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PubMed2005

Positive and negative associations of human leukocyte antigen variants with the onset and prognosis of adult glioblastoma multiforme.

Associations of genetic factors with malignant gliomas have been modest. We examined the relationships of human leukocyte antigen (HLA) and related polymorphisms to glioblastoma multiforme in adult Caucasians (non-Hispanic Whites) from the San Francisco Bay area. For 155 glioblastoma multiforme patients and 157 control subjects closely matched by ethnicity, age, and gender, PCR-based techniques resolved alleles at HLA-A, -B, -C, and -DRB1 loci along with short tandem repeat polymorphisms of MICA exon 5 and TNFb. By multivariable logistic regression, B*13 and the B*07-Cw*07 haplotype were positively associated with glioblastoma multiforme (P=0.01 and <0.001, respectively), whereas Cw*01 was the only variant showing a negative association (P=0.05). Among glioblastoma multiforme patients, progression to death after diagnosis was slower in those with A*32 (relative hazard, 0.45; P<0.01) and faster in those with B*55 (relative hazard, 2.27; P<0.01). Thus, both the occurrence and the prognosis of glioblastoma multiforme could be associated with specific but different HLA genotypes. B*07 and the B*07-Cw*07 haplotype are much more common in Caucasians than other ethnic groups in the U.S., which may partially explain the higher incidence of glioblastoma multiforme in Caucasians.

Adult↗
PubMed2000

Identification of a novel HLA-Cw*05 allele, Cw*0503.

HLA-Cw*05 is one of the least polymorphic subgroups of HLA-C; so far only two alleles, namely Cw*0501 and Cw*0502, have been reported. We report here the identification of a third allele, Cw*0503, in a Caucasian individual. Cw*0503 is closely related to Cw*0501 with only six nucleotide substitutions clustering over a fragment of 48 nucleotides at the beginning of exon 4. All these six substitutions at the same positions have been found only in HLA-B*44 alleles, suggesting that Cw*0503 is a result of recombination between Cw*0501 and one of B*44 alleles.

Alleles↗
PubMed1996

Minimal phenotype panels. A method for achieving maximum population coverage with a minimum of HLA antigens.

Vaccination with peptides that induce a specific immune response is a potential prophylactic or therapeutic strategy against viral infections and tumors. Because of the extensive polymorphism of the HLA loci, synthetic peptide vaccines must consist of a cocktail of peptides that bind specifically to different HLA molecules. Such cocktails should be optimized for the target population as each population has its specific HLA gene frequencies. To achieve maximum population coverage with a minimum number of peptides, information is needed on the ranking of the most frequent HLA phenotypes. We introduce the minimal phenotype panel, which is the smallest combination of HLA antigens selected so that the proportion of individuals in a population that express at least one of the antigens in the panel exceeds a desired minimum value. We developed a method for assembling minimal phenotype panels based on known HLA class I gene frequencies. We give an example based on a set of 2446 well-defined HLA-typed, random, healthy, unrelated, Dutch Caucasoid individuals. In addition, we discuss the possibility of assembling minimal phenotype panels based on two-locus haplotypes, which enables the assembly of phenotype panels from the antigens of both loci.

Epitopes↗
PubMed1990

Major histocompatibility complex markers and red cell antibodies to the Rh (D) antigen. Absence of association.

Between 20 and 35 percent of Rh(D) antigen-negative individuals do not develop antibodies to D even after multiple transfusions of Rh-positive red cells. To evaluate the possibility that antibody production after exposure to the D antigen was related to a major histocompatibility complex immune response gene, analysis of the HLA genotypes of 38 Rh-sensitized women and their families was performed. No significant deviations were found in the frequency of any individual HLA class I, II, or III allele or of any extended haplotype (fixed allelic combinations of HLA-B, HLA-DR, and the complement components BF, C2, C4A, and C4B). Type 1 errors due to the extreme allelic polymorphism of the HLA system, as well as the ethnic variation in patient groups, may have contributed to HLA allele-antibody responder relationships reported in earlier studies.

