SEARCH · PubMed Health

Results for “HLA polymorphism”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,747 records · Page 97Linked to original sources

PubMed2004

HLA-A*2402 and a microsatellite (D6S248) are secondary independent susceptibility markers to ankylosing spondylitis in Basque patients.

Ankylosing spondylitis (AS) is universally associated with human leukocyte antigen B27 (HLA-B27), although other genes could determine the development and clinical expression of the disease. HLA-A9 (A*2402) allele was previously found to be associated in Basque patients. The objective of this study is to perform a more precise analysis of microsatellite polymorphisms in HLA-A*2402 and B27 haplotypes to elucidate the significance of this association. A group of 50 unrelated AS patients and 113 controls of Basque origin were studied. Eight microsatellites in the class I major histocompatibility complex region with vicinity to HLA-A and -B were analyzed and the strength of allelic associations to AS and linkage disequilibrium (LD) between alleles were evaluated. Allele 15 at the microsatellite locus D6S248, 1000 Kb telomeric to HLA-A showed a strong positive association with the disease (OR:6; pc=4.7x10(-4)) and it could not be explained by LD to HLA-B27, HLA-A*2402 or any other loci. We found that D6S248-15 allele together with HLA-A*2402 could be B27-independent markers of additional susceptibility gene/s localised in the region telomeric to HLA-A in Basque AS patients.

Alleles↗

PubMed1988

Extensive DNA polymorphism at the factor XIIIa (F13A) locus and linkage to HLA.

A 1,161-bp EcoRI fragment from the 5' end of the cDNA coding for human factor XIIIa (gene symbol F13A) was used to identify RFLPs in human DNAs. Several different RFLPs were identified with 15 different restriction enzymes. Two RFLPs detected with the restriction enzyme BamHI and one multiallelic RFLP detected with BclI were used for further studies. Linkage relationships between these three polymorphisms and the HLA complex were studied in DNA samples from the 40 Centre d'Etude du Polymorphisme Humain families. Combining all of the data to form highly informative haplotypes, we found linkage to HLA with a maximum lod score of 11.44 at a recombination fraction of .25 for males and .35 for females. These three RFLPs at the FXIIIa locus provide a highly informative marker for the short arm of chromosome 6 with an observed heterozygosity of 91%. Using this marker and the HLA locus, one can confirm or exclude the assignment of gene loci to most of chromosome 6p.

Chromosome Mapping↗

PubMed2002

Increased HLA- A*11 in Chinese children with steroid-responsive nephrotic syndrome.

Human leukocyte antigen (HLA) associations have been frequently reported in childhood steroid-responsive nephrotic syndrome (SRNS) in other populations. The aim of this study was to characterize the immunogenetic background of Singaporean Chinese patients with childhood SRNS. We determined the HLA class I (HLA- A* and HLA-B*) as well as class II (HLA- DRB1*, HLA- DQB1*) gene polymorphisms using the polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) technique, in patients with SRNS (n=64) and normal controls (n=236 for HLA- A*, n=80 for HLA- B*, HLA- DRB1* and HLA- DQB1*). The frequency of HLA- A*11 allele was significantly higher in the SRNS patients compared to controls (78.1% vs 54.2%, respectively; relative risk, RR=3.01, Pc=0.011). However, there was no significant difference in the allele frequencies of HLA- B*, HLA- DRB1* and HLA- DQB1* between the SRNS patients and controls, unlike that in previous studies. Our data suggest that the immunogenetic background of Singaporean Chinese with childhood SRNS was different from that in other populations. As HLA- A*11 has been strongly associated with other autoimmune diseases, it is conceivable that the HLA- A*11-specific motif may play a role in the development of the abnormal T-cell-mediated immune response that may be responsible for triggering the proteinuria seen in SRNS.

Adrenal Cortex Hormones↗

PubMedDate not supplied

[New aspects in the pathogenesis of Bechterew disease].

