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PubMed1993

DNA conformation polymorphism analysis of DR52 associated HLA-DR antigens by polymerase chain reaction: a simple, economical and rapid examination for HLA matching in transplantation.

HLA-DRB1 and -DRB3 alleles of DR52-associated (DR52ass) HLA-DR antigens were genotyped by a polymerase chain reaction (PCR) - based simple and practical method. Genomic DNAs from two hundred Japanese panels were subjected to PCR with two pairs of primers to separately amplify the DR52ass-DRB1 (DR3, 5, 6, and 8) alleles and DRB3 (DR52) alleles. The specific amplification revealed that 128 and 76 panels possessed DR52ass alleles and DRB3 alleles, respectively. PCR products from these panels were heat-denatured, electrophoresed in a non-denaturing polyacrylamide gel, and visualized by silver staining. Electrophoretic mobilities of the DNA samples were compared with those of the typing standards with known genotypes of DR52ass-DRB1 and DRB3 alleles. This method, designated PCR-DNA conformation polymorphism (DCP) analysis, allowed genotyping of the DR52ass-DRB1 and DRB3 alleles of panels without any sequence-specific oligonucleotide probe (SSOP) or restriction endonuclease, and the entire process after PCR could be completed within a few hours. Because the DR52ass-DRB1 and DRB3 alleles assigned by this method were shown to be identical to those determined by the PCR-SSOP method, PCR-DCP analysis was suggested to be a simple and practical HLA genotyping method.

Alleles↗
PubMed1983

A monoclonal antibody recognizing HLA-DR2 on malignant and activated cells.

A monoclonal antibody, designated NDS15.38, which recognizes a polymorphic determinant of HLA-DR, was produced from a fusion in which mice were immunized with the human B lymphoblastoid cell line GIR2 (HLA type A1, B8, 27, Cw2, DR2,7). NDS15.38 functions efficiently as an affinity column and purifies a two-chain complex of molecular weight 33 000 and 30 000 under reducing conditions. The monoclonal antibody reacts with HLA-DR2-positive B lymphoblastoid cell lines and B lymphocytes from patients with chronic lymphatic leukemia in an indirect radioactive binding assay. However, NDS15.38 does not appear to react with peripheral blood B lymphocytes from normal individuals. Using a peroxidase staining technique, NDS15.38 was shown to react with phytohemagglutin (PHA)-stimulated lymphocytes and with apparently activated B cells in the germinal centers of lymph nodes from individuals who were tissue typed as HLA-DR2. Thus it appears that NDS15.38 recognizes a polymorphic determinant of HLA-DR on malignant and stimulated cells, but not on resting cells.

Animals↗
PubMed2000

Vitamin D receptor gene polymorphism in multiple sclerosis and the association with HLA class II alleles.

We have previously reported that the association between Bsm I polymorphism, one of the vitamin D receptor genes (VDRG) polymorphism, and multiple sclerosis (MS). In this report, we investigated the further possible role or relevance of VDRG in the pathogenesis of MS. Apa I polymorphism was detected by PCR-RFLP from the DNA of 77 conventional MS patients and 95 healthy controls. The study of the Bsm I and Apa I haplotypes was carried out by employing previously reported Bsm I data. The AA genotype and the [A] allele in the profiles were significantly more prevalent in MS patients than in controls (P=0.0070 and P=0.0321, respectively). In the [A] allele-positive MS patients, the positive rate of DPB1*0501 in HLA was significantly higher than that of the [A] allele-positive controls and that of the [A] allele-negative MS patients even when the corrected P value (P(corr)) was applied (P(corr)=0.0220 and P(corr)=0.0077, respectively). The frequency of DRB1*1501 was higher in the [A] allele-positive patients than in the [A] allele-positive controls and the [A] allele-negative patients (P(uncorr)=0.0431 and P(uncorr)=0.0089, respectively), but the P values did not reach statistical significance after P corrections. The rate of Bsm I and Apa I haplotypes was much higher in bA/bA-positive MS patients than in the controls (P=0.0003), and in the bA positive MS patients, the positive rate of DPB1*0501 was higher than that of the bA-positive controls and that of the bA-negative MS patients (P(corr)=0.0308 and P(corr)=0.0033, respectively). These results indicate that VDRG polymorphism may be associated with susceptibility to MS, and HLA alleles may correlate with risk for MS together with VDRG.

