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A novel two-allele pentanucleotide tandem duplication polymorphism is described within the 3' untranslated region of the HLA-linked HSP70-2 gene, for which a PstI polymorphism is known. All four haplotype combinations were found.
We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10(-1064) and IFN-gamma genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12.93, P < 0.0001). Analysis of VDR genotype in prospective BMT recipients could indicate patients at risk of severe aGVHD. Analysis of VDR genotype in prospective BMT donors may identify individuals who have greater transplant-related mortality, and also allow appropriately restricted use of increased immunosuppressive prophylaxis.
We have examined 56 unrelated individuals from Malaysian aborigines for their DNA polymorphism of the HLA-B gene by sequence specific oligonucleotide probe (SSO) method. Using the SSO hybridization, we found that one specific DNA allele with a B*1513 like pattern of epitope combination (ECB1513) was dominant among the Melayu Asli (Af = 41.9%) and the Senoi (Af = 24%). To determine the nucleotide sequences of ECB1513, a DNA fragment spanning from the beginning of exon 1 to the middle of exon 4 of the HLA-B gene was amplified by polymerase chain reaction (PCR) from two ECB1513 positive individuals, and the PCR products were cloned and sequenced. This sequencing analysis confirmed that ECB1513 was identical to HLA-B*1513 in exon 1, 2, 3, and 4. Amino acid sequence of this major allele, HLA-B*1513, in the aborigines especially around the peptide binding groove (B and F pockets), was compared with that of African B*5301 that had been suggested to confer resistance to malaria infection in Africa. The amino acid residues composing of the F pocket were completely identical in B*1513 and B*5301. These observations suggest that a common environmental factor, the malaria infection, might have independently enhanced the selection of functional change in the polymorphic portion of HLA-B gene in Africa and in South-East Asia.
Sustained myeloid engraftment is an important determinant of outcome in hematopoietic stem cell transplantation (HSCT). Human tumor necrosis factor (TNF)-alpha is encoded by a gene, TNFA, located in the class III region of the major histocompatibility complex on chromosome 6, flanked by the human leukocyte antigen (HLA) class I and II regions. A number of polymorphisms in the promoter region of the TNFA gene have been associated with increased production of TNF-alphain vivo. Additionally, raised TNF-alpha levels have been reported to have a detrimental effect on the outcome in HSCT, in particular on early complications such as acute graft vs host disease, failure to engraft, and transplant-related mortality. There is evidence of linkage disequilibrium (LD) between TNFA promoter polymorphisms and extended HLA haplotypes. We have genotyped 73 cell lines and 189 donor/recipient pairs (undergoing HSCT) for their TNFA polymorphism, all of which had been well characterized with respect to their HLA genes. We found evidence of strong LD between HLA genes and TNFA; however, there was also evidence for recombination events having taken place, as we found that a number of transplant pairs who were matched for their HLA haplotypes were not matched for their TNFA alleles. We analyzed early outcomes in the transplant recipients and found a significant delay in engraftment in those pairs where both donor and recipients possessed an AG allele (associated with higher TNF-alpha levels). Our results suggest a functional effect of TNFA polymorphisms on myeloid engraftment in unrelated HSCT.
The high polymorphism of the HLA system has been used as a powerful genetic tool to single out individuals and populations. By studying characteristic allele frequencies and extended HLA haplotypes in different populations, it is possible to identify ethnic groups and establish the genetic relationships among them. In the present study, HLA-A, -B, -C, -DR and -DQ typing at the serological/antigenic and the DNA level has been used for the first time to assign specific HLA frequencies and haplotypes to Spaniards and Basques and compare them with frequencies in other populations, particularly with North Africans. Allelic frequencies do not significantly differ between Spaniards and Basques. HLA genetic distances and their respective dendrogram together with the results on complete HLA haplotypes place Basques and Spaniards closer to paleo-North African populations than to other Europeans. This goes in favour of the Basques being a relative genetic isolate coming from the primitive Iberian/paleo-North African people. In addition, a tentative assignment of the most common Spanish HLA haplotypes to the different people who populated Iberia according to historical records has been done.
In this report we discuss the results of the association of chronic active hepatitis (B virus) and coeliac disease with HLA class I and class II antigens, in patients of Latin American Caucasian origin. Evidence is presented showing that the alleles involved differ from those reported in other Caucasian populations of different ethnic background. Differences were observed both at the serology and at the DNA (RFLP) level. The relevance of these findings regarding the clinical implications as well as the molecular mechanisms involved in the associations are discussed.