The association of HLA-B27 with ankylosing spondylitis (AS), first described more than 20 years ago, triggered intensive research all over the world. AS is a disease model to study the interplay between genetic, immunologic, and environmental factors in the induction of rheumatic disease. Over the past years, substantial advances have taken place in the area of the molecular and cellular immunology of the HLA-B27 molecule, HLA-B27 subtype polymorphism, peptide binding and presentation to cytotoxic T cells, and their relevance to disease. New insights into the pathogenesis of the spondylarthropathies come from the development of animal models, namely HLA-B27/human beta 2-microglobulin transgenic rats, and HLA-B27 transgenic, beta 2-microglobulin knock-out mice. The role of gram-negative bacteria and gut inflammation in the development of ankylosing spondylitis continues to be the focus of interest in many studies. In this review, recent hypotheses of the pathogenesis of AS and its relationship to HLA-B27 are discussed.

Animals↗

PubMed2003

Candidate gene studies in focal dystonia.

BACKGROUND: Genetic susceptibility factors for focal idiopathic torsion dystonia (F-ITD) are not established. Mutations in the DYT1 gene can cause focal dystonia, and an association with a polymorphism in the D5 receptor gene (DRD5) has been reported but not confirmed. OBJECTIVE: To investigate a possible role of DYT1 polymorphisms, a CA repeat in the D5 receptor gene (DRD5), the human leukocyte antigen (HLA)-DRB locus, and four polymorphisms in the homocysteine metabolism in the pathogenesis of F-ITD. METHODS: Initially, 100 German patients and 100 matched control subjects were investigated. A second French population with 121 F-ITD patients and matched control subjects was also studied. RESULTS: Two polymorphisms of the beta-cystathionine synthase gene were associated with F-ITD in the German population, but this finding was not replicated in a second independent F-ITD patient and control group of French origin. None of the other investigated polymorphisms was associated with F-ITD. The authors failed to confirm a previously reported association with a polymorphism in DRD5. CONCLUSION: No evidence for an involvement of DYT1, DRD5, HLA-DRB, or polymorphisms in the homocysteine pathway in the pathogenesis of F-ITD was found.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed2000

Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis.

OBJECTIVE: To determine whether tumor necrosis factor (TNF) polymorphisms are associated with susceptibility to rheumatoid arthritis (RA) independently of the HLA-DR shared epitope. METHODS: Fifty-two Spanish families with one or more affected members were typed for HLA-DRB1, TNF promoter polymorphisms, and TNFa and TNFb microsatellites. We performed an association analysis comparing transmitted versus not transmitted haplotypes, with or without shared epitope, to determine whether there is an independent effect of TNF genetic markers on RA susceptibility. RESULTS: TNFa6,b5 was significantly associated with susceptibility to RA. The haplotypes containing these markers were preferentially transmitted to the affected offspring, even if these haplotypes lacked the HLA-DR shared epitope. TNF promoter polymorphisms were not associated with susceptibility to RA. CONCLUSION: The data suggest that TNFa/b is an independent marker of RA susceptibility, pointing to a genetic role of the TNF region in the pathogenesis of RA.

Alleles↗

PubMed2002

Selection of unrelated bone marrow donors by serology, molecular typing and cellular assays.

As compared to hematopoietic stem cell transplantation (HSCT) with HLA genotypically identical donors, phenotypically matched unrelated HSCT is associated with lower survival. Serologically undisclosed HLA disparities account for the increased rate of post-transplant complications. With more than 1300 alleles currently identified, high-resolution molecular typing techniques have to be applied to distinguish the extensive degree of allelic polymorphism of the HLA system. Whereas a HLA-ABDR-serologically identical donor can be identified in the International Registry for >90% of the patients, only half of them can benefit of a highly compatible donor if donor selection is based on allele level matching for HLA-A/B/Cw/DRB1/B3/B5/DQB1 loci. During the last 10 years, we identified only approximately 20% of all known HLA alleles in the searches for our mainly Caucasoid patients. Rare alleles (i.e. alleles that represent <1% of a given serotype) do not have a major impact in patient/donor matching. Most of the incompatibilities are clustered in a limited number of serotypes that can be targeted first during the searches. However, due to linkage disequilibrium (e.g. B-Cw or DRB1-DQB1), incompatibilities at a given locus are often associated with disparities at adjacent loci. In vitro cellular assays such as the cytotoxic T-lymphocyte precursor frequency (CTLpf) analysis may contribute in discriminating functionally relevant HLA class I disparities, as well as minor antigen mismatches in case of sensitized donors. When a rare variant or an uncommon association in the patient's HLA haplotype has been found, the tissue typing laboratory may recommend considering a mismatched donor early in the search procedure instead of continuing a search with a low probability of success.