Adult↗
PubMed1994

HLA supratypes in an Italian population.

A supratype analysis of a North Italian population was performed, using 16 polymorphisms in the HLA region spanning the HLA-A-DP segment. Fourteen supratypes were identified, mostly corresponding to those found in other Caucasoid populations. The degree of their conservation both within the B-DR/DQ region and in the regions telomeric and centromeric from HLA-A and DP was evaluated and linkage disequilibria among several DR and DP alleles were identified. Notably, the degree of association with DP increased when the DR marker was part of a conserved B-DR/DQ supratype. These data are relevant to the definition of the genetic structure of the population and to the prediction of probabilities of histocompatibility matching between unrelated individuals.

HLA Antigens↗
PubMed1997

HLA-DRB1*04 subtypes are associated with increased inflammatory activity in early rheumatoid arthritis.

The sequence polymorphism of HLA-DRB1 molecules in 84 rheumatoid arthritis (RA) patients with early RA has been analysed to evaluate whether particular HLA-DR alleles influence disease progression in the early stage of the disease. Clinical data were analysed by grouping the patients according to disease-associated haplotype combinations (DRB1*04,04/DRB1*04,01/DRB1*04,X/DRB1*01,X) in comparison to patients who did not carry these haplotypes (DRB1*X,X). Our results indicate that patients with early RA who are homozygous for DRB1*04 exhibit an elevated inflammatory activity and an increase of joint affections. In addition, the amino acid polymorphism (QR/KRAA) at position 70-74 seems to affect the production of rheumatoid factors. These results support the role of HLA-DRB1 alleles in the pathogenesis of RA and indicate that patients with particular HLA-DRB1*04 haplotype combinations may require intensified therapeutic interventions in the early stage of the disease to prevent disease progression.

Adult↗
PubMed1990

Disease-associated human histocompatibility leukocyte antigen determinants in patients with seropositive rheumatoid arthritis. Functional role in antigen-specific and allogeneic T cell recognition.

The susceptibility to develop seropositive rheumatoid arthritis (RA) has been linked to specific genomic polymorphisms within the HLA complex. Two different haplotypes have been associated with the disease, HLA-DR1 and HLA-DR4. To investigate the link between such phenotypic disease associations and potential immune mechanisms we used alloreactive and antigen-specific human T cell clones. Here we describe a panel of alloreactive T cell clones directed to polymorphic determinants encoded by the third hypervariable region (hvr) of the HLA-DR beta 1-chain. T cell determinants defined by these clones are shared among HLA-DR1, HLA-Dw4, HLA-Dw13, HLA-Dw14, and HLA-Dw15, and are frequent in a population of RA patients. To study the role of such disease-associated epitopes in antigen-restricted T cell recognition we generated T cell clones from RA patients specific for mycobacterial antigens, Epstein-Barr virus antigens, and tetanus toxoid. In all three antigenic systems T cell clones were restricted to either HLA-DR1 or HLA-DR4. These data suggest that the polymorphisms within the first and second hvr of the HLA-DR beta 1-chain that are distinct in HLA-DR1 and HLA-DR4 and not associated with the disease are crucially involved in the recognition of antigens. Polymorphic determinants encoded by the third hvr are shared among disease-associated haplotypes and may function to mediate the interaction of alloreactive T cell receptor molecules with the HLA complex.

Alleles↗
PubMed1987

HLA DQ alpha and DQ beta restriction fragment length polymorphisms associated with Felty's syndrome and DR4-positive rheumatoid arthritis.

HLA DQ alpha and DQ beta cDNA probes were used to study TaqI generated restriction fragment length polymorphisms (RFLPs) in DR4-positive patients with Felty's syndrome (FS), seropositive rheumatoid arthritis (RA), and in HLA-DR4 positive controls. The results of this analysis revealed two DQ beta RFLP patterns (DQ beta 3a and DQ beta 3b) associated with DR4, of which DQ beta 3b was found at significantly higher frequency in patients with FS (73%) or with RA (52%) than in DR4 controls (29%). Hind III generated RFLPs provide evidence that DQ beta 3b is in strong linkage disequilibrium with the gene encoding the serologically recognized epitope TA10. Results obtained using a DQ alpha chain probe revealed polymorphic differences between DQ alpha chain genes associated with different DR types, thereby providing a possible explanation for the lack of association between RA and other DR haplotypes in linkage disequilibrium with TA10. We conclude that both DQ alpha and DQ beta genes may be important in determining HLA-linked susceptibility to severe forms of RA.