Female↗
PubMed1992

[Analysis of polymorphism at the human class I MHC locus, HLA-G].

HLA-G is one of the non-classical HLA class I gene and its expression has been identified in cytotrophoblasts and in some choriocarcinoma cell lines. It encodes apparently non-polymorphic antigen and is considered to play an important role in the fetomaternal immune system. However, the monomorphism of the HLA-G gene has not been established firmly. In order to examine the polymorphism of the HLA-G locus, a clone 7.0E was isolated from a genomic library using a probe derived from 3' untranslated region of HLA-G (Orr). Additionally, PCR/SSCP analysis of the HLA-G 3' untranslated region was carried on 35 DNA samples of unrelated individuals taking advantage of the fact that HLA-G (Orr) and 7.0E differed in 14bp length in the amplified fragments. The nucleotide sequence of 7.0E was homologous to HLA-G (Orr), but the sequence was more closely related to a cDNA sequence of BeWo-G7 which has been cloned from mRNA of BeWo cells. Among these 3 clones no amino acid substitution was found in the coding region, Thus, 7.0E should represent a genomic clone of BeWoG7. PCR/SSCP analysis showed that 33 out of 35 samples (94%) contained 7.0E gene, 29 contained HLA-G (Orr) gene (83%). Two samples (6%) contained only HLA-G (Orr), and 6 samples contained only 7.0E (17%). Among 29 DNA samples containing HLA-G (Orr), 3 samples showed the shift in electrophoretic mobility in HLA-G (Orr), suggesting minor sequence differences in HLA-G alleles. From these results it is concluded that HLA-G antigen is monomorphic, but there are several alleles recognizable by DNA sequence and/or SSCP analysis.

Base Sequence↗
PubMed2005

[High resolution DNA typing for HLA-A, B, Cw genes by polymerase chain reaction-sequence specific oligonucleotide probes method in the Shenyang Han population].

OBJECTIVE: To investigate, at the DNA level, the polymorphism of HLA-A, -B, -Cw genes in the Chinese of Han ethnicity in Shenyang. METHODS: Hybridization with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) was used to determine HLA-A, -B and -Cw genotypes of 108 unrelated healthy individuals from a Chinese Han population. These Hans were born and living in the Shenyang area. RESULTS: The numbers of alleles identified were 21 for HLA-A, 43 for HLA-B, and 23 for HLA-Cw. All the allele frequency distributions were consistent with the Hardy-Weinberg equilibrium. CONCLUSION: Using molecular method, the present authors have analyzed the characteristic of HLA I distribution in a group of indigenous Hans in Shenyang and thus have provided more accurate gene data for use in related researches.

Adolescent↗
PubMed1991

HLA associations with Hashimoto's thyroiditis.

There is disagreement over the HLA-DR associations of Hashimoto's (goitrous) thyroiditis. We have studied 86 English Caucasian patients with this condition whose DR types were determined by restriction fragment polymorphism analysis. HLA-DR3 was significantly more frequent in these patients than in 100 controls (chi 2 = 7.09; P less than 0.01). The relative risk was 2.23 and aetiological fraction 0.29. HLA-DPB and DQB alleles were analysed in a proportion of these subjects by enzymatic DNA amplification and oligonucleotide probing. The only significant finding was an excess of HLA-DQw2 (in linkage disequilibrium with DR3) in the Hashimoto group (chi 2 = 7.43, P less than 0.007). These results do not support a difference between goitrous and atrophic thyroiditis based on respective associations with HLA-DR5 and DR3, but confirm a recent study in which HLA-DR3 was associated with Hashimoto's thyroiditis. However, it is possible that genes telomeric to DR3 may be involved in determining which type of thyroiditis a patient with autoimmune hypothyroidism develops.

Female↗
PubMed2000

Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis.

