内蒙古地区蒙古族HLA-A、B、DRB1基因座多态性分析

应用序列特异性寡核苷酸探针反向斑点杂交技术对内蒙古地区蒙古族106名无关健康个体的HLA-A、B和DRB1 基因座进行基因分型, 以研究内蒙古地区蒙古族人群HLA-A、B、DRB1基因座的等位基因及其组成的单倍型频率分布特征。 采用最大数学预期值算法计算HLA基因座的等位基因频率和单倍型频率。106 名内蒙古地区蒙古族个体的HLA-A、B、DRB1基因座分别检出13、29、13个等位基因。高频单倍型分别为 HLA-A*02-B*46 (0.0510); HLA-A*02-B*13(0.0495); HLA-A*02-B*51(0.0442); HLA-B*13-DRB1*07 (0.0555); HLA- B*46-DRB1*09(0.0378); HLA-B*35-DRB1*13(0.03300); HLA-A*02-B*13-DRB1*07(0.033019); HLA-A*02-B*46- DRB1*09(0.031985)。研究表明: 内蒙古地区蒙古族人群HLA基因座的等位基因和单倍型具有较高的遗传多态性。HLA- A*24-B*14, HLA-A*32-B*63在该民族具有极强的连锁不平衡。     

Allele and haplotype frequencies of human leukocyte antigen-A, -B, -C,-DRB1, and -DQB1 in Chinese patients with hematological diseases

The human leukocyte antigen (HLA) system plays a central role in the immune response to pathogens, as well as in organ and allogenic hematopoietic stem cell transplantation (HSCT). Finding a five-locus (i.e., HLA-A, -B, -C, -DRB1, and -DQB1) matched unrelated donor for a patient awaiting HSCT is a major clinical challenge, due to the lack of HLA-identical sibling donors and the high polymorphism of HLA. To date, most studies providing HLA allele frequencies (AF) and haplotype frequencies (HF) in Chinese populations have focused on donors instead of the recipients and have provided data for three loci (HLA-A, -B, and -DR); however, data from five-locus HLA typing in a large sample of patients, especially those with hematological diseases, remains unavailable. Therefore, this study was designed to determine HLA AF and two-, three-, four- and five-locus HF in a large cohort of Chinese Han patients with hematological diseases. The AF and the HF were determined using high-resolution HLA typing data from 2,878 patients. The total number of HLA-A, -B, -C, -DRB1, and -DQB1 alleles was determined to be 48, 92, 49, 52, and 24, respectively. Hardy-Weinberg equilibrium (HWE) analyses indicated significant deviations from HWE for HLA-A, -C, -DRB1, and -DQB1 AF, but not for HLA-B locus. The three most common alleles at each locus were A*11:01, A*24:02, A*02:01; B*46:01, B*40:01, B*13:02; C*01:02, C*07:02, C*06:02; DRB1*09:01, DRB1*15:01, DRB1*07:01; DQB1*03:01, DQB1*03:03, and DQB1*06:01. Our data may help to determine whether the current bone marrow registry contains sufficient diversity to meet the demand.     

HLA‐DRB1 and HLA–DQB1 genes on susceptibility to and protection from allergic bronchopulmonary aspergillosis in patients with cystic fibrosis

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity pulmonary disease that affects both patients with cystic fibrosis (CF) and those with asthma. HLA‐DRB1 alleles have previously been associated with ABPA–CF susceptibility; however, HLA‐DQB1 allele associations have not been clearly established. The aim of the present study was to investigate HLA class II associations in patients with ABPA–CF and determine their roles in susceptibility or protection. Patients with ABPA–CF, patients with CF without ABPA, patients with asthma without ABPA (AST), and healthy controls were included in this study. DNA was extracted by automatic extractor. HLA‐DRB1 and ‐DQB1 genotyping was performed by the Luminex PCR‐SSOP method (One Lambda, Canoga Park, CA, USA). Allele specific PCR‐SSP was also performed by high‐resolution analysis (One Lambda). Statistical analysis was performed with SSPS and Arlequin software. Both HLA‐DRB1*5:01 and ‐DRB1*11:04 alleles occurred with greater frequency in patients with ABPA–CF than in those with AST and CF and control subjects, corroborating previously published data. On the other hand, analysis of haplotypes revealed that almost all patients with ABPA–CF lacking DRB1*15:01 or DRB1*11:04 carry either DRB1*04, DRB1*11:01, or DRB1*07:01 alleles. In the HLA‐DQB1 region, the HLA‐DQB1*06:02 allele occurred more frequently in patients with ABPA–CF than in those with AST and CF and healthy controls, whereas HLA‐DQB1*02:01 occurred less frequently in patients with ABPA–CF. These data confirm that there is a correlation between HLA‐DRB1*15:01, –DRB1*11:04, DRB1*11:01, –DRB1*04 and –DRB1 * 07:01 alleles and ABPA–CF susceptibility and suggest that HLA‐DQB1*02:01 is an ABPA–CF resistance allele.     