Alleles↗

PubMed1986

Functional defect of heat-inactivated human lymphocytes in mixed-lymphocyte culture.

Possible causes were examined for the inability of heat-inactivated lymphocytes to induce proliferative responses in mixed-lymphocyte cultures (MLC). Cells heated at 45 degrees C for 60 min lost greater than 90% of their capacity to stimulate in primary (1 degree) or secondary (2 degrees) MLC. This was not due to accelerated or delayed proliferation, nor to a simple quantitative loss of antigen since a 10-fold increase in stimulators or sequential addition of heated stimulators at 4-hr intervals was ineffective. Heated B lymphocytes had approximately 80% expression of HLA-DR and DQ antigens compared to unheated B cells when measured by flow cytometry using monoclonal antibodies detecting both monomorphic and polymorphic antigens. Contrary to some reports, there was no evidence of direct suppression or induction of suppression by heated stimulators or their supernatants. Reconstitution of 1 degree and 2 degrees MLC with crude MLC supernatants or more purified interleukin 1 (Il-1) or interleukin 2 (Il-2) was unsuccessful. The results indicate the heat-induced defect occurs immediately and is not due to direct or indirect suppression, insufficient amounts of Il-1 or Il-2, nor loss of polymorphic Class II HLA determinants. Heat inactivation of stimulator function may result from failure to present an "immunogenic grid" or loss of accessory molecules required in lymphocyte interactions.

B-Lymphocytes↗

PubMed2001

DNA typing system for HLA-A2 alleles by polymerase chain reaction with sequence-specific primers.

OBJECTIVE: To establish a PCR-SSP method for discriminating as many HLA-A*02 alleles, which could easily be introduced into a routine laboratory. METHODS: In this study we typed HLA-A*02 polymorphisms by a sequence-specific primer (SSP) method, which involved round 1 and round 2 PCR reactions to detect 17 HLA-A*02 alleles (they are HLA-A*0201-0217 alleles) covering exon 2 and exon 3. RESULTS: We have found that DNA sample concentration and purity were the most important variable in determining the quality of the result. For identifying correct band size, the size marker used was important. We noticed that different PCR machines performed differently. By this method, we detected 20 HLA-A*02 positive genomic DNA samples and found 4 kinds of HLA-A*02 alleles. They were HLA-A*0201, 0203, 0206 and 0210. CONCLUSION: The HLA-A*02 PCR-SSP method was proven to be a reliable and easily applicable typing method. Our results suggest that the SSP described here provides an optimal HLA-A*02 typing technique that may be useful in selecting donor-recipient pairs in bone marrow transplantation between unrelated individuals.

Alleles↗

PubMed1998

Structural differences between HLA-DQ molecules associated with myasthenia gravis characterized by molecular modeling.

Myasthenia gravis (MG) is characterized by muscle weakness due to autoimmunity against the nicotinic acetylcholine receptor (nAChR). MG is associated with polymorphisms in HLA-DQ genes and the aim of the present study was to characterize structural differences in the peptide binding groove of HLA-DQ molecules positively and negatively associated with MG. Three dimensional models of the positively associated DQ2 (DQB1*02) and negatively associated DQ6 (DQB1*0603) molecules were constructed by homology modeling techniques. The differences in peptide binding properties were primarily localized to peptide-anchor pockets P7 and P9, which might be of importance for the binding of disease-associated peptides from the nAChR.

HLA-DQ Antigens↗

PubMed1987

Determination of DR beta 1 alleles of DR4/Dw subtypes by oligonucleotide probing.

The extensive Dw polymorphism of HLA-D has, to date, been defined using cumbersome and lengthy techniques involving T-cell proliferative reactions. These techniques have not necessarily provided information about the genotype at any single locus of HLA-D because the products of more than a single locus of HLA-D (e.g., DR beta 1 and DR beta 2 of the DR2 haplotypes and in some cases DQ) can contribute to T-cell proliferation and thus to assignment of Dw phenotype. We have recently reported that DR beta 1 alleles relating to the Dw polymorphism can vary by only a single, or a very few, nucleotide differences; the products of this locus are recognized in allo- and restricted responses. Given the importance of defining this polymorphism, we have used specific oligonucleotides as hybridization probes to differentiate between these very closely related alleles. This approach provides the basis for a rapid method for HLA-D typing which, as additional sequence information becomes available, will likely be generally applicable. In addition, oligonucleotide probing allows definition of a gene transcript from an individual locus of HLA-D rather than the phenotype results provided by Dw typing.

