (AML, 766 cases), chronic myeloid leukemia (CML, 330 cases), acute lymphoblastic leukemia (ALL, 605 cases), aplastic anemia (AA, 229 cases), myelodysplastic syndrome (MDS, 204 cases) were performed, and the susceptible or protective HLA alleles of the above-mentioned diseases were analyzed by Chi-square test and Fisher exact test with unrelated hematopoietic stem cell donors as control. The Results indicated that A*0201, B*4402, C*0701, DRB1*1201, DRB1*1401, and DQB1*0602 might be susceptible genes of AML, while A*1101, A*3303, B*5801, C*0302, DRB1*0301, DQB1*0201 and DQB1*0502 might be protective genes of AML. A*3303 might be a protective gene of CML, and DRB1*1401 might be a susceptible gene of CML. ALL's susceptible genes included A*0201, A*0210, B*5201, DRB1*1201, DRB1*1401 and DQB1*0602, but its protective genes included DQB1*0502. For AA, A*0201, A*0206, B*1511, DRB1*0901, DRB1*1401, DQB1*0303, DQB1*0602 might be susceptible genes, while A*3303, B*5801, C*0302, DRB1*1602 and DQB1*0502 might be protective genes. A*0201, A*0206, B*1511, DRB1*0901, DRB1*1401, DQB1*0303. A*0201, B*1558, B*4801, B*5201, DRB1*1401, DRB1*1501, and DQB1*0602 might be susceptible genes of MDS, and A*3303, B*4601, B*5801, C*0302, and DRB1*0901 might be protective genes of MDS. On the basis of HLA high-resolution genotyping for the first time, this study comprehensively analyzed HLA alleles associated with different hematological diseases in the Chinese population, which should provide clues for further study on the pathogenesis of these diseases.     

HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia

Genetic control of immune reactions has a major role in the development of rheumatic heart disease (RHD) and differs between patients with rheumatic fever (RF). Some authors think the risk of acquiring RHD is associated with the HLA class II DR and DQ loci, but other views exist, due to the various HLA-typing methods and ways of grouping cases. Our goal was to determine the relations between HLA class II alleles and risk of or protection from RF in patients with relatively homogeneous clinical manifestations. A total of 70 RF patients under the age of 18 years were surveyed in Latvia. HLA genotyping of DRB1*01 to DRB1*18 and DQB1*0201-202, *0301-305, *0401-402, *0501-504, and *0601-608 was performed using polymerase chain reaction sequence-specific primers. Data for a control group of 100 healthy individuals typed for HLA by the same method were available from the databank of the Immunology Institute of Latvia. Of the RF patients, 47 had RHD and 8 had Sydenham's chorea. We concluded that HLA class II DRB1*07-DQB1*0401-2 and DRB1*07-DQB1*0302 could be the risk alleles and HLA class II DRB1*06 and DQB1*0602-8, the protective ones. Patients with mitral valve regurgitation more often had DRB1*07 and DQB1*0401-2, and patients with multivalvular lesions more often had DRB1*07 and DQB1*0302. In Sydenham's chorea patients, the DQB1*0401-2 allele was more frequent. Genotyping control showed a high risk of RF and RHD in patients with DRB1*01-DQB1*0301-DRB1*07-DQB1*0302 and DRB1*15-DQB1*0302-DRB1*07-DQB1*0303.     

HLA class II DR-DQ amino acids and insulin-dependent diabetes mellitus: application of the haplotype method.