Arthritis, Rheumatoid↗
PubMed1999

HLA class I homozygosity accelerates disease progression in human immunodeficiency virus type 1 infection.

Polymorphic products of HLA class I genes restrict cytotoxic T lymphocyte responses to the constantly evolving spectrum of HIV-1 antigens. Accordingly, homozygosity at class I loci can reduce the repertoire for such HLA-dependent interactions, leading to accelerated disease progression. To test this hypothesis we studied subjects from two distinct HIV/AIDS cohorts: 140 Dutch homosexual men and 202 Rwandan heterosexual women followed up to 13 years from HIV-1 seroconversion. We performed intermediate- and selective high-resolution molecular typing at HLA class I (A, B, and C) and high-resolution typing at HLA class II DRB1 and DQB1. Homozygosity at the HLA-A or -B locus or both was found at increasingly high frequency among individuals with successively more rapid progression to late-stage HIV-1-related conditions. In the combined cohorts (n = 342) the odds ratio (OR) due to HLA-A or -B antigen homozygosity in rapid versus slow progressors was 3.8 (p = 0.003); for Dutch men alone the OR was 3.5 (p = 0.102), and for Rwandan women the OR was 4.1 (p = 0.009). In contrast, homozygous genotypes at either HLA-C, DRB1, or DQB1 alone, or DRB1-DQB1 haplotypes, did not exert any deleterious effect on HIV-1 disease progression. These findings suggest strongly that diversity in addition to sequence specificity at HLA-A and -B loci can influence the rate of disease progression following HIV-1 infection.

Cohort Studies↗
PubMed2002

[Genotyping of HLA-DRB1 by PCR-SSP in Yunnan Lahu ethnic groups].

OBJECTIVE: To investigate polymorphism of HLA-DRB1 in Chinese Lahu population in Yunnan. METHODS: Polymerase chain reaction-sequence specific primers (PCR-SSP) were used to determine HLA-DRB1 genotypes of 110 unrelated healthy Lahu minority people of Yunnan Province. RESULTS: Sixteen alleles of DRB1 were detected in this study. The results of test showed that the genotype distributions observed were corresponded with the Hardy-Weinberg equilibrium. CONCLUSION: This study has obtained a more comprehensive and accurate data set of the normal allele frequencies of HLA-DRB1 in Chinese Lahu population in Yunnan Province, which may be of significance in the studies on population genetics and disease association.

Asian People↗
PubMed2003

[Genotyping of HLA-Cw locus in Chinese Yi ethnic group by PCR-SSP].

BACKGROUND: To analyze the genetic polymorphism of HLA-Cw locus in Chinese Yi ethnic group by DNA typing for further study on its association with HIV infection and progression to AIDS. METHODS: A rapid genotyping method for HLA-Cw by PCR-SSP was set up. It combined twenty-six specific primers and one pair of internal control primer to form twenty-four one-step reactions for each sample. Totally 102 unrelated healthy Chinese Yi ethnic individuals were typed. RESULTS: Twelve HLA-Cw alleles were detected in Chinese Yi ethnic group with HLA-Cw*01, Cw*07 and Cw*08 as the most common genes, which accounted for a frequency of 0.333 3, 0.250 0 and 0.176 5 respectively; four kinds of non-serologically defined HLA-Cw genes i.e. Cw*12, Cw*1301, Cw*14 and Cw*15 were found in this population. Hardy-Weinburg test showed that the genotype distribution observed was correspondent with the expected (chi2=65.983 1, df=66, P>0.05). CONCLUSIONS: This study provides the data of HLA-Cw gene frequency in Chinese Yi ethnic group, which may contribute to research on anthropology, disease association and vaccine application. The result also confirmed that PCR-SSP was a reliable and fast method for HLA-Cw genotyping.

