ABSTRACT
HLA-B*49:01:01:22 differs from HLA-B*49:01:01:01 by a single nucleotide C->G change in intron 5 at gDNA 2451.
Subject(s)
Alleles , High-Throughput Nucleotide Sequencing , Histocompatibility Testing , Introns , Kidney Transplantation , Tissue Donors , Humans , Histocompatibility Testing/methods , India , Exons , Base Sequence , Polymorphism, Single Nucleotide , Sequence Analysis, DNA/methods , HLA-B39 Antigen/geneticsABSTRACT
HLA-B*15:689, HLA-B*35:603 and HLA-B*49:01:25, three novel HLA class I alleles detected by next-generation sequencing.
Subject(s)
Alleles , Exons , High-Throughput Nucleotide Sequencing , Histocompatibility Testing , Humans , HLA-B35 Antigen/genetics , HLA-B15 Antigen/genetics , HLA-B15 Antigen/immunology , HLA-B Antigens/genetics , Sequence Analysis, DNA , Codon , Base Sequence , HLA-B39 Antigen/genetics , HLA-B39 Antigen/immunology , Tissue DonorsABSTRACT
BACKGROUND: HLA-B27 and -B57 were found in people with low levels of HIV-1 DNA, suggesting that HLA class I molecules may influence the size of HIV-1 reservoir. Aim of the study was to explore the association between HLA class I molecules and HIV-1 DNA in people with chronic HIV-1 infection. METHODS: Post-hoc analysis of the APACHE trial, on adults with chronic HIV-1 infection, prolonged suppressive antiretroviral therapy and good immunological profile. HIV-1 DNA was quantified in peripheral blood mononuclear cells (PBMCs); HLA-A, -B and -C were tested on genomic DNA. Crude odds ratios (OR) with their respective 95% Wald confidence intervals (95% CIs) were estimated by univariable logistic regression for HLAs with a p-value <0.10. RESULTS: We found 78 and 18 patients with HIV-1 DNA ≥100 copies/106PBMCs and with HIV-1 DNA <100 copies/106PBMCs, respectively. HLA-A24 was present in 21 (29.6%) participants among subjects with HIV-1 DNA ≥100 copies/106PBMCs and 1 (5.9%) among those with HIV-1 DNA <100 copies/106PBMCs (OR = 5.67, 95%CI = 0.79-46.03; p = 0.105); HLA-B39 was present in 1 (1.4%) with HIV-1 DNA ≥100 copies/106PBMCs and in 3 (17.6%) with HIV-1 DNA <100 copies/106PBMCs (OR = 13.71, 95%CI = 1.33-141.77; p = 0.028) and HLA-B55 in 3 (4.2%) and 3 (17.6%), respectively (OR = 4.43, 95%CI = 0.81-24.29; p = 0.087). All the three patients with HLA-B39 and HIV-1 DNA <100 copies/106PBMCs did not have HLA-A24. CONCLUSIONS: In patients with HIV-1 infection who maintained a good virological and immunological profile, HLA-B39 and -B55 may be associated with lower levels of HIV-1 DNA.
Subject(s)
HIV Infections , HIV-1 , Adult , DNA , HIV Infections/drug therapy , HIV Infections/genetics , HIV-1/genetics , HLA-A24 Antigen , HLA-B27 Antigen , HLA-B39 Antigen , Humans , Leukocytes, Mononuclear , Viral LoadABSTRACT
OBJECTIVE: Different genetic polymorphisms of human leukocyte antigen (HLA) have been associated with the risk and prognosis of autoimmune and infectious diseases. The objectives of this study were to determine whether there is an association between HLA genetic polymorphisms and the susceptibility to and mortality of coronavirus disease 2019 (COVID-19) patients. DESIGN: Observational and prospective study. SETTING: Eight Intensive Care Units (ICU) from 6 hospitals of Canary Islands (Spain). PATIENTS: COVID-19 patients admitted in ICU and healthy subjects. INTERVENTIONS: Determination of HLA genetic polymorphisms. MAIN VARIABLE OF INTEREST: Mortality at 30 days. RESULTS: A total of 3886 healthy controls and 72 COVID-19 patients (10 non-survivors and 62 survivor patients at 30 days) were included. We found a trend to a higher rate of the alleles HLA-A*32 (p=0.004) in healthy controls than in COVID-19 patients, and of the alleles HLA-B*39 (p=0.02) and HLA-C*16 (p=0.02) in COVID-19 patients than in healthy controls; however, all these p-values were not significant after correction for multiple comparisons. Logistic regression analysis showed that the presence of certain alleles was associated with higher mortality, such as the allele HLA-A*11 after controlling for SOFA (OR=7.693; 95% CI=1.063-55.650; p=0.04) or APACHE-II (OR=11.858; 95% CI=1.524-92.273; p=0.02), the allele HLA-C*01 after controlling for SOFA (OR=11.182; 95% CI=1.053-118.700; p=0.04) or APACHE-II (OR=17.604; 95% CI=1.629-190.211; p=0.02), and the allele HLA-DQB1*04 after controlling for SOFA (OR=9.963; 95% CI=1.235-80.358; p=0.03). CONCLUSIONS: The new finding from our preliminary study of small sample size was that HLA genetic polymorphisms could be associated with COVID-19 mortality; however, studies with a larger sample size before definitive conclusions can be drawn.
Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , HLA Antigens/genetics , Polymorphism, Genetic , APACHE , Aged , Alleles , COVID-19/mortality , Case-Control Studies , Female , Genotype , HLA-A3 Antigen , HLA-B39 Antigen/genetics , HLA-C Antigens/genetics , Humans , Intensive Care Units , Male , Middle Aged , Odds Ratio , Organ Dysfunction Scores , Preliminary Data , Prognosis , Prospective Studies , Regression Analysis , Spain/epidemiologyABSTRACT
Biomarkers that are able to identify patients at risk of drug-induced liver injury (DILI) after treatment with infliximab could be important in increasing the safety of infliximab use. We performed a genetic analysis to identify possible human leukocyte antigen (HLA) associations with DILI in European Caucasian users of infliximab in a retrospective study of 16 infliximab-DILI patients and 60 matched controls. In infliximab-associated liver injury, multiple potentially causal individual HLA associations were observed, as well as possible haplotypes. The strongest associated HLA allele was HLA-B*39:01 (P = 0.001; odds ratio [OR] 43.6; 95% confidence interval [CI] 2.8-infinity), which always appeared with another associated allele C*12:03 (P = 0.032; OR 6.1; 95% CI 0.9-47.4). Other associations were observed with HLAs DQB1*02:01 (P = 0.007; OR 5.7; 95% CI 1.4-24.8), DRB1*03:01 (P = 0.012; OR 4.9; 95% CI 1.2-20.5), and B*08:01 (P = 0.048; OR 3.4; 95% CI 0.9-13.2), which also appeared together whenever present in cases. Additional associations were found with HLA-DPB1*10:01 (P = 0.042; OR 20.9; 95% CI 0.7-infinity) and HLA-DRB1*04:04 (P = 0.042; OR 20.9; 95% CI 0.7-infinity). A strong association with HLA-B*39:01 was identified as a potentially causal risk factor for infliximab-induced DILI. Future work should aim to validate this finding and explore possible mechanisms through which the biologic interacts with this particular allele.
Subject(s)
Anti-Inflammatory Agents/adverse effects , Chemical and Drug Induced Liver Injury/genetics , HLA Antigens/genetics , Infliximab/adverse effects , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Adolescent , Adult , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/immunology , Child , Female , Genome-Wide Association Study , HLA-B39 Antigen/genetics , HLA-B8 Antigen/genetics , HLA-DQ beta-Chains/genetics , HLA-DRB1 Chains/genetics , Humans , Male , Middle Aged , Pharmacogenetics , Phenotype , Retrospective Studies , Risk Assessment , Risk Factors , Young AdultSubject(s)
Glycogen Storage Disease Type V/diagnosis , Spondylarthropathies/etiology , Aged , Diagnosis, Differential , Female , Glycogen Storage Disease Type V/complications , Glycogen Storage Disease Type V/physiopathology , HLA-B39 Antigen/genetics , Humans , Muscle, Skeletal/physiopathology , Polymyositis , Positron Emission Tomography Computed TomographyABSTRACT
Antibody identification by a bead array assay in a kidney patient revealed several HLA-specific antibodies including one directed against the HLA-B7 antigen. Low-resolution typing of the patient indicated the presence of an HLA-B*07 allele. To rule out an HLA-specific autoantibody the HLA-typing of the patient was further refined by nucleotide sequencing on a next-generation sequencing platform and eventually showed an HLA-B*39:01:01:03 and HLA-B*07:181N genotype. Thereby the allospecific nature of the antibody was proven. The HLA-B7-specific antibody could be explained by an immunization during the first kidney-transplantation in 1996 with an HLA-B*07 positive donor. When assessing the plausibility of antibodies, the presence of nonexpressed alleles should be taken into consideration.