Alleles↗

PubMed1990

Polymorphism of major histocompatibility complex extended haplotypes bearing HLA-DR3 in patients with rheumatoid arthritis with gold induced thrombocytopenia or proteinuria.

The distribution of DR3 and of extended haplotypes bearing DR3 was studied in three groups of subjects: 35 patients with rheumatoid arthritis (RA) with gold induced thrombocytopenia or proteinuria, 185 patients with RA without these side effects, and 300 normal healthy controls. The extended haplotypes bearing DR3 were analysed with cDNA probes for DR alpha, DR beta, DQ alpha, and DQ beta genes. The data showed that the prevalence of DR3 was significantly higher in patients who developed gold induced thrombocytopenia or proteinuria than in normal controls or patients with RA without these side effects. Distribution of three extended haplotypes bearing DR3 (B8, DR3; B18,DR3; non-B8,non-B18,DR3) in patients with RA with thrombocytopenia or proteinuria was significantly different from that in normal controls, but not from that in patients with RA without these toxic reactions. Southern blot analysis of DR, DQ genes with cDNA probes showed that the extended haplotype bearing B8,DR3, which carries DQA2.1 and DQB2.1 genes, was present in a significantly higher proportion of patients with RA with gold induced thrombocytopenia or proteinuria (22/24, 92%) than in patients with RA without these side effects (32/45, 71%) or normal subjects (40/61, 66%). The data suggest that the genomic region on chromosome 6 involved in susceptibility to gold induced thrombocytopenia or proteinuria should be extended to the DQA2, DQB2 gene loci.

Arthritis, Rheumatoid↗

PubMed2003

MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish patients.

In order to investigate major histocompatibility complex (MHC) class I chain-related gene A (MICA), tumor necrosis factor (TNFa), -308TNFA, and human leukocyte antigen (HLA-DR/DQ) polymorphisms in mixed connective tissue disease (MCTD), we analyzed 24 patients and 229 healthy controls from Sweden. MICA and TNFa typing was performed by polymerase chain reaction (PCR) and genotyping. HLA-DR and -DQ were genotyped using PCR-sequence specific primers (PCR-SSP) and PCR-sequence-specific oligonucleotide probe (PCR-SSOP), respectively. For analysis of -308TNFA polymorphisms we performed PCR with restriction endonuclease enzymes. We found that the MICA5.1-5.1 genotype was positively associated with MCTD. Shared epitope genes (DRB1*01 and DRB1*04) were also significantly positively associated with MCTD. Polymorphism of -308TNFA was not differently distributed in MCTD patients compared with controls. Furthermore, we demonstrated that frequencies of three estimated haplotypes were increased in MCTD patients compared with controls. Interestingly, the haplotype with MICA allele 4 together with DRB1*04 and TNF1 alleles gives the most specific pattern for MCTD patients compared with controls. Our study demonstrates a clear contribution of HLA loci in susceptibility to MCTD in the Swedish population. Susceptibility to MCTD may be linked to the MICA4/HLA-DRB1*04/TNF1 haplotype and MICA 5.1-5.1 genotype. Mixed connective tissue disease was also associated with shared epitope genes, which in RA has been associated with a more severe disease. Whether these genotypes affect the clinical phenotype of MCTD needs to be determined.

Adult↗

PubMed1995

Polymorphism of human minor histocompatibility antigens: T cell recognition of human minor histocompatibility peptides presented by HLA-B35 subtype molecules.