Study of the HLA class II allele polymorphism and phylogenetic analysis in Vojvodina population

The polymorphism at the HLA DRB1 and DQB1 loci in the population of Vojvodina was studied by PCR-SSP method. A total of 13 DRB1 and 5 DQB1 specificities displaying population-specific frequency distribution pattern were described. The most frequent HLA Class II alleles in Vojvodina population were: HLA-DRB1*11 (af = 0.30), −DRB1*04 (af = 0.28), −DRB1*07 (af = 0.21), −DRB1*13 and −DRB1*16 (af = 0.18), −DQB1*03 (af = 0.64), −DQB1*05 (af = 0.39) and −DQB1*02 (af = 0.35). The haplotypes with high frequencies (≥0.02) included HLA DRB1*11 DQB1*03 (0.0825), DRB1*04DQB1*03 (0.0725), DRB1*07DQB1*02 (0.0475). The allele DRB1*07 showed the strongest association with DQB1*02 (Δ = 0.0261, gC² = 4.437) and DRB1*13 allele with DQB1*06 (Δ = 0.0222, gC² = 4.247). The allelic frequencies and populations distance dendrogram revealed the closest relationship of Vojvodina population with Hungarians, Croat, and Greeks which can be the result of turbulent migration within this region and admixture with neighbour populations during the history.     

Analysis of HLA DR2&;DQ6 (DRB1*1501, DQA1*0102, DQB1*0602) Haplotypes in Iranian Patients with Multiple Sclerosis

Multiple sclerosis (MS) is prototype of inflammatory demyelinating disease of the central nervous system .The etiology of MS remains unclear, but according to current data the disease develops in genetically susceptible individuals and may require additional environmental triggers. The human leukocyte antigen (HLA) class II alleles (DRB1*1501, DQA1*0102, DQB1*0602) may have the strongest genetic effect in MS. In this study, the role of these alleles were investigated in 183 Iranian patients with multiple sclerosis and compared with 100 healthy individuals. HLA typing for DRB1*1501, DQA1*0102, DQB1*0602 was performed by polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP) method. The results show that, HLA DR B1*1501 was significantly more frequent among MS patients (46% vs. 20%, PV = 0.0006) but DQA1*0102 haplotype was negatively associated with MS (30% vs. 50%, PV = 0.0049) and no significant association was found with DQB1*0602 and MS patients in comparison with control group (24% and 30%, PV = 0.43). No significant correlation was observed among these alleles with sex, type of disease; initial symptoms, expanded disability status scale (EDSS), as well as age at onset and familial MS. This study therefore indicates that there is no association of above HLA haplotypes with clinical presentation, disease duration, and disability in Iranian patients with MS which is in line with other previous studies in different ethnic groups.     

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 common Scandinavian human leucocyte antigen ancestral haplotype 62.1 as prognostic factor in patients with advanced malignant melanoma

Purpose  We have previously demonstrated an association of the human leukocyte antigen (HLA), HLA-A2 allele with ovarian and prostate cancer mortality as well as a segregation of the ancestral HLA haplotype (AHH) 62.1 [(A2) B15 Cw3 DRB1*04] in patients with stage III–IV serous ovarian cancer. The objective of the present study was to determine the role of the HLA phenotype on the prognosis in stage III–IV malignant melanoma patients. Patients and methods  A cohort of metastatic malignant melanoma patients (n = 91), in stage III (n = 26) or IV (n = 65) were analysed for HLA-A, -B, -Cw and -DRB1 types by PCR/sequence-specific primer method. The frequencies of HLA alleles in the patients were compared to that of healthy Swedish bone marrow donors. The effect of HLA types on prognosis was defined by Kaplan–Meier and Cox analysis. Results  The presence of the AHH 62.1 in clinical stage IV patients was significantly and independently associated with the worst survival rate recorded from the appearance of metastasis (HR = 2.14; CI = 1.02–4.4; P = 0.04). In contrast, the period from the primary diagnosis to metastasis was the longest in patients with this haplotype (HR = 0.40; CI = 0.17–0.90; P = 0.02). Conclusions  Melanoma patients in our cohort with 62.1 AHH which is associated with autoimmune diseases have an initial strong anti-tumour control with longer metastasis-free period. These patients have rapid progression after the appearance of metastasis, responding poorly to chemo- or/and immunotherapy. This apparently paradoxical clinical process could be due to the interplay between tumour clones escape and immune surveillance ending up with a rapid disease progression. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythematosus: TNFB-MHC haplotypes