Insulin-dependent diabetes mellitus (IDDM) HLA class II DRB1-DQA1-DQB1 data from four populations (Norwegian, Sardinian, Mexican American, and Taiwanese) have been analyzed to detect the amino acids involved in the disease process. The combination of sites DRB1#67 and 86; DQA1#47; and DQB1#9, 26, 57, and 70 predicts the IDDM component in these four populations, when the results and criteria of the haplotype method for amino acids, developed in the companion paper in this issue of the Journal, are used. The following sites, either individually, or in various combinations, previously have been suggested as IDDM components: DRB1#57, 70, 71, and 86; DQA1#52; and DQB1#13, 45, and 57 (DQB1#13 and 45 correlates 100% with DQB1#9 and 26). We propose that DQA1#47 is a better predictor of IDDM than is the previously suggested DQA1#52, and we add DRB1#67 and DQB1#70 to the HLA DR-DQ IDDM amino acids. We do not claim to have identified all HLA DR-DQ amino acids-or highly correlated sites-involved in IDDM. The frequencies and predisposing/protective effects of the haplotypes defined by these seven sites have been compared, and the effects on IDDM are consistent across the populations. The strongest susceptible effects came from haplotypes DRB1 *0301/DQA1 *0501/ DQB1*0201 and DRB1*0401-5-7-8/DQA1*0301/ DQB1*0302. The number of strong protective haplotypes observed was larger than the number of susceptible ones; some of the predisposing haplotypes were present in only one or two populations. Although the sites under consideration do not necessarily have a functional involvement in IDDM, they should be highly associated with such sites and should prove to be useful in risk assessment.     

The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian,multiplex families.

We report here our analysis of HLA class II alleles in 180 Caucasian nuclear families with at least two children with insulin-dependent diabetes mellitus (IDDM). DRB1, DQA1, DQB1, and DPB1 genotypes were determined with PCR/sequence-specific oligonucleotide probe typing methods. The data allowed unambiguous determination of four-locus haplotypes in all but three of the families. Consistent with other studies, our data indicate an increase in DR3/DR4, DR3/DR3, and DR4/DR4 genotypes in patients compared to controls. In addition, we found an increase in DR1/DR4, DR1/DR3, and DR4/DR8 genotypes. While the frequency of DQB1*0302 on DR4 haplotypes is dramatically increased in DR3/DR4 patients, DR4 haplotypes in DR1/DR4 patients exhibit frequencies of DQB1*0302 and DQB1*0301 more closely resembling those in control populations. The protective effect of DR2 is evident in this data set and is limited to the common DRB1*1501-DQB1*0602 haplotype. Most DR2+ patients carry the less common DR2 haplotype DRB1*1601-DQB1*0502, which is not decreased in patients relative to controls. DPB1 also appears to play a role in disease susceptibility. DPB1*0301 is increased in patients (P < .001) and may contribute to the disease risk of a number of different DR-DQ haplotypes. DPB1*0101, found almost exclusively on DR3 haplotypes in patients, is slightly increased, and maternal transmissions of DRB1*0301-DPB1*0101 haplotypes to affected children occur twice as frequently as do paternal transmissions. Transmissions of DR3 haplotypes carrying other DPB1 alleles occur at approximately equal maternal and paternal frequencies. The complex, multigenic nature of HLA class II-associated IDDM susceptibility is evident from these data.     

HLA class II polymorphism in autochthonous population of Gorski kotar, Croatia

The aim of this study was to examine frequencies and haplotypic associations of HLA class II alleles in autochthonous population of Gorski kotar (Croatia). HLA-DRB1, -DQA1 and -DQB1 alleles were determined by DNA based PCR typing in 63 unrelated inhabitants from Gorski kotar whose parents and ancestors were born and lived in tested area for at least over four generations. A total of 13 HLA-DRB1, 12 DQA1 and 14 DQB1 alleles were identified. The most frequent HLA class II genes in Gorski kotar population are: HLA-DRB1*13 (af = 0.150), -DRB1*03 (af = 0.142), -DRB1*07 (af = 0.119), and -DRB1*11 (af = 0.119), HLA-DQA1*0501 (af = 0.278), -DQA1*0102 (af = 0.183), -DQA1*0201 (af = 0.127) and HLA-DQB1*0301 (af = 0.157), -DQB1*0201 (af = 0.139), -DQB1*0501 (af = 0.111). We have identified 24 HLA class II three-locus haplotypes. The most common haplotypes in Gorski kotar population are DRB1*03-DQA* 0501-DQB1*0201 (0.120), DRB1*11-DQA1*0501-DQB1*0301 (0.111) and DRB1*07-DQA1*0201-DQB1*0202 (0.094). The allelic frequencies and populations distance dendrogram revealed the closest relationships of Gorski kotar population with Slovenians, Germans, Hungarians and general Croatian population, which is the result of turbulent migrations within this microregion during history.     