Exposure to grass pollens during the pollen season, reveals in sensitive patients symptoms of allergic rhinitis, conjunctivitis and/or bronchial asthma. It is not well understood why, in some patients, only symptoms of rhinitis occur while in others similar exposure causes symptoms of asthma and rhinitis. An association study is reported here, where the possible contribution of human leucocyte antigen (HLA)-DR gene polymorphisms to differential phenotypic expression of symptoms in patients with grass-pollen allergy was determined. HLA-DR genotyping was performed by the polymerase chain reaction with the sequence-specific primers method in 82 patients with symptoms of seasonal allergic rhinitis and/or bronchial asthma and 52 healthy nonatopic control subjects. A significant association was found between HLA-DRB1*02, B5* haplotype and asthma phenotype in patients with grass-pollen allergy when compared to patients with rhinitis only. Significantly higher total serum immunoglobulin E levels were observed in patients with HLA-DRB1*01 alleles in comparison to patients without these alleles. The data in this study suggest that human leucocyte antigen-DR locus, or other genes in linkage disequilibrium, may play an important role in asthma phenotype expression in patients with grass-pollen allergy as well as in determining total immunoglobulin E levels in these patients.
We studied 201 unrelated French Basque individuals for HLA and Bf polymorphisms. The haplotypes of eighty-seven of them were deduced from family studies. The results show the frequency of the Bf F1 allele (0.1393) which is the highest one currently reported. They confirm the high frequencies of HLA-Aw19.2 and B18 previously reported in that population and show that a whole haplotype with strong linkage disequilibria, namely Aw19.2, Cw5, B18, Bf F1, DRw3 is frequent. On the other hand, the gene frequency of Bf S is decreased (0.5497) as compared with the other European Caucasoïd populations, while a slight increase in the Bf F gene frequency (0.2960) appears. These results point out that it is of importance to consider the genetic background choosing the population where linkage disequilibria are to be studied.
BACKGROUND: Polymorphism among class I molecules of the major histocompatibility complex (MHC) confers allotypic specificity on the peptides that these molecules bind and present to cytotoxic T lymphocytes. Evolution of new human HLA class I alleles usually involves gene recombination events that replace a segment of one allele with the homologous region of another. In this study, the impact of these evolutionary changes has been assessed by comparison of the peptide-binding specificities of six related HLA-B allotypes. RESULTS: Endogenous peptides bound by HLA-B*5401, HLA-B*5501, HLA-B*5502, HLA-B*5601, HLA-B*6701 and HLA-B*0702 were characterized. Despite differing by 1-9 of the amino-acid residues comprising their peptide-binding sites, all these allotypes share a dominant preference for peptides that have proline at position 2. Polymorphism results in differing selection of carboxy-terminal and secondary anchor residues, but the peptide-binding specificities are sufficiently similar that there is overlap in the repertoires of peptides bound by these allotypes. Complete sequence determination of individual peptides revealed four that could be isolated from two or more allotypes. Members of the closely related HLA-B22 family--HLA-B*5401, HLA-B*5501, HLA-B*5502 and HLA-B*5601--show only minor differences in their peptide-binding specificities. This marked similarity is reflected at the functional level, as alloreactive cytotoxic T lymphocytes generated against HLA-B*5401 and HLA-B*5501 exhibited cross-reactive recognition. CONCLUSION: The isolation of identical endogenously bound peptides from six HLA-B allotypes demonstrates overlap in the repertoires of peptides bound in vivo by different allotypes. We speculate that the shared preference for binding peptides with proline at position 2 reflects a selective pressure to retain this specificity, which may be based upon peptide availability in vivo. Characterization of the overlap between the repertoires of peptides bound by HLA-B allotypes could simplify the development of peptide-based vaccines that are targeted to cytotoxic T cells, as single peptides would be effective for humans of different HLA types.