We investigated the Nco I restriction fragment length polymorphism (RFLP) of the tumor necrosis factor beta (TNFB) gene in 173 patients with systemic lupus erythematosus (SLE), 192 unrelated healthy controls, and eleven panel families, all of German origin. The phenotype frequency of the TNFB*1 allele was significantly increased in patients compared to controls (63.6% vs 47.1%, RR = 1.96, p <0.002). The results of a two-point haplotype statistical analysis between TNFB and HLA alleles show that there is linkage disequilibrium between TNFB*1 and HLA-A1, Cw7, B8, DR3, DQ2, and C4A DE. The frequency of TNFB*1 was compared in SLE patients and controls in the presence or absence of each of these alleles. TNFB*1 is increased in patients over controls only in the presence of the mentioned alleles. Therefore, the whole haplotype A1, Cw7, B8, TNFB*1, C4A DE, DR3, DQ2 is increased in patients and it cannot be determined which of the genes carried by this haplotype is responsible for the susceptibility to SLE. In addition, two-locus associations were analyzed in 192 unrelated healthy controls for TNFB and class I alleles typed by serology, and for TNFB and class II alleles typed by polymerase chain reaction/oligonucleotide probes. We found positive linkage disequilibrium between TNFB*1 and the following alleles: HLA-A24, HLA-B8, DRB1*0301, DRB1*1104, DRB1*1302, DQA1*0501, DQB1*0201, DQB1*0604, and DPB1*0101. TNFB*2 is associated with HLA-B7, DRB1*1501, and DQB1*0602.This study was supported by grants from the Federal Ministry of Research and Technology (BMFT/DFVLR, 01 VM 8608/9), the German Academic Exchange Service (DAAD, 322/501/014/0), and SFB (217).This work is part of the doctoral thesis of M. P. Bettinotti.     

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 Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

Background and Aim

The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.

Methods

High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.

Results

The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).

Conclusions

HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.     

Polymorphism of Leukocyte and Erythrocyte Antigens in Chronic Kidney Disease Patients in Southern Brazil

We investigated the polymorphism of human leukocyte antigens (HLA) and Duffy erythrocyte antigens in chronic kidney disease (CKD) patients in southern Brazil. One hundred and eighty-three CKD patients, over 18 years old, on hemodialysis, were included. HLA-A, -B and -DRB1 typing was performed using the LABType®SSO (One Lambda, Inc.). Duffy phenotypes were determined by gel column agglutination using anti-Fy^a and anti-Fy^b monoclonal anti-sera. The patients'' predominant ages ranged between 51 and 70 years (43%) and the predominant gender, ethnic group and dialysis period were, respectively, male (62%), white (62%) and 1–3 years (40%). The highest and lowest frequencies of Duffy phenotypes were Fy(a+b+) and Fy(a−b−), respectively. Nineteen HLA-A, 30 HLA-B and 13 HLA-DRB1 allele groups were identified. The most frequent HLA allele groups were HLA-A*01, -A*02, -A*03, -A*11, -A*24; HLA-B*07, -B*15, -B*35, -B*44, -B*51; HLA-DRB1*03, -DRB1*04, -DRB1*07, -DRB1*11 and -DRB1*13. Statistically significant differences were observed in the Duffy and HLA polymorphisms compared between CKD patients and healthy subjects. The Fy(a+b−) phenotype (p<0.0001, OR = 2.56, 95% CI = 1.60–4.07) was the most frequent in the patients (p<0.05), and the Fy(a+b+) phenotype (p = 0.0039, OR = 1.71, 95% CI = 1.18–2.51) was the most frequent in the healthy subjects in the same region of Paraná state (p<0.05). Regarding HLA, the HLA-B*42, -B*45, -B*51 and -DRB1*03 allele groups were the most frequent in the patients (p<0.05), and the HLA-B*44 allele group was the most frequent in the healthy subjects in the same region of Brazil (p<0.05). The polymorphism of these two markers among CKD patients in southern Brazil and healthy subjects of other studies, suggests that these markers might be involved with CKD development. Further studies should be undertaken to analyze the markers'' influence on CKD and the long-term results from kidney transplantation.     