Subject(s)
Alleles , HLA-B39 Antigen/genetics , HLA-B7 Antigen/genetics , Isoantibodies/genetics , Kidney Transplantation/methods , Transplant Recipients , Adult , Base Sequence , Female , Gene Expression , Genotype , HLA-B39 Antigen/immunology , HLA-B7 Antigen/immunology , High-Throughput Nucleotide Sequencing , Histocompatibility Testing , Humans , Polymerase Chain Reaction , Protein Isoforms/genetics , Protein Isoforms/immunology , Sequence Alignment , Sequence Analysis, DNA , Tissue Donors , Transplantation, HomologousABSTRACT
HLA-B*39:119 allele differs from HLA-B*39:01:01:01 by a single nucleotide substitution at position 488.
Subject(s)
Alleles , HLA-B39 Antigen/genetics , Asian People , China , HumansABSTRACT
BACKGROUND: We analysed the previously reported association of the HLA-A*24:02, B*18 and B*39 alleles with type 1 diabetes and diabetes associated autoimmunity in the Finnish population applying HLA-DR/DQ stratification. MATERIALS & METHODS: Haplotype transmission was analysed in 2424 nuclear families from the Finnish Paediatric Diabetes Register. Survival analysis was applied to study the development of islet autoantibodies and further progression to clinical diabetes in the prospective follow-up cohort from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study. The subjects were genotyped for specific HLA class I alleles by sequence-specific hybridization using lanthanide labelled nucleotide probes. RESULTS: The HLA-B*39:06 allele was found almost exclusively on the (DR8)-DQB1*04 haplotype in which its presence changed the disease risk status of the whole haplotype from neutral to predisposing. The HLA-A*24:02 and the B*39:01 alleles increased the diabetes-associated risk of the DRB1*04:04-DQA1*03-DQB1*03:02 haplotype but the alleles were in linkage disequilibrium and no independent effect could be detected. Within the DIPP cohort, neither the A*24:02 nor the B*39:01 allele were associated with seroconversion but were in contrast associated with increased progression from seroconversion to clinical disease. DISCUSSION & CONCLUSIONS: The independent predisposing effect of the HLA-B*39:06 allele with type 1 diabetes was confirmed in the Finnish population but the association of the A*24:02 and B*39:01 alleles remained inconclusive whilst both A*24:02 and B*39:01 affected the progression rate from seroconversion to autoantibody positivity to overt type 1 diabetes.
Subject(s)
Autoantibodies/biosynthesis , Diabetes Mellitus, Type 1/genetics , Genetic Predisposition to Disease , HLA-A24 Antigen/genetics , HLA-B39 Antigen/genetics , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Adult , Alleles , Child , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Disease Progression , Family , Female , Finland , Gene Expression , HLA-A24 Antigen/immunology , HLA-B39 Antigen/immunology , HLA-DQ Antigens/immunology , HLA-DR Antigens/immunology , Haplotypes , Humans , Kaplan-Meier Estimate , Linkage Disequilibrium , Male , Prognosis , Prospective StudiesABSTRACT
Full-length sequences of HLA-B*39:05:01 and B*39:38Q , confirmed by cloning and sequencing in Chinese donors.
Subject(s)
Alleles , Base Sequence , Exons , HLA-B39 Antigen/genetics , Mutagenesis, Insertional , Sequence Deletion , Asian People , Cloning, Molecular , Codon/chemistry , Gene Expression , Genotype , HLA-B39 Antigen/immunology , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Introns , Polymerase Chain Reaction , Sequence Alignment , Sequence Analysis, DNA , Tissue DonorsABSTRACT
The new HLA-B*39:01:01:04 allele differs from HLA-B*39:01:01 by a C â T substitution in intron 1.
Subject(s)
Alleles , HLA-B39 Antigen/genetics , Introns , Polymorphism, Single Nucleotide , Transplant Recipients , Asian People , Base Sequence , Codon/chemistry , Exons , Gene Expression , Genotype , HLA-B39 Antigen/immunology , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Polymerase Chain Reaction , Sequence Alignment , Sequence Analysis, DNA , Severe Combined Immunodeficiency/pathology , Severe Combined Immunodeficiency/therapyABSTRACT
HLA-B*39:97N differs from HLA-B*39:01:01 by a two nucleotide insertion at position 604-605.