Distribution of HLA class Ⅰ and class Ⅱ haplotypes in Chinese Han population based on family segregation

HLA haplotype analysis has important application value in human population genetics, anthropological research and HLA matching transplantation. Based on HLA-A, -B, -C, -DRB1 and -DQB1 genotyping data from 663 families including 663 leukemia patients and 991 related donors, the allele frequency (AF) and haplotype frequency (HF) of two-, three- and five-locus haplotype distribution patterns in the Chinese Han population were determined by family segregation. A total of 38 alleles at A locus, 75 alleles at B locus, 35 alleles at C locus, 53 alleles at DRB1 locus and 22 alleles at DQB1 locus were discovered in this population. The frequencies of these alleles were basically consistent with those of previous reports except for some tiny differences. The study found 11 A-C, 15 C-B, 4 B-DRB1 and 11 DRB1-DQB1 two-locus haplotypes with a frequency over 2%. The number of A-C-B and A-B-DRB1 three-locus haplotype with a frequency over 1% were 11 and 3 respectively. The most common HLA-A-C-B-DRB1-DQB1 haplotype (HF>1%) were A*3001-C*0602-B*1302-DR*0701-DQ*0202 (4.30%), A*0207-C*0102-B*4601-DR*0901-DQ*0303 (3.07%), A*3303-C*0302-B*5801-DR*0301-DQ*0201 (1.49%) and A*1101-C*0102-B*4601-DR*0901-DQ*0303 (1.01%). The results are helpful for finding matching donors for hematopoietic stem cell transplant patients and also contribute to transplant immunology, HLA-related diseases, research of human genetics and other fields.     

The role of HLA-DRB1*04 alleles and their association with HLA-DQB genes in genetic susceptibility to rheumatoid arthritis in Hungarian patients

We investigated the HLA-DRB, and DQB polymorphism and haplotypes in RA subjects of Hungarian origin by PCR typing using sequence-specific primers. Molecular subtyping of HLA-DRB1*04 alleles in RA patients showed strongest association with highest relative risk with DRB1*0404. A significantly decreased frequency of DRB1*0403 was observed in patients compared to controls. A significant number of patients carried DR4 haplotypes on DQB1*0302 (54%) relative to DQB1*0301 which was present on 36% of the haplotypes. When compared to controls, the frequency was higher in the latter allele only. Few unique DRB-DQB haplotypes were observed in Hungarian RA patients. In spite of the fact, that the Hungarian population has been isolated linguistically over centuries, a considerable racial admixture has occurred following immigration and invasions, thus the present study confirms in Hungarian patients with RA, previous findings for RA and HLA in European countries.     

Is the association between TNF-alpha-308 A allele and DMT1 independent of HLA-DRB1, DQB1 alleles?

The aim of the study was to assess chosen factors of genetic susceptibility to DMT1: DRB1, DQB1, and TNF-alpha polymorphisms-308 (G/A) in children with DMT1 and their up-to-now healthy siblings. Then we tested whether the association between TNF-alpha genes and DMT1 is independent of HLA. 87 diabetic children, their 78 siblings, and 85 persons from healthy control group were followed up. The highest risk of DMT1 was connected with alleles: DRB1*0401 (OR = 3.39; CI: 1.55-7.41), DRB1*0301 (OR = 2.72; CI: 1.48-5.01), DQB1*0201 (OR = 4.04; CI: 2.17-7.52), DQB1*0302 (OR = 5.08; CI: 2.54-10.14), and TNF-alpha-308 A allele (OR = 2.59; CI: 1.23-5.44). Moreover linkage disequilibrium for TNF-alpha-308 A allele with DRB1*0301 and DQB1*0201 was observed in both diabetic children and their siblings. Diabetic children and their siblings present similar genetic risk factors for DMT1. The association between TNF-alpha-308 A allele and DMT1 is dependent of HLA-DRB1 and DQB1 alleles.     