Five-locus HLA typing of hematopoietic stem cell donor volunteers using PCR sequence specific primers

We have developed a strategy for five-locus human leukocyte antigen (HLA) typing of hematopoeitic stem cell (HSC) donors using the polymerase chain reaction with sequence-specific primers (PCR-SSP). The PCR-SSP method is robust, reproducible, and accurate. New PCR-SSP mixtures can be added as required and all reactions are carried out under the same conditions, which can easily be applied to the typing of other loci, e.g., ABO blood groups. Initially, 127 PCR-SSP reactions were used to detect simultaneously HLA-A, -B, -C, -DRB1/3/4/5, and DQB1 alleles, differentiated generally to the level of the first two digits of the allele name, essentially equivalent to the serological split specificity. Approximately 40% of subjects were tested against a further 29 HLA-A, -B SSP mixtures to exclude rare alleles and unambiguously assign a two-digit HLA allele family. This gave an overall typing resolution equivalent to or greater than the split specificity level and covered all HLA-A, -B, -C, -DRBland DQB1 alleles listed in the WHO's Nomenclature for Factors of the HLA System, 2000. The Welsh Bone Marrow Donor Registry has used this strategy to HLA type over 35,000 HSC donors over 9 years. Comprehensive and accurate five-locus HLA typing allows confident and rapid identification of potential matched HSC donors for patients requiring stem cell transplantation generally without the need for typing additional loci. This allows resources to be focused directly on allele level typing of DRB1 and other loci. This strategy decreases overall donor work-up time, which is a major benefit to patients.     

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.     

The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (P_{HLA-A-aa-site-62} = 7.4×10⁻²⁹; P _{HLA-B-aa-site-116} = 6.5×10⁻¹⁹; P _{HLA-C-aa-site-156} = 6.8×10⁻⁸ respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.     

Association between HLA-DRB1, HLA-DRQB1 alleles,and CD4<Superscript>+</Superscript>CD28<Superscript>null</Superscript> T cells in a Chinese population with coronary heart disease

CD4⁺CD28^null T cells are present in increased numbers in the peripheral blood of patients with acute coronary syndrome. However, the triggers of expansion of these cells are unclear. Susceptibility to coronary heart disease (CHD) is strongly associated with alleles of human leukocyte antigen (HLA), but it is not equally strong in different human populations. The objective of the study was to investigate association between CD4⁺CD28^null T cells and HLA-DRB1 alleles. The HLA alleles were determined by polymerase chain reaction with sequence-specific primers (PCR-SSP) method, in a group of CHD patients and control subjects from the same area. The number of CD4⁺CD28^null T cells was measured using the flow cytometry technique. The HLA-DRB1*01 (RR = 4.705, P < 0.005) and DRB1*04 (RR = 3.554, P < 0.005) alleles showed the strongest association with CHD in the Chinese population, and increased numbers of CD4⁺CD28^null T cells were found in association with HLA-DRB1*04 (17.1%) and DRB*01 (12.9%), while decreased numbers of CD4⁺CD28^null T cells were present in subjects with DRB1*15 (0.8%). CHD in Chinese population is strongly associated with HLA-DRB1*01 and DRB1*04 haplotypes, and formation of CD4⁺CD28^null T cells was related to HLA-DRB1*01, DRB1*04, and DRB1*15 alleles.     

Importance of human leukocyte antigen (HLA) class I and II alleles on the risk of multiple sclerosis

Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (OR = 0.82, p = 0.034) and B*12 (including B*44/45, OR = 0.76, p = 0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: OR = 0.54, p = 0.0041; additive: AP = 0.47, p = 4 × 10(-06)), DRB1*15 and C*12 (multiplicative: OR = 0.37, p = 0.00035; additive: AP = 0.58, p = 2.6 × 10(-05)), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes.     