Subject(s)
Alleles , Codon, Nonsense , Exons , Frameshift Mutation , HLA-B39 Antigen/genetics , Tissue Donors , Base Sequence , Bone Marrow Transplantation , Gene Expression , Genome, Human , HLA-B39 Antigen/immunology , Histocompatibility Testing , Humans , Polymerase Chain Reaction , Sequence Alignment , Sequence Analysis, DNAABSTRACT
HLA-B*39:01:23 differs from HLA-B*39:01:01 by a single nucleotide substitution at position 153 C > T.
Subject(s)
Alleles , Exons , HLA-B39 Antigen/genetics , Polymorphism, Single Nucleotide , Tissue Donors , Base Sequence , Bone Marrow Transplantation , Codon/chemistry , Gene Expression , Genome, Human , HLA-B39 Antigen/immunology , Histocompatibility Testing , Humans , Introns , Polymerase Chain Reaction , Sequence Alignment , Sequence Analysis, DNAABSTRACT
B*38:01 and B*39:06 are present with phenotypic frequencies <2% in the general population, but are of interest as B*39:06 is the B allele most associated with type 1 diabetes susceptibility and 38:01 is most protective. A previous study derived putative main anchor motifs for both alleles based on peptide elution data. The present study has utilized panels of single amino acid substitution peptide libraries to derive detailed quantitative motifs accounting for both primary and secondary influences on peptide binding. From these analyses, both alleles were confirmed to utilize the canonical position 2/C-terminus main anchor spacing. B*38:01 preferentially bound peptides with the positively charged or polar residues H, R, and Q in position 2 and the large hydrophobic residues I, F, L, W, and M at the C-terminus. B*39:06 had a similar preference for R in position 2, but also well-tolerated M, Q, and K. A more dramatic contrast between the two alleles was noted at the C-terminus, where the specificity of B*39:06 was clearly for small residues, with A as most preferred, followed by G, V, S, T, and I. Detailed position-by-position and residue-by-residue coefficient values were generated from the panels to provide detailed quantitative B*38:01 and B*39:06 motifs. It is hoped that these detailed motifs will facilitate the identification of T cell epitopes recognized in the context of two class I alleles associated with dramatically different dispositions towards type 1 diabetes, offering potential avenues for the investigation of the role of CD8 T cells in this disease.
Subject(s)
HLA-B38 Antigen/genetics , HLA-B38 Antigen/metabolism , HLA-B39 Antigen/genetics , HLA-B39 Antigen/metabolism , Peptides/metabolism , Amino Acid Sequence , HLA-B38 Antigen/immunology , HLA-B39 Antigen/immunology , Humans , Peptides/chemistry , Peptides/immunology , Protein BindingABSTRACT
A 19-year-old woman with a history of recurrent aphthous stomatitis and genital ulceration was diagnosed with Behçet disease. She was treated with steroids and immunosuppressive agents for more than 30 years, but multiple complications manifested including ileocecal ulcer, aortic valve regurgitation, renal failure, ischemic enterocolitis, and arteriosclerotic obliterans until her death at the age of 56 from pneumonia. An autopsy examination demonstrated an entirely calcified aorta and major aortic branches. The ascending aorta was dilatated 55 mm in diameter and branches were all stenosed. Microscopically, the aortic arch and its branches showed collagenous fibrosis of the outer media and adventitia, whereas coronary and abdominal aortic branches showed conventional atherosclerosis. Although the ante-mortem diagnosis was angio-Behçet disease, its pathophysiology along with her clinical history, morphology of the lead pipe-like aorta, predominant destruction of the outer arteries, and a human leukocyte antigen (HLA) haplotype of B39 were all suggestive of Takayasu arteritis. Thus, this case implies that HLA-B39 may be associated with the pathogenesis of arteritis like Takayasu arteritis, even if the primary disease is Behçet disease.
Subject(s)
Behcet Syndrome/diagnosis , HLA-B39 Antigen/metabolism , Takayasu Arteritis/etiology , Aorta/pathology , Aorta, Thoracic/pathology , Aortic Valve Insufficiency , Autopsy , Behcet Syndrome/complications , Behcet Syndrome/drug therapy , Behcet Syndrome/pathology , Fatal Outcome , Female , Fibrosis/etiology , Fibrosis/pathology , Humans , Pneumonia/complications , Takayasu Arteritis/diagnosis , Takayasu Arteritis/pathology , Vascular Calcification , Young AdultABSTRACT
The new allele B*39:01:15 differs from B*39:01:01 by a point mutation at position 315 (G>T) of exon 2.