We report on a study performed to determine a boundary of the region with the potential to contribute to the predisposition to human narcolepsy (the susceptibility region) in the human leukocyte antigen (HLA) region. We investigated a Japanese narcolepsy family, in which a de novo chromosomal recombination occurred between the HLA-DRB1 and HLA-B genes in the proband. The recombinant chromosome carrying HLA-DRB1*1501 was transmitted to the affected child and grandchild, suggesting that a strong genetic factor(s) predisposing to the disorder was (were) present on the chromosome, and that the recombination breakpoint could be regarded as a boundary to the susceptibility region. To search for the breakpoint, we carried out allele typing at various polymorphic sites, e.g., microsatellite repeat polymorphisms, restriction fragment length polymorphisms, and single-nucleotide polymorphisms in the HLA region, and examined haplotypes with the polymorphic sites in the family members. Haplotype analyses revealed that the recombination breakpoint was present approximately 50 kb to the telomeric side of the palmitoyl-protein thioesterase-2 (PPT2) gene in the HLA class III region. From the gene map of the HLA region, the cyclic AMP response element-binding protein-related protein gene (CREB-RP) appeared to be located at the telomeric end in the 50-kb region. Therefore, the data presented here suggest that the susceptibility region for the disorder in the family is present on the centromeric side of the CREB-RP gene in the recombinant Chromosome 6 carrying HLA-DRB1*1501.
The particular alleles of the HLA-DQ locus may control the low immune response to natural antigens by a dominant genetic trait through the immune suppression mediated by CD8+ suppressor T cells. The suppressor T cells may be activated by DQ-restricted and antigen-specific CD4+ suppressor/inducer T cells, because (1) a statistically significant association and linkage between low immune responsiveness to the natural antigens and the HLA-DQ gene were observed; (2) antigen-specific CD4+ T cells restricted by the DQ molecules encoded for by the HLA-DQ allele associated with low responsiveness were evidenced in many low responders; and (3) anti-HLA-DQ mAb restored the immune response to natural antigens, in some low responders. This HLA-DQ-controlled polymorphism of immune response to the natural antigens may account for the association between HLA-DQ alleles and organ-specific autoimmune diseases.
BACKGROUND: Peanut allergy is a common and severe phenotype of food allergy with a strong genetic component; HLA class II polymorphisms are attractive candidate genes for this disorder. OBJECTIVE: To determine possible genotypic associations of HLA class II with peanut allergy and attempt replication of previously reported associations. METHODS: Sibling pairs discordant for peanut allergy were genotyped (low resolution) by polymerase chain reaction-based methods to 7 DQ and 18 DR allele groups. A chi2 analysis was undertaken against sibling controls with statistical adjustment for multiple analyses. RESULTS: Seventy-three children with confirmed peanut allergy (mean age, 6.5 years; male, 72%; asthma, 58%; atopic dermatitis, 62%; allergic rhinitis, 67%; other food allergies, 41%) and 75 of their siblings who eat peanut (mean age, 8 years; male, 52%; asthma, 12%; atopic dermatitis, 22%; allergic rhinitis, 37%; other food allergy, 7%) were genotyped. Distribution of DQ7 (29% of children with peanut allergy vs 47% sibling controls) was statistically significantly different (P = .04) before statistical correction for multiple comparisons was made by multiplying them by the number of alleles tested (and not statistically significant after correction; P = .30). Distribution of DR11 was nearly statistically significant without statistical adjustment (26% with peanut allergy vs 41% of sibling controls; P = .07; corrected P = 1.3). Alleles that were previously reported to have a weak association with peanut allergy (DRB1 *03, *08; DQB1 *0302, *04) were not verified in this cohort (unadjusted P > .44). CONCLUSIONS: We could not establish an association between the HLA class II alleles evaluated in this cohort of sibling pairs discordant for peanut allergy.
HLA-antigens are extremely polymorphic. A calculation of the polymorphism shows a number of 398.476.343 possible HLA-phenotypes, if HLA-A, -B, -C and -DR antigens are taken into account. The compatibility of HLA-antigens of recipient and donor plays a crucial role in transplantation: HLA-antigens are the traits, which are recognized by the immune system of the recipient in the frame of a rejection of the transplant or by the donor in the frame of a graft-versus-host reaction. Large international statistics show that HLA-incompatibility between recipient and donor leads to short transplant function periods, while compatibility brings about good transplant function. Therefore, matching of HLA-antigens plays an important role in transplantation of solid organs, mainly kidneys (3, 4, 5), and is completely necessary in bone marrow transplantation. Also in pregnancy, HLA-antigens are important: If HLA compatibility between mother and child is high, the risk for habitual abortion is higher than in normal pregnancies (6, 7).
The risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (> 10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion. HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies form 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA-DRB*1501, DQB1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7, 1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB1*01, DQB1*0501, DQA1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.
This study investigated, through cohort analysis, whether HLA-DRB1 and -DQB1 variability is related to human papillomavirus (HPV) infection prevalence and persistence. HLA-DRB1 and -DQB1 genes were typed in 620 samples from the Ludwig-McGill cohort. HPV positivity was tested in specimens collected every 4 months during the first year of follow-up. Persistent and long-term infections were defined as at least 2 or 3 consecutive positive results for the same HPV type, respectively. The magnitudes of associations were estimated by unconditional logistic regression analysis adjusted for potential confounders. The DRB1*0301-DQB1*0201 haplotype was associated with a 2-fold reduction in risk for transient and persistent HPV infections. DRB1*1102-DQB1*0301 showed a lower-risk effect only for persistence. DRB1*1601-DQB1*0502 and DRB1*0807-DQB1*0402 were associated with a 7-fold and a 3-fold increase, respectively, in risk for persistence. The results suggest that HLA class II polymorphisms are involved in clearance and maintenance of HPV infection.
OBJECTIVE: The contribution of CTLA-4 alleles to the pathogenesis of systemic sclerosis (SSc) was studied in Japanese patients. METHODS: CTLA-4 typing in 2 dimorphic sites, +49 A/G and -308 C/T, was carried out in 62 SSc patients and 107 normal subjects by the PCR-RFLP (restriction fragment length polymorphism) method. HLA-DRB1*15 and *08 genotyping were carried out by the PCR-SSCP (simple-stranded DNA conformation polymorphism) method. RESULTS: In SSc the frequency of the +49A allele increased slightly (40.3%), but was not significant. In SSc with diffuse scleroderma and SSc with anti-topoisomerase I antibody, the +49A also increased (43.8%, and 48.0%, respectively) but again was not significant. A significant increase in the +49A was not observed in SSc with HLA-DRB1*1502 or ORB1*0802. In contrast, the +49A had significantly increased in SSc with the anti-RNP antibody [52.9%, p = 0.0337, Odds ratio (OR) = 2.27 (95% confidential interval (CI) = 1.09-4.71)]. HLA-DRB1*1502 and *0802 had no influence on the association of anti-RNP antibody with the +49A. The +49AA genotype increased significantly in SSc without lung fibrosis [31.8%, p = 0.0456, OR = 3.37 (CI = 1.16-9.87)], especially in limited SSc without lung fibrosis [33.3%, p = 0.0319, OR = 3.62 (CI = 1.16-11.29)]. The dimorphism at -308 did not associate with SSc. CONCLUSION: In Japanese scleroderma, the +49A allele of CTLA-4 increased in the presence of SSc with the anti-RNP antibody.
Human leukocyte phenotypes and genes in the HLA class II regions were studied in 46 Japanese patients with myasthenia gravis. When the HLA phenotypes of the patients with myasthenia gravis were compared with the controls, an increased frequency of HLA-DRw53 was observed in females less than 30 years of age. The genomic DNAs of the HLA-DRw53-positive patients and DRw53-positive controls were analyzed by using four complementary DNA probes for HLA class II genes. With DQB complementary DNA as the probe, a higher incidence of the 6.5-kb or 8.2-kb BamHI fragment was observed in the patients (76.0%) compared with the controls (19.0%). In contrast, no significant difference was observed between patients and controls when complementary DNAs for DRB, DQA, and DPB were used as probes. These results indicate that the genetic background of Japanese females with early-onset myasthenia gravis is different from other patients with myasthenia gravis, and that DQB genes can greatly influence the onset of myasthenia gravis.
The gamma-aminobutyric acid receptor type B 1 (GABA(B) R1) is located approximately at 200 kb telomeric to HLA-A on chromosome 6. It has 11 single-nucleotide polymorphisms (SNPs). We studied the most common of its SNPs (T1974C) in a panel of 118 normal Caucasians from New England and 161 epileptic patients of Caucasian ancestry residing in USA. The frequency of the polymorphism did not differ between patients and controls. Here, we report that the allele C of this SNP in the GABA(B) R1 gene is in linkage disequilibrium with HLA-A11 (P<0.00001) and to a lesser extent with HLA-A1 (P<0.01).