Genetic susceptibility to type 1 autoimmune hepatitis in white northern Europeans is related to female sex, HLA alleles encoding the six amino acid sequence LLEQKR at positions 67-72 of the DRB1 polypeptide, and CTLA-4 gene polymorphism. The principal HLA alleles associated with type 1 autoimmune hepatitis in Britain and North America are DRB1*0301 and DRB1*0401. In this model of susceptibility, lysine at position 71 of the expressed DR molecule is the critical amino acid. In Japan, Argentina and Mexico, susceptibility is linked to DRB1*0405 and DRB1*0404. These two alleles encode arginine at position 71 rather than lysine, but they share the motif LLEQ-R with DRB1*0401 and DRB1*0301. Thus, K or R at position 71 in the context of LLEQ-R may be critical for susceptibility. This "shared motif" or "epitope" may optimize T-cell recognition of autoantigen, and other alleles that encode lysine at DRbeta71 may also affect susceptibility and outcome, possibly by increasing the density of lysine or arginine 71 molecules on the surface of antigen-presenting cells. Since the DRB1*0301 allele is part of the extended ancestral 8.1 haplotype, it carries with it additional risk factors for autoimmunity, including TNFA*2 and C4A*Q0. Type 1 autoimmune hepatitis is a polygenic disorder and other yet undefined polymorphic genes may be non-specific immunoregulators. These additional MHC encoded genes and other non-MHC encoded genes may be important determinants of disease susceptibility and severity in type 1 autoimmune hepatitis.

Abatacept↗
PubMed1988

Segregation of HLA-DR, -DQ and -DP phenotypes and restriction fragment length polymorphic fragments in two recombinant families.

Members of two families were typed for HLA-DR, -DQ and -DP specificities by means of sera and local PLT bulk reagents. One B:C and one DR:DP cross-over were identified in both families. The restriction fragment length polymorphism (RFLP) was analyzed by southern blotting and the use of DR beta, DR alpha, DQ beta, DQ alpha, DP beta and DP alpha probes. Previous observations concerning typical RFLP patterns for serological DR/DQ- and cellular DP-specificities were confirmed. With respect to recombinant haplotypes, RFLP was informative in both families. All polymorphic fragments-(DRB, DQA and B as well as DPA and B)-segregated together in the HLA-B:DR cross-overs. In the DR:DP recombinant children, the DR and DQ fragments were separated from DP fragments, demonstrating that DP-types as defined by PLT and RFLP map close together. No cross-hybridization between the segregating fragments was detected with the various probes.

Female↗
PubMed1995

TAP polymorphism in patients with Behçet's disease.

OBJECTIVE: To determine if susceptibility to Behçet's disease (BD) is associated with polymorphism of HLA-DRB1, HLA-DQB1, DQB1, and TAP1 and TAP2 genes. METHODS: Fifty eight Spanish BD patients and 116 ethnically matched unrelated healthy subjects were typed at the HLA-DRB1 and HLA-DQB1 loci using polymerase chain reaction/sequence specific oligotyping (PCR/SSO). TAP1 and TAP2 alleles were assigned using amplification refractory mutation system-PCR. RESULTS: TAP1C was absent in BD patients, but was found in 12.1% of control subjects (pcorr < 0.05; relative risk = 0.06). Additionally, a linkage disequilibrium between HLA-DQB1*0501 and TAP2B was observed in BD patients (delta = 0.095, pcorr < 0.02), but not in the control group (delta = -0.0031, p > 0.05). CONCLUSIONS: The complete absence of TAP1C alleles in BD patients may indicate that TAP1 polymorphism is not without some significance in the development of BD. Furthermore, the existence of a linkage disequilibrium between HLA-DQB1*0501 and TAP2B in our patients suggests that the gene conferring susceptibility for BD is inherited as an extended haplotype in the population studied.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Lack of association of HLA class I genes and TNF alpha-308 polymorphism in toluene diisocyanate-induced asthma.