To investigate the polymorphism of human minor histocompatibility (mH) antigens, PBLs from 23 Japanese individuals and 25 German individuals with HLA-B35 were studied by using four human mH antigen-specific, HLA-B35-restricted CTL clones. The CTL clones killed PHA-stimulated PBLs from all 23 Japanese individuals. On the other hand, they killed the PHA-stimulated PBLs from 19 of 25 German individuals and partially killed the PHA-stimulated PBLs from three German individuals (CTL weakly sensitive cell line); those from another three individuals (CTL-resistant cell line) were not killed by the CTL clones. All of three CTL weakly sensitive cell lines carry HLA-B*3503 molecules, whereas the three CTL-resistant cell lines carry HLA-B*3502, B*3507, and B*3508 molecules. The cytotoxicity of the CTL clones for three CTL weakly sensitive cell lines was enhanced by stimulation of human mH peptides isolated from HLA-B*3501 molecules purified from C1R-B*3501 cells. Small amounts of human mH peptides were isolated from B*3503 molecules purified from these three CTL weakly sensitive cell lines. Taken together, these results indicate that weak recognition by the CTL clones of three CTL weakly sensitive cell line results from a small amount of the human mH peptides presented by B*3503 molecules. The CTL-resistant cell line carrying B*3507 loaded with the human mH peptides was killed by four CTL clones, whereas the cell lines carrying B*3502 or B*3508 loaded with the peptides were not. The human mH peptides were not isolated from B*3507 molecules purified from the cell lines expressing this subtype, whereas small amounts of the human mH peptides were isolated from B*3502 and B*3508 molecules purified from the cell lines expressing the subtypes. These results indicate that failure of the CTL recognition of the cell line carrying B*3507 is due to a lack of human mH antigens in this cell line. The failure of the CTL recognition of the cell lines carrying B*3502 and B*3508 is not explained by only the amount of the human mH peptides binding to these B35 subtype molecules because the amount of the human mH peptides eluted from B*3502 and B*3508 molecules purified from the cell lines carrying these B35 subtypes is almost the same as that eluted from B*3503 molecules purified from the cell lines carrying B*3503.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1999

Frequencies of HLA-DRB1, -DQB1 and -DPB1 alleles in Czech population.

The frequencies of phenotypes, alleles and allelic subtypes of DRB1 and DQB1 HLA loci in 420 unrelated individuals from the Czech population were determined. The frequencies of DPB1 alleles of the HLA locus were determined in 92 individuals. The assays were performed using the polymerase chain reaction (PCR) method or the restriction fragment length polymorphism (RFLP) analysis. The most frequent DRB1 allele was *07, the most frequent DQB1 allele was *03 and the most frequent DPB1 allele detected was *04. These assays define the extent of polymorphism of the HLA system and are useful for determining the selection strategy of HLA-identical donor-recipient pair suitable for bone marrow transplantation.

Alleles↗

PubMed2004

HLA-Cw1214 allele arisen via recombination between HLA-Cw070201 and HLA-Cw*120201.

Allelic polymorphism of the major histocompatibility complex arises mostly from gene conversion. Intralocus gene conversion usually involves limited fragments of DNA, whereas recombination involving large fragments of DNA is considered to be a rare event. During routine sequencing-based typing of donors for the National Marrow Donor Program, a new HLA-C allele was identified in a Caucasian donor. The allele, HLA-Cw*1214, proved to be the product of recombination between HLA-Cw*070201 and HLA-Cw*120201. Exons 1, 2, the 3' end of exon 3 and exon 4 (with one mismatch) belong to HLA-Cw*120201, whereas part of exon 3 belongs to HLA-Cw*070201. Sequencing with primers based in exon 2 and exon 3 showed that intron 2 of the new allele also belonged completely to HLA-Cw*1202. The recombination event apparently occurred within exon 3 with the first point of recombination somewhere between codons 92 and 134 and the second one between codons 157 and 181.

Alleles↗

PubMed2006

Generation of the B*41 group of alleles as indicated by intron sequences.

The generation of the B*41 alleles has been analysed using exon 1, intron 1, exon 2, intron 2 and exon 3 sequences. Results showed that B*4102 may have been generated as the first B*41 allele by a recombination mechanism between B*400102 and B*0801 or B*4201 involving intron 2. B*4101, B*4104 and B*4107 alleles could have been generated from B*4102 by a gene conversion event taking three different fragments from sequences belonging to intron 2/exon 3 of B*45, B*50 or B*49 alleles. B*4105 and B*4106 could be generated from B*4101 allele by point mutations, and B*4103 generation is unclear due to the lack of intron 2. The importance of introns in HLA-B allele polymorphism generation is stressed.

Alleles↗

PubMed2006

Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection.

Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level.

Adaptation, Biological↗