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At least 19 recordsLinked to original sources
PubMed1991

Specific HLA-DQA and HLA-DRB1 alleles confer susceptibility to Sjögren's syndrome and autoantibody production.

Primary Sjögren's syndrome (1. SS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the salivary glands and autoantibody production. In order to identify genetic factors that play a role in pathogenesis and predict extent of disease, we used Southern blot and polymerase chain reaction (PCR) methods to detect polymorphisms of the HLA-DRB1 (DR), HLA-DRB3 (DRw52), and HLA-DQA1 genes among 75 Caucasoid 1. SS patients and 150 Caucasoid controls living in the same geographic region of Southern California. We found significantly increased frequency of HLA-DR3 (P less than .001), HLA-DW52a (P less than .001), and HLA-DQA4 (P less than .05), in comparison to normal controls. Also, an increased frequency of heterozygosity for HLA-DQA1/DQA4 (P less than .05) was present among 1. SS patients. Autoantibodies to SS-A and to SS-B were significantly associated with DR3 (P less than .001), HLA-DQA4, (P less than .05), and DQA4/DQA1 heterozygotes (P less than .01). Among the 1. SS patients, clinical and laboratory features such as hypergammaglobulinemia, symmetric peripheral neuropathy, and hypothyroidism were significantly associated with HLA-DR3 (P less than .01) but not with HLA-DR2 (P greater than .10). In comparison, 1. SS patients with leukocytoclastic vasculitis were more frequently HLA-DR2 (P less than .05). These results using PCR methods confirm and extend prior studies that have used serologic methods.

Adolescent↗
PubMed1992

HLA DQA, DQB, and DRB genotyping by oligonucleotide analysis: distribution of alleles and haplotypes in British caucasoids.

A precise method for comprehensive HLA DQA and DQB genotyping using gene amplification and hybridization with sequence-specific oligonucleotide (SSO) probes is described. Twenty-four SSO probes were used to detect all DQ allotypes defined by nucleotide sequence variation in the second exons of the DQ genes, using a standard set of conditions for all probes at each locus. Five hundred individuals were genotyped for 8 DQA1 and 16 DQB1 alleles by using this method and for 33 alleles of the DRB1, DRB3, DRB4, and DRB5 genes by using previously described SSO probes. The 4-locus DQB1-DQA1-DRB1-DRB3/4/5 haplotypes present were characterized on the basis of known linkage disequilibrium between class II alleles. Fifty-two different haplotypes that have previously been described were further characterized at the nucleotide sequence level and two novel haplotypes were identified. The distributions of these alleles and haplotypes in 177 randomly selected healthy Caucasoid controls from the United Kingdom are reported. These results identify further haplotypic diversity in the HLA class II region, even though strong linkage disequilibrium exists between the DR and DQ gene loci.

Adult↗
PubMed1992

Linkage between HLA-DRB1 and -DRB3 types in the Japanese population analyzed by oligonucleotide genotyping.

We analyzed linkage between HLA-DRB1 and -DRB3 types in 219 Japanese donors by oligonucleotide genotyping. In the Japanese population, DRB1*1201 was linked with DRB3*0101 in all donors analyzed; in contrast, most Caucasian DRB1*1201 is known to be linked with DRB3*02(01/02) (*0201 or *0202). However, most DRB1*1202 was linked with DRB3*0301. Thus, the two DRw12-related DRB1 types are linked with DRB3 types distinct from each other. All the three DRw14-related DRB1 types, DRB1*1401, DRB1*1402, and DRB1*1405, were linked with DRB3*02(01/02) in the Japanese population, contrasting with the known linkage between DRB1*1402 and DRB3*0101 in other ethnic populations. The serologically "blank" DR type, DRB1*1403, was linked with DRB3*0101. Other DRB1 types, DRB1*0301, DRB1*11(01/04) (*1101 or *1104), and DRB1*13(01/02) (*1301 or *1302) in the Japanese population were linked mostly with the same DRB3 types, like those known in other ethnic populations.