Subject(s)
Alleles , Arthritis, Rheumatoid/genetics , HLA-B39 Antigen/genetics , Point Mutation , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Base Sequence , Codon , Exons , HLA-B39 Antigen/immunology , Histocompatibility Testing , Humans , Molecular Sequence Data , Sequence Alignment , Sequence Analysis, DNA , TaiwanABSTRACT
The aim of the study was to evaluate the presence of nonfrequent, rare and very rare alleles among Croats and to estimate whether they are associated with specific alleles at other human leukocyte antigen (HLA) loci. This retrospective study included the typing results from the last 10 years; total number of individuals included was approximately 45,000. Among 17 alleles so far observed only once in our population, 6 (A*24:41, B*07:02:28, B*35:03:03, B*39:40N, DRB1*13:23 and DRB1*14:111) belong to very rare alleles, 2 (B*44:16 and DRB1*01:31) belong to rare alleles according to the 'Rare Alleles Detector' tool ( www.allelefrequencies.net), while for the B*35:101:01 allele published data exist only in the IMGT/HLA database. The remaining eight HLA alleles observed only once among Croats are considered as frequent according to the 'Rare Alleles Detector'. Those 17 HLA alleles are not declared as common well defined (CWD) alleles in the CWD allele catalogue 2.0.0. Haplotype analysis of nonfrequent alleles detected in our sample supports the idea that different populations, although similar in some aspects regarding HLA allele and haplotype distribution, still have some unique characteristics. This is the case for A*01:02, B*39:10 and DRB1*13:32 which form haplotypes unreported to date among our subjects.
Subject(s)
Alleles , Gene Frequency , HLA-A1 Antigen/genetics , HLA-B39 Antigen/genetics , HLA-DRB1 Chains/genetics , Haplotypes , Croatia , Databases, Nucleic Acid , Female , Humans , MaleABSTRACT
To further characterise the effect of the HLA-B*39 allele on type 1 diabetes risk we assessed its role in different HLA-DR/DQ haplotypes and genotypes using 1764 nuclear families with a diabetic child collected in the framework of the Finnish Paediatric Diabetes Register. HLA assays were based on sequence specific hybridization using lanthanide labelled oligonucleotide probes. Transmissions of major HLA-DR/DQ haplotypes with and without the HLA-B*39 allele to diabetic index cases were analysed by direct haplotype and allele counting. The HLA-B*39 allele significantly increased the disease risk conferred by DRB1*04:04-DQA1*03-DQB1*03:02 and (DR8)-DQB1*04 haplotypes. The same effect was observed on genotype level as disease association for the HLA-B*39 allele was observed in multiple genotypes containing DRB1*04:04-DQA1*03-DQB1*03:02 or (DR8)-DQB1*04 haplotypes. Finally we considered the two common subtypes of the HLA-B*39 allele, B*39:01 and B*39:06 and observed their unequal distribution when stratified for specific DR-DQ haplotypes. The risk for type 1 diabetes conferred by certain DR/DQ haplotypes is modified by the presence of the HLA-B*39 and this confirms the independent disease predisposing effect of the HLA-B*39 allele. The results can be applied in enhancing the sensitivity and specificity of DR/DQ based screening programs for subjects at disease risk.
Subject(s)
Alleles , Diabetes Mellitus, Type 1/genetics , Genetic Predisposition to Disease , HLA-B39 Antigen/genetics , HLA-DRB1 Chains/genetics , Haplotypes , Finland , Humans , Registries , Sequence Analysis, DNAABSTRACT
AIMS/HYPOTHESIS: Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia. METHODS: A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 years. RESULTS: Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p ≤ 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p ≤ 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying ≥ 3 risk markers conferring >85% 5 year risk. CONCLUSIONS/INTERPRETATION: These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.
Subject(s)
Autoantibodies/immunology , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/immunology , HLA-A24 Antigen/genetics , HLA-B18 Antigen/genetics , HLA-B39 Antigen/genetics , HLA-DQ Antigens/genetics , Adolescent , Adult , Child , Child, Preschool , Diabetes Mellitus, Type 1/genetics , Female , Humans , Infant , Infant, Newborn , Male , Risk Assessment , Young AdultABSTRACT
The HLA-B*39:42 allele differs from the closest matching allele B*39:01:01:01 by two nucleotide substitutions in exon 3.