BACKGROUND: Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational asthma and it affects 5-15% of the exposed population suggesting an underlying genetic susceptibility. METHODS: To investigate the role of genetic factors in the development of TDI-induced asthma, we analyzed the distribution of human leukocyte antigen (HLA) class I genes and of tumor necrosis factor (TNF)-alpha A-308G polymorphism in 142 patients with TDI-induced asthma and in 50 asymptomatic exposed subjects. RESULTS: Neither the distribution of HLA class I antigens nor the distribution of TNF-alpha A-308G polymorphism was different between patients with TDI-induced asthma and asymptomatic exposed subjects. CONCLUSIONS: These results suggest that HLA class I antigens and TNF-alpha A-308G are not associated with susceptibility or resistance to the development of TDI-induced asthma.

Adult↗
PubMedDate not supplied

Lack of an association between diffuse systemic sclerosis and HLA-DR1 or HLA-DR5.

The HLA-DR locus of the major histocompatibility complex encodes class II molecules which participate in immune responses through regulation of T cell interaction with antigen presenting cells. Previous association studies between HLA-DR antigens and the autoimmune disease, systemic sclerosis (or scleroderma), have yielded conflicting results. Some investigators have reported an association between this disease and HLA-DR1, while others have demonstrated an association with HLA-DR5. In this study, we used restriction fragment length polymorphisms in the HLA-DR locus to compare allelic frequencies of HLA-DR1 and HLA-DR5 in scleroderma patients with diffuse disease and healthy control subjects. No significant difference in the allelic frequency of either antigen was observed between the groups. These results suggest that HLA-DR1 and HLA-DR5 antigens are unlikely to contribute significantly to disease susceptibility in scleroderma.

Alleles↗
PubMed1985

Comparison of HLA class I gene sequences. Derivation of locus-specific oligonucleotide probes specific for HLA-A, HLA-B, and HLA-C genes.

The major histocompatibility complex in man contains at least 20 class I genes. Included within this family are three closely linked loci with 11-47 codominant alleles that encode the classical transplantation antigens HLA-A, -B, and -C. The study of individual HLA-A, -B, and -C genes is complicated both by the high degree of sequence homology among all members of the class I gene family and by the high degree of polymorphism exhibited by HLA-A, -B, and -C genes. Identification of potential locus-specific regions suitable for use as unique probes has been limited by the small number of nucleotide sequences available for comparison. In the present study, the nucleotide sequences of two cDNA clones, designated HLA-4 and HLA-10, that encode previously unsequenced alleles of HLA-C and HLA-A genes, respectively, are compared with those of other class I genes. From these intergenic and interallelic comparisons, it was deduced that the nucleotide sequence encoding amino acids 291-299 of the transmembrane region showed sufficient divergence between loci and similarity between alleles, to be suitable for the generation of locus-specific probes. Synthetic oligonucleotides were generated and shown to be highly locus-specific in hybridization. These probes were used successfully for the quantitation of the relative amounts of mRNA transcribed in human liver from HLA-A, -B, and -C genes; they should greatly simplify future studies of restriction fragment length polymorphisms of HLA-A, -B, and -C alleles as genetic markers of disease susceptibility.

Alleles↗
PubMed1983

Cellular enzyme-linked immunospecific assay (CELISA). III. Use of the CELISA to quantitate monoclonal antibodies bound to HLA antigens and to subset-specific antigens on cell surfaces.

The cellular enzyme-linked immunospecific assay (CELISA) quantitates the binding of antibody to cell-surface antigens. When conditions that produced the maximum specific enzymatic activity of the conjugate were used, the CELISA was able to screen hybridoma supernatant fluids for polymorphic anti-HLA monoclonal antibodies using as few as 20,000 normal human peripheral blood mononuclear target cells per well. The CELISA detected as little as 24 pg (0.55 fM or 330 X 10(6) molecules) of cell-surface HLA alloantigen and as little as 40 pg of monoclonal antibody bound to cell-surface antigen. In conjunction with various monoclonal antibodies to human peripheral blood mononuclear cell differentiation antigens, the CELISA was used to quantitate levels of different peripheral blood mononuclear cell subsets in normal and diseased people objectively, thus providing a simple, sensitive, and inexpensive alternative to immunofluorescence microscopic and flow cytometric techniques normally used to phenotype peripheral blood mononuclear cells.