Alleles↗
PubMed1992

Comparison of HLA class II alleles in Gypsy and Czech populations by DNA typing with oligonucleotide probes.

Czechs (CZ) and Gypsies (GY) have lived in the same country for several centuries but seem to have different migratory origins. We have studied 99 CZ and compared them with 34 GY from an isolated group living in Czechoslovakia. DRB1, DRB3, DRB4, DRB5, DQA1, DQB1 and DPB1 alleles were determined by PCR followed by oligonucleotide hybridization. DRB1*0701 was the most frequent DR allele in CZ (af = 36.3%). In GY, after DRB1*0701, DRB1*1404 was the second most frequent allele (af = 29.4%), while in CZ this allele was not found. Both groups differed also in the distribution of DR4 subtypes. In CZ, DRB1*0401 was the most frequent subtype (50.0%) of DR4. In GY, DRB1*0408 was the predominant type (44.4%). A new DQB1 pattern was found in GY, which we have called DQB1*3.4. This allele was similar to DQB1*0301 in codon 26, but in codon 57 it resembled DQB1*0302. All cells having this new allele were also positive for DRB1*0408. Four-locus associations in CZ showed haplotypes similar to those previously found in other Caucasoid populations. In GY we observed more unusual haplotypes, some previously seen in the Orient, possibly reflecting GY ancestry.

Alleles↗
PubMed1992

Alloimmunization to platelet antigen HPA-1a (PIA1) is strongly associated with both HLA-DRB3*0101 and HLA-DQB1*0201.

Antibodies to the platelet HPA-1a antigen can elicit in the newborn a condition known as neonatal alloimmune thrombocytopenic purpura (NAITP). Previous studies based on RFLP analysis showed that 100% of HPA-1a-negative women who produced anti-HPA-1a antibodies (responders) were HLA-DRw52a (DRB3*0101). However, this specificity could also be found in some HPA-1a-negative women not producing anti-HPA-1a antibodies (nonresponders). We have analyzed in detail by PCR-SSOP the HLA-DR, -DQ, and -DP loci of 36 responders and 10 nonresponders. We found that while the allele DRB3*0101 was present in the vast majority of responders (91%), there were exceptions. Furthermore, the DQB1*0201 allele was found to be present in almost all responders (94%), but again was also found in nonresponders. The risk of alloimmunization to HPA-1a in an HPA-1b homozygous mother significantly increases with the presence of either allele, the odds ratio being 39.7 for DQB1*0201 and 24.9 for DRB3*0101. Sequencing of exon 2 of these two alleles from responders indicated no sequence difference when compared with the consensus sequences. This indicates that they do not represent variants when compared with the same alleles found in some nonresponders.

Alleles↗
PubMed1992

HLA-DRB3 gene alleles in Caucasian patients with Graves' disease.

Graves' disease (GD) is a human leukocyte antigen (HLA) linked organ-specific autoimmune disease. In German GD patients the disease is associated with HLA specificities of the HLA-DRw52 family (HLA-DR3, -DR5, and DR6; HLA-DRB3 positive HLA haplotypes). Recently, a strong association with a HLA-DRB3 restriction fragment length polymorphism gene has been described. To study HLA-DRB3 alleles and their association with the disease, a large cohort of controls (n = 3724) and GD patients (n = 304) was analyzed. HLA-DR allelic combinations revealed an increase in HLA-DR3/DR5 heterozygous patients (relative risk 2.9; P < 0.001). HLA-DRB3 alleles, as defined by DNA typing in HLA-DR matched groups revealed a significant increase in DRB3*0101 homozygosity (relative risk 17.5; P < 0.001) in HLA-DR3 homozygous patients. In GD patients with ophthalmopathy (grade II or higher, according to Werner) DRB3*0101/*0202 heterozygosity revealed an increased relative risk of 5.5 (P < 0.001). Non-HLA-DR3 homozygous, DRB3*0101/*0202 heterozygous patients were at the highest risk for endocrine ophthalmopathy (relative risk 10; P < 0.001). Our data, based on DNA typing methods of HLA-D genes, provide evidence that the susceptibility is strongly associated with HLA-DRB3 genes.