Alleles↗
PubMed2003

Associations between patients with endometriosis and HLA class II; the analysis of HLA-DQB1 and HLA-DPB1 genotypes.

BACKGROUND: Although the aetiology of endometriosis remains unclear, many immunological abnormalities involving changes in cell-mediated and humoral immunity may be associated with endometriosis. Several disorders are thought to be associated with particular HLA antigen types. This study examines the possible association between HLA-DQ and DP. METHODS: A total of 83 patients diagnosed with endometriosis following laparoscopic examination were typed for the HLA-DQB1 and DPB1 alleles using PCR-restriction fragment length polymorphism (RFLP). The HLA DQB1 and DPB1 allele frequencies in these patients and in 222 controls were compared. RESULTS: The prevalence of HLA-DQB1*0301 in the patient group was 16.3% (27/166 alleles), compared with 8.3% in the overall control group (37/444 alleles) and 7.7% in the females of the control group (18/234 alleles). Thus, the prevalence of the HLA-DQB1*0301 allele was significantly greater in patients with endometriosis, compared with the general controls [OR 2.13, 95% CI 1.25-3.64, P = 0.004 (chi(2) analysis), Corrected P-values; Pc = 0.049] and with the general female controls [OR 2.33, 95% CI 1.24-4.39, P = 0.008 (chi(2) analysis), Pc; NS]. There was no significant association in the frequencies of DPB1 alleles between the patients and controls. CONCLUSIONS: The HLA systems may be involved in the aetiology of endometriosis, although further study is needed.

Adult↗
PubMed1991

Negative cross-match selection of HLA-DR compatible kidneys for highly sensitised patients.

Patients who have developed alloantibodies against almost all foreign HLA antigens are very difficult to transplant, because the cross-match with potential donors is often positive. The ideal donor for such patients is an HLA identical or compatible donor, but due to the enormous polymorphism of the HLA complex, the chance of finding such a donor is very small. The acceptable mismatch program, which takes advantage of the HLA-A and B antigens toward which the patient has not developed antibodies, and HLA-DR matching in the computerised selection of kidney donors, has significantly decreased the waiting time for these highly sensitised patients. Furthermore, graft survival is similar to that of non-highly sensitised patients.

Graft Survival↗
PubMed1999

HLA-Cw*1701 is associated with two sub-Saharan African-derived HLA haplotypes: HLA-B*4201, DRB1*03 and HLA-B*4202 without DRB1*03.

Different extended haplotypes have been described for many ethnic groups, such as African-Americans. The complotype FC(1,90)0 is in linkage disequilibrium with HLA-B42, DRB1*0302 in African-Americans and Southern African Xhosa individuals, suggesting a common ancestry. In order to analyze the distribution of Cw*17 alleles (Cw*1701, 1702) in relation to this African-derived extended haplotype, we studied a large panel of samples from African-American individuals and additionally a group of selected samples carrying HLA-B42, DR3 and HLA-B42, non-DR3 antigens. HLA alleles were assigned using sequence-specific amplification (SSP) and sequence-specific oligonucleotide probe hybridization (SSOP). We have found that all haplotypes (10 in total) carrying the extended haplotypes [HLA-B42, FC(1,90)0, DRB1*0302] were positive for HLA-Cw*1701. Interestingly, HLA B*4201 was found in all samples (17 in total) carrying HLA-B42, DR3, Cw*1701, whereas HLA-B*4202 was found in 10 out of 13 samples from individuals carrying HLA B42, Cw*1701 non-DR3. These findings suggest that HLA-Cw*17 polymorphism is conserved in different ethnic populations and that HLA-B42 alleles seem to separate at least different African-derived haplotypes. The historical context of these findings are important for the study of human evolution and they may be useful for the development of strategies in the search for possible donors in organ transplantation for African-derived populations.

Africa South of the Sahara↗
PubMed1989

Molecular analysis of the HLA-DR5 haplotype.