Correlation Between HLA-A,B and DRB1 Alleles and Severe Fever with Thrombocytopenia Syndrome

ObjectiveSevere fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever caused by a tick-borne bunyavirus (SFTSV) in East Asian countries. The role of human leukocyte antigen (HLA) in resistance and susceptibility to SFTSV is not known. We investigated the correlation of HLA locus A, B and DRB1 alleles with the occurrence of SFTS.MethodsA total of 84 confirmed SFTS patients (patient group) and 501 unrelated non-SFTS patients (healthy individuals as control group) from Shandong Province were genotyped by PCR-sequence specific oligonucleotide probe (PCR-SSOP) for HLA-A, B and DRB1 loci.Allele frequency was calculated and compared using χ² test or the Fisher''s exact test. A corrected P value was calculated with a bonferronis correction. Odds Ratio (OR) and 95% confidence intervals (CI) were calculated by Woolf’s method.ResultsA total of 11 HLA-A, 23 HLA-B and 12 HLA-DRB1 alleles were identified in the patient group, whereas 15 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles were detected in the control group. The frequencies of A*30 and B*13 in the SFTS patient group were lower than that in the control group (P = 0.0341 and 0.0085, Pc = 0.5115 and 0.252). The ORs of A*30 and B*13 in the SFTS patient group were 0.54 and 0.49, respectively. The frequency of two-locus haplotype A*30-B*13 was lower in the patient group than in the control group(5.59% versus 12.27%, P = 0.037,OR = 0.41, 95%CI = 0.18–0.96) without significance(Pc>0.05). A*30-B*13-DRB1*07 and A*02-B*15-DRB1*04 had strong associations with SFTS resistance and susceptibility respectively (Pc = 0.0412 and 0.0001,OR = 0.43 and 5.07).ConclusionThe host HLA class I polymorphism might play an important role with the occurrence of SFTS. Negative associations were observed with HLA-A*30, HLA-B*13 and Haplotype A*30-B*13, although the associations were not statistically significant. A*30-B*13-DRB1*07 had negative correlation with the occurrence of SFTS; in contrast, haplotype A*02-B*15-DRB1*04 was positively correlated with SFTS.     

HLA Genes in Mayos Population from Northeast Mexico

HLA class I and class II alleles have been studied in 60 unrelated people belonging to Mayos ethnic group, which lives in the Mexican Pacific Sinaloa State. Mayos HLA profile was compared to other Amerindians and worldwide populations’ profile. A total of 14,896 chromosomes were used for comparisons. Genetic distances between populations, Neigbour-Joining dendrograms and correspondence analyses were performed to determine the genetic relationship among population. The new specific Mayo HLA haplotypes found are: HLA-A*02-B*35-DRB1*1406-DQB1*0301; HLA-A*02-B*48-DRB1*0404-DQB1*0302; HLA-A*24-B*51-DRB1*0407-DQB1*0302 and HLA-A*02-B*08-DRB1*0407-DQB1*0302. However, the typical Meso American HLADRB1*0407 represents a 40% of all DRB1 alleles. While common HLA characteristics are found in Amerindian distant ethnic groups, still new group specific HLA haplotypes are being found, suggesting that a common founder effect (i.e. high DRB1*0407) is noticed. Moreover, new HLA haplotypes are almost certainly appearing along time probably due to specific pathogen (?) selection for diversity. Mayo language is close to the Tarahumara one (another geographically close group); notwithstanding both groups are not genetically close according to our results, showing again the different evolution of genes and languages, which do not correlate. Finally, Sinaloa is one of the Mexican States in which more European genes are found. However, the results presented in this paper, where no European HLA genes are seen in Mayos, should have a bearing in establishing transplant programs and in HLA and disease studies.Key Words: Amerindians, HLA, mayos, mexica, nahua, transplant.     

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.     

Association of DLA‐DQB1 alleles with exocrine pancreatic insufficiency in Pembroke Welsh Corgis

Exocrine pancreatic insufficiency (EPI) is a digestive disorder resulting from the insufficient secretion of enzymes from the pancreas. In dogs, this condition is often attributed to pancreatic acinar atrophy, wherein the enzyme‐producing acinar cells are believed to be destroyed through an autoimmune process. Although EPI affects many diverse breeds, to date, molecular studies have been limited to the German Shepherd dog. A recent study of major histocompatibility genes in diseased and healthy German Shepherd dogs identified both risk and protective haplotypes. Herein, we genotyped DLA‐DQB1 in Pembroke Welsh Corgis to determine whether dog leukocyte antigen alleles contribute to the pathogenesis of EPI across dog breeds. We evaluated 14 affected and 43 control Pembroke Welsh Corgis, which were selected based on an age of onset similar to German Shepherd dogs. We identified one protective allele (odds ratio = 0.13, P‐value = 0.044) and one risk allele (odds ratio = 3.8, P‐value = 0.047). As in German Shepherd dogs, the risk allele is a duplication of DLA‐DQB1 (alleles DQB1*013:03 and 017:01); however, Pembroke Welsh Corgis have acquired a single polymorphism on DQB1*017:01. Thus, the DLA‐DQB1 duplication is a risk allele for EPI in at least two breeds.