HLA-DQ primarily confers protection and HLA-DR susceptibility in type I (insulin-dependent) diabetes studied in population-based affected families and controls.

The association between HLA-DR and -DQ and insulin-dependent diabetes mellitus (IDDM) in a defined high-incidence area was analyzed in a total of 58 population-based patients, representing 77% of IDDM patients with age at onset below 16 years, and in 92 unrelated parents in control families without IDDM. HLA haplotypes were confirmed by analyzing first-degree relatives in both groups. Seven different methods were used to analyze risk: (1) odds ratio, (2) absolute risk, (3) haplotype relative risk, (4) transcomplementation relative risk, (5) relative predisposing effects, (6) stratification analysis, and (7) test of predisposing allele on haplotype. DQB1*0302 indicated somewhat higher risk than did DR4, while DR3 had a higher risk than DQB1*0201; however, the 95% confidence intervals of the risk estimates overlapped. The positive association between IDDM and the DQB1*0201-DQA1*0501-DR3 haplotype seems to be due to DR3 or to an unknown linked gene. More important, DQA1*0301 was present among 93% of the patients, and this allele in various transcomplementation combinations with DQB1 alleles showed closer association to IDDM than did any other alleles. The strong negative association of the DQB1*0602 allele also in the presence of either DR4 or DQB1*0302 or both suggests that, in a high-risk population for IDDM, HLA-DQ primarily confers protection, perhaps by induction of tolerance. Consistent with known functions, HLA-DR may primarily confer susceptibility, perhaps by induction of autoreactive T lymphocytes.     

用PCR-RFLP方法研究藏族HLA-DQA1和-DQB1基因多态性

应用目前HLA研究领域中成熟的,有效的PCR-RFLP基因分型技术,从DNA水平对藏族健康群体进行了HLA-DQA1(49人)和-DQB1(49人)基因分型,这在国内外属首次。所采用的PCR-RFLP基因分型技术是在HLA-DQA1和-DQB1各等位基因全部序列已知的情况下,对其第2个外显子碱基序列扩增进而进行RFLP分析的方法。这种方法得到的RFLP的所有片段都是已知序列,因而精确度很高,同时为发现新的等位基因提供了成熟而有效的分析方法。研究结果表明,在藏族DQA1的8个等位基因,DQA1*0301的基因频率最高(36.74％)。DQA1*0601(4.08％)、*0103(4.08％)和*0401(5.10％)最低。在DQB1的16个等位基因中,OQB1*0302(16.33％)、*0303(15.31％)和*0602(15.31％)为最常见,没有观察到*0504。统计分析表明,在DQA1各等位基因分布上,藏族与新疆汉族、北方汉族、上海汉族十分相近;与维吾尔族和哈萨克族也没有明显差异。在OQB1各等位基因的分布上,藏族与汉族、维族、哈族之间略有差异,而汉族、维族、哈族之间也存在一些差异。     

Genetic history of Aleuts of the Komandor islands from results of analyzing variability of class II HLA genes

Variability of the HLA class II genes (alleles of the DRB1, DQA1, and DQB1 loci) was investigated in a sample of Aleuts of the Commanders (n = 31), whose ancestors inhabited the Commander Islands for many thousand years. Among 19 haplotypes revealed in Aleuts of the Commanders, at most eight were inherited from the native inhabitants of the Commander Islands. Five of these haplotypes (DRB1*0401-DQA1*0301-DQB1*0301, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*0802-DQA1*0401-DQB1*0402, DRB1*1101-DQA1*0501-DQB1*0301, and DRB1*1201-DQA1*0501-DQB1*0301) were typical of Beringian Mongoloids, i.e., Coastal Chukchi and Koryaks, as well as Siberian and Alaskan Eskimos. Genetic contribution of the immigrants to the genetic pool of proper Aleuts constituted about 52%. Phylogenetic analysis based on Transberingian distribution of the DRB1 allele frequencies favored the hypothesis on the common origin of Paleo-Aleuts, Paleo-Eskimos, and the Indians from the northwestern North America, whose direct ancestors survived in Beringian/southwestern Alaskan coastal refugia during the late Ice Age.     