Animals↗
PubMed2007

Pyrosequencing-based strategies for improved allele typing of human leukocyte antigen loci.

Successful transplantation of tissue during solid organ and bone marrow transplantation relies on accurate determination of the human leukocyte antigen (HLA) phenotype of the potential donor(s) and recipient. Matching donor with recipient for a kidney transplant generally means finding a six-antigen match by looking at each of two alleles at HLA-A, -B, and -DR loci. For bone marrow transplantation the HLA-C and -DQ alleles are also considered. Molecular techniques, including sequencing, are capable of precisely defining HLA alleles. Because of the large number of possible allelic combinations there are numerous ambiguities associated with heterozygous genotypes even when sequence-based typing protocols are used. Sequencing-by-synthesis methodology employed by Pyrosequencing represents an improvement when applied to HLA genotyping that allows resolution of many ambiguous allelic pairs. Out-of-phase sequencing of HLA alleles by Pyrosequencing can resolve cis/trans ambiguities that would otherwise require the sequencing of isolated cloned DNAs. Single-nucleotide polymorphism typing of HLA for the presence of specific variants is also beneficial for monitoring HLA-encoded genetic risk to autoimmune diseases, such as celiac disease, rheumatoid arthritis, and type 1 diabetes mellitus.

Alleles↗
PubMed2026

HLA-DRB1*14 is associated with lower odds of symptomatic SARS-CoV-2 infection in Mexican individuals.

Mexico has been one of the countries most affected by the COVID-19 pandemic. Several factors can influence the susceptibility to SARS-CoV-2 infection, particularly highly polymorphic genes in the HLA system. Therefore, this pilot study analyzed the association between HLA-DRB1 genetic polymorphisms and the susceptibility and/or resistance to symptomatic SARS-CoV-2 infection in a population from the Metropolitan Area of the Valley of Mexico. Individuals with a confirmed SARS-CoV-2 infection were recruited (n = 90), as well as a seronegative control group without reported symptomatic infection (n = 60). The HLA-DRB1 locus was typed using NGS. We found a significant increase in the frequency of the HLA-DRB1*14 allele in the control group (OR&#xa0;=&#xa0;0.37; 95% CI: 0.18-0.72; p = 0.003; pc = 0.03). These data suggest that HLA-DRB1*14, a prevalent allele in the Mexican population, is associated with a reduced risk of symptomatic SARS-CoV-2 infection in this cohort.

Humans↗
PubMed1990

New HLA-DR2-related specificities detected in South African blacks and individuals of mixed ancestry.

This study describes a new HLA-DR2-related specificity DR2LUM (CT) present in South African Blacks and individuals of mixed ancestry (Cape Coloureds). It can be distinguished from the "classic" DR2 specificities. DRw15 and DRw16, using serological and Southern blot techniques. Although no HLA-Dw specificity could be assigned to the DR2LUM(CT) cells, borderline typing reactions with Dw2 HTCs were observed. Southern blot analysis using a DRB probe and the TaqI enzyme has shown that DR2LUM(CT) shared a 1.6 kb fragment with DRw15 and a 4.7 kb fragment with DR1 and DRw10, indicating sequence homology between DR2LUM(CT) and these alleles. In addition, another unusual HLA-DR2 haplotype was found. The DR antigen was typed serologically as DRw16 but showed a combination of restriction fragments which are associated with both the DRw15 and DRw16 specificities. This study demonstrates the value of investigating non-Caucasoid populations in further characterizing the polymorphisms of the HLA class II genes.

Autoradiography↗