Alleles↗
PubMed1992

Association between IgE response against Bet v I, the major allergen of birch pollen, and HLA-DRB alleles.

The association of the human IgE response against Bet v I, the major allergen of birch pollen, and the HLA-DR and DQ phenotype was studied. Birch pollen allergic patients showed a typical case history, positive skin-prick test, and positive RAST with birch pollen extracts. They were divided into two groups. Group I (n = 37) consisted of individuals generating IgE antibodies that selectively reacted with Bet v I. Their serum IgE did not react with minor allergens from birch pollen as tested by immunoblot analysis, nor did they show a response against allergens from a panel of grass and other tree pollen or perennial allergens from animals and fungi as determined by skin-prick test. Patients belonging to group II (n = 34) possessed IgE reacting with Bet v I plus one or more additional allergens. The control group consisted of 637 healthy blood donors. Comparison of the frequencies of RFLP-defined HLA-DR and DQ alleles in patients and the control group revealed that the distribution of DRB3 alleles in group I patients differed significantly from that in the control group: A higher frequency of the DRw52a/c alleles in comparison to the control group (pcorr less than 0.02) was observed. In addition, alleles defined by nucleotide sequences coding for the amino acid sequence tyrosine-phenylalanine-histidine at positions 30-32 of the beta chain of DR molecules were found with a higher frequency in patient group I (pcorr less than 0.02), too. These alleles comprise DRw52a/c and some DRB1 alleles.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1992

Analysis of complex genetic systems by ARMS-SSCP: application to HLA genotyping.

We have developed a new method for analysis of complex genetic systems by a combination of the Amplification Refractory Mutation System (ARMS) and Single-Strand Conformation Polymorphism (SSCP) analysis: ARMS-SSCP. Thus, a complex allelic series is subdivided into a number of groups by ARMS followed by the identification of specific alleles using SSCP analysis. We have shown that the HLA alleles at the DRB3 and DQB1 loci were distinguishable from each other using ARMS-SSCP. In 36 individuals typed for the DRB3 and 48 individuals typed for the DQB1 loci, ARMS-SSCP results were in complete agreement with those obtained using the established method of sequence-specific oligonucleotide (SSO) hybridisation. With silver staining, ARMS-SSCP is a rapid, non-radioactive and reliable method which also offers the possibility for detecting new HLA alleles. We have demonstrated that ARMS-SSCP can be performed using fluorescent PCR primers, a feature which gives the method potential for automation.

Base Sequence↗
PubMed1991

HLA-DRB3 typing by restriction digestion of locus-specific amplified DNA.

Locus HLA-DRB3 codes for the serologically defined supertypic specificity DRw52 in HLA-DR3, -5 and -w6 haplotypes. Three specificities of DRw52 (DRw52a, -b and -c) can further be distinguished by cellular techniques or by DNA typing with allele-specific oligonucleotide probes. These specificities were recently reported to have significant importance in antigen presentation. To avoid a time-consuming hybridization procedure, we have developed a simple typing system using PCR and subsequent digestion by allele-specific restriction endonucleases. A system was established with locus-specific amplification of HLA-DRB3 and digestion by the enzymes KpnI, ScaI and HinfI which recognize unique restriction sites within the amplified region. This allowed HLA-DRB3 typing on agarose gel by determining whether the amplification product has been digested or not. This typing system was compared to conventional oligotyping by analyzing 145 RFLP-typed individuals for their DRw52 specificity using both methods. Agarose typing correlated well with oligotyping and was shown to be more simple and practical even in heterozygous individuals.

Base Sequence↗
PubMed1992

HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.