Genetic History of Aleuts of the Commander Islands as Revealed by the Analysis of the HLA Class II Gene Variability

Variability of the HLA class II genes (alleles of the DRB1, DQA1, and DQB1 loci) was investigated in a sample of Aleuts of the Commanders (n = 31), whose ancestors inhabited the Commander Islands for many thousand years. Among 19 haplotypes revealed in the Aleuts of the Commanders, at most eight were inherited from the native inhabitants of the Commander Islands. Five of these haplotypes (DRB1*0401-DQA1*0301-DQB1*0301, DRB1*1401-DQA1*0101-DQB1*0503, DRB1*0802-DQA1*0401-DQB1*0402, DRB1*1101-DQA1*0501-DQB1*0301, and DRB1*1201-DQA1*0501-DQB1*0301) were typical of Beringian Mongoloids, i.e., Coastal Chukchi and Koryaks, as well as Siberian and Alaskan Eskimos. Genetic contribution of the immigrants to the genetic pool of the proper Aleuts constituted about 52%. Phylogenetic analysis based on Transberingian distribution of the DRB1 allele frequencies favored the hypothesis on the common origin of the Paleo-Aleuts, Paleo-Eskimos, and the Indians from the northwestern North America, whose direct ancestors survived in Beringian/southwestern Alaskan coastal refugia during the late Ice Age.     

High resolution molecular typing of HLA class II region in the population of the island of Krk, Croatia

The HLA class II alleles (DRB1, DRB3, DRB5, DQA1, and DQB1) and haplotypic associations were studied in the population of the island of Krk using the PCR-SSOP method and the 12th International Histocompatibility Workshop primers and probes. Allele and haplotypic frequencies were compared with the general Croatian population. Significant differences were observed between the population of the island of Krk and Croatians for: a) three broad specificities at DRB1 locus (DRB1*01, *15, and *07), b) one allele at DRB3 locus (DRB3*0301), c) one allele at DQA1 locus (DQA1*0201), d) one allele at DQB1 locus (DQB1*0303). Four unusual haplotypic associations, which have not yet been described in the Croatian population, DRB1*1301-DQA1*0103-DQB1*0607, DRB1*1302-DQA1*0102-DQB1*0605, DRB1*1305-DQA1*0102-DQB1*0605 and DRB1*1305-DQA1*0103-DQB1*0603 were observed in the population from the island of Krk.     

Human leukocyte antigen and interleukin 2, 10 and 12p40 cytokine responses to measles: is there evidence of the HLA effect?

HLA class I and class II associations were examined in relation to measles virus-specific cytokine responses in 339 healthy children who had received two doses of live attenuated measles vaccine. Multivariate linear regression modeling analysis revealed suggestions of associations between the expression of DPA1*0201 (p=0.03) and DPA1*0202 (p=0.09) alleles and interleukin-2 (IL-2) cytokine production (global p-value 0.06). Importantly, cytokine production and DQB1 allele associations (global p-value 0.04) revealed that the alleles with the strongest association with IL-10 secretion were DQB1*0302 (p=0.02), DQB1*0303 (p=0.07) and DQB1*0502 (p=0.06). Measles-specific IL-10 secretion associations approached significance with DRB1 and DQA1 loci (both global p-values 0.08). Specifically, suggestive associations were found between DRB1*0701 (p=0.07), DRB1*1103 (p=0.06), DRB1*1302 (p=0.08), DRB1*1303 (p=0.06), DQA1*0101 (p=0.08), and DQA1*0201 (p=0.04) alleles and measles-induced IL-10 secretion. Further, suggestive association was observed between specific DQA1*0505 (p=0.002) alleles and measles-specific IL-12p40 secretion (global p-value 0.09) indicating that cytokine responses to measles antigens are predominantly influenced by HLA class II genes. We found no associations between any of the alleles of HLA A, B, and Cw loci and cytokine secretion. These novel findings suggest that HLA class II genes may influence the level of cytokine production in the adaptive immune responses to measles vaccine.