A panel of eleven HLA-DR5 homozygous lymphoblastoid cell lines was investigated for structural heterogeneity on the product level. HLA class II antigens were isolated by immunoprecipitation with different anti-class II monoclonal antibodies and separated by two-dimensional (2-D) gel electrophoresis. As a result, three distinct DRB1, one commonly expressed DRB3, and two distinct DQ gene products could be identified that combined to four different haplotypes associated with HLA-DR5. A hitherto serologically undetected split of HLA-DRw11 was presented by three cell lines. HLA-DRw11 and HLA-DRw12 were found to be related allospecifities that differ only in their DRB1 locus products, but are closely associated with the supertypic DRB3 allele HLA-DRw52b and with HLA-DQw7. The DRB3 alleles HLA-DRw52a and DRw52c were not detected in our cell line panel, indicating that these supertypic determinants are in negative linkage disequilibrium with HLA-DR5. Our data suggest that intra HLA-DR/DQ crossing-over events contribute to the development of the HLA class II polymorphism. Evidence is presented that the T cell defined HLA-D allospecifities are commonly determined by DRB1 and DQ gene products.

Amino Acids↗
PubMed2002

Molecular analysis of HLA-DRB1, DQA1, DQB1, DQ promoter polymorphism and extended class I/class II haplotypes in the Seri Indians from Northwest Mexico.

The study of the genetics of the Major Histocompatibility Complex (MHC) in Amerindians is of great value in understanding the origins and migrations of these native groups, as well as the impact of immunogenetics on the epidemiology of diseases affecting these populations. We analyzed, using Polymerase Chain Reaction and Sequence Specific Oligonucleotide Probes (PCR-SSOP), DRB1, DQA1, DQB1 alleles and the promoter regions of DQA1 and DQB1 genes in 31 unrelated and 24 related Seri, a Mexican Indian group, from the state of Sonora (Northwest Mexico). The class II genotypes of this population were found to be in genetic equilibrium. The allele frequency (AF) of the prevalent DRB1 alleles were DRB1*0407 (48.4%), DRB1*0802 (33.9%) and DRB1*1402 (16.1%). The most frequent DQA1 and DQB1 alleles were DQA1*03011 (AF = 50.00%), DQA1*0401 (AF = 33.87%) and DQA1*0501 (AF = 16.13%); DQB1*0302 (AF = 50.00%), DQB1*0402 (33.87%) and DQB1*0301 (16.13%); which were in combination with DRB1*0407, DRB1*0802 and DRB1*1402, respectively. Three QAP and three QBP alleles were present (QAP 3.1, 4.1, 4.2; QBP 3.1, 3.21, 4.1) associated with the typical published DQA1 and DQB1 alleles. Four class II haplotypes were present in family members: DRB1*0407-QAP-3.1-DQA1*03011-QBP-3.21-DQB1*0302; DRB1*0802-QAP-4.2-DQA1*0401-QBP-4.1-DQB1*0402; DRB1*1402-QAP-4.1-DQA1*0501-QBP-3.1-DQB1*0301 and DRB1*0701-QAP-2.1-DQA1*0201-QBP-2.1-DQB1*0201. The family data were used to confirm extended haplotypes. A total of 21 haplotypes were found when A* and B* loci were also considered. The three most frequent combinations included A*0201-B*3501-DRB1*0407, A*3101-B*5101-DRB1*0802, and A*0201-B*40-DRB1*1402.

Emigration and Immigration↗
PubMed1990

HLA-DQ beta-chain restriction fragment length polymorphism as a risk marker in type 1 (insulin-dependent) diabetes mellitus: a Finnish family study.

Finnish Type 1 (insulin-dependent) diabetic families were analysed for HLA-DQ beta-chain polymorphism using a short intron-specific probe. A simple hybridization pattern was obtained in which all fragments were associated significantly with Type 1 diabetes. The simultaneous presence of two different risk markers, the allelic 12-kilobase and 4-kilobase fragments were strongly associated with Type 1 diabetes since 50% of the patients had this combination compared with only 2% of the control subjects. The cosegregated 7.5/3.0 kilobase fragments, which were associated with HLA-DR2 and DRw6 were not detected among the diabetic patients but were present in 48% of the control subjects. Our results provide further support for the location of susceptibility determining factors in the HLA-DQ gene area. The clear-cut, simple restriction fragment length polymorphism pattern obtained here, which bears a resemblance to a two allelic system, therefore makes this method applicable for estimating the risk of Type 1 diabetes at the population level.

Adolescent↗
PubMed2006

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.

Genetic Predisposition to Disease↗