The familial predisposition to chronic inflammatory bowel disease and the increased concordance rate in monozygotic twins with Crohn's disease, suggest that genetic factors influence disease susceptibility. A 100% association with the supertypic HLA class II specificity DRw52a was recently described in white North American patients with primary sclerosing cholangitis, with or without concurrent ulcerative colitis. HLA class II alleles of the DR, DQ, and DP subregions were determined by genomic typing techniques in a large group of Swedish patients with ulcerative colitis or Crohn's disease as well as in a series of patients with primary sclerosing cholangitis. No statistically significant HLA class II association was observed in any of the investigated diseases or when the patients were subgrouped according to disease site or occurrence of extraintestinal manifestations, except an insignificant increase of the DRw17, DQw2 haplotype in patients with primary sclerosing cholangitis. The failure to confirm the well established DRw17 association in Swedish patients with sclerosing cholangitis probably represents a statistical type II error. Furthermore, this study did not verify the recently described strong DRw52a association in sclerosing cholangitis--52% of the patients were DRw52a positive compared with 28% of the controls (p less than 0.05, pc NS). This discrepancy was probably caused by different typing techniques. The DRw52a specificity was determined directly by hybridising HLA-DRB3 genes, group specifically amplified by the polymerase chain reaction, with an allele specific oligonucleotide probe, whereas in the previously mentioned study DRw52a was assigned by indirect serological criteria, which overestimate the frequency of this allele.

Blotting, Southern↗
PubMed1992

Molecular analysis of HLA-DRB1*08/12 alleles: identification of two additional alleles.

A nonradioactive oligotyping method that takes advantage of selective amplification using the polymerase chain reaction (PCR) and oligonucleotide probe hybridization was developed to distinguish all reported HLA-DRB1*08/12 alleles. Selective amplification was achieved using a primer complementary to the sequence encoding YSTGECY at positions 10-16 in the first hyperpolymorphic region (HPMR). This selective amplification of the HLA-DRB1*08/12 subset of alleles provides a refinement in HLA oligotyping that permits unambiguous oligotyping of many heterozygotes that cannot be resolved using less selective amplification alternatives. The amplified DNA was hybridized with a panel of then digoxigenin-labeled probes to resolve oligotypes that correspond to all reported HLA-DRB1*08/12 alleles. Oligotyping of HLA-DRB1*08/12 samples revealed two previously unknown HLA-DRB alleles. One allele, DRB1*0805, differs from DRB1*0801 by a leucine to alanine substitution at position 74. This allele is of particular interest because it is very similar to HLA-DRB1*08 alleles (YSTGECY and lack of an associated HLA-DRB3 gene), but it lacks leucine at position 74, which is characteristic of all previously reported DRB1*08 alleles. The second HLA-DRB1*08 allele, DRB1*0804, differs from DRB1*0802 by a glycine to valine substitution at position 86.

Alleles↗
PubMed1992

Major histocompatibility complex class II alleles in Kawasaki syndrome--lack of consistent correlation with disease or cardiac involvement.

Recent refinements in molecular genetic typing have allowed the precise determination of the extensive polymorphism now recognized in class II major histocompatibility complex (MHC) genotypes. This could have important applications in Kawasaki syndrome (KS), where the relative contribution of genetic factors is now well known. Accordingly, 44 Caucasian, 13 Asian, and 5 American black patients, as well as 221 Caucasian controls were typed for HLA-DRB1, DRB3, DRB4, DQA1, DQB1, and DPB1 alleles by oligonucleotide probe hybridization of polymerase chain reaction amplified genomic DNA using probes and primers supplied by the 11th International Histocompatibility Testing Workshop. Among the 15 HLA-DRB1, 3 DRB3, 9 DQA1, 15 DQB1, and 19 DPB1 alleles examined, none were found to be significantly associated with KS, except for an increased frequency of HLA-DRB3*0301 in Houston Caucasian patients when compared to Houston Caucasian controls (38 vs 11%, pc = 0.012, RR = 5.0). Twelve patients developed coronary artery involvement of whom 7 had aneurysms and 5 had dilatation (8 Caucasians, 2 blacks, 2 Asians). No specific HLA class II allele was associated with this disease complication. Despite a regional association, our data fail to support a consistent role for MHC class II alleles in the pathogenesis of KS.

Alleles↗