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PubMed1997

Polymorphism in the alpha 1 helix of the HLA-B heavy chain can have an overriding influence on peptide-binding specificity.

Previously, we reported overlap in the repertoires of peptides endogenously bound by a group of HLA-B allotypes related to HLA-B7. Extending such analysis to four members of the B17 family and seven members of the B15 family shows that allotypes that share sequence identity in the alpha 1 helix of the class I heavy chain possess markedly similar peptide-binding specificities. Members of the B17 family share a preference for peptides with serine, threonine, or alanine at position 2 and aromatic residues at the carboxyl terminus. Strikingly, the presence of a segment of the B17 alpha 1 helix in B*1516 and B*1517 confers the B17-like peptide-binding motif. The strong influence of natural variation in the alpha 1 helix is exemplified by the differences in peptide-binding specificity of B15 allotypes related by conversion events that replaced segments of the alpha 1 helix. In contrast, evolutionary changes that are confined to the alpha 2 domain confer less dramatic change. They do not perturb the primary anchors of the peptide-binding motif but can modulate the specificity through development and diversification of secondary anchors. Our results, in combination with those obtained previously for other HLA-B allotypes, suggest a general trend whereby polymorphism in the alpha 1 helix is the overriding influence on peptide-binding specificity of HLA-B allotypes, while amino acid substitutions in the alpha 2 domain play a more modulatory role.

Alleles↗
PubMed1997

Pathogenic gene responsible for the predisposition of Behçet's disease.

HLA-B51 is well known to be associated with Behçet's disease (BD) in many different ethnic groups. The hypothesis may be presented that B51 molecules are primarily involved in BD development through specific antigen presentation. Furthermore, HLA-C genotyping by the polymerase chain reaction-sequence specific primers method suggests that the BD pathogenic gene is not the HLA-C gene itself but some other gene located near the HLA-B gene. Polymorphic analysis of the Tau-a microsatellite between the HLA-B and TNF genes indicates that the pathogenic gene of BD is not the HLA-B51 gene itself but other gene located around the HLA-B gene. Recent studies suggest that many novel genes exist in the region between the TNF and HLA-B or HLA-C genes such as MIC and PERB, etc. and furthermore, many unidentified new genes have been suggested to exist in this region. In this paper, the present situation of the investigations on the genetic predisposition responsible for BD was reviewed.

Animals↗
PubMed1990

Modern European cranial variables and blood polymorphisms show comparable spatial patterns.

Spatial patterns in cranial traits for modern European populations are compared with patterns described by Sokal et al. (1989) for blood polymorphisms. Spatial patterns in these variables are described from both one-dimensional and directional autocorrelation correlograms. Manhattan distances computed among one-dimensional correlograms are used (1) to cluster variables with similar patterns and (2) to test the hypothesis that these clusters are to some extent accounted for by the type of variable. The one-dimensional correlograms for cranial traits do not show a significant contrast with either red cell antigens or the set of blood polymorphisms that excludes HLA. The only contrast that accounts for any of the cluster structure among one-dimensional correlograms is that between HLA and non-HLA variables. A cluster analysis of the directional correlograms demonstrates that cranial traits reflect patterns comparable to those for blood polymorphisms. This finding implies that patterns in cranial variables can be accounted for by the same, or similar, population processes as those inferred from patterns in blood polymorphisms. The implications of this finding for the likely origin of the northwest-southeast cline seen in some modern blood polymorphisms and modern cranial variables, but not in Neolithic cranial variables, are discussed.

Antigens↗
PubMed1999

Actinic prurigo and polymorphic light eruption: common pathogenesis and the importance of HLA-DR4/DRB1*0407.

Actinic prurigo (AP) and polymorphic light eruption (PLE) both belong to the group of idiopathic photodermatoses, but it remains controversial whether AP is a distinct photodermatosis or a variant of PLE. The aim of this study, by collecting data from 119 patients with features of these disorders, was to establish whether specific criteria could be used to distinguish AP from PLE prospectively. We found that presence of the eruption on both exposed and covered sites, its occurrence in winter, persistence of lesions beyond 4 weeks, mucosal and conjunctival involvement, excoriation and scarring of the skin were important features of AP which were not typical of PLE. On this basis, confident clinical diagnoses could be reached in 103 of 119 patients (87%), 57 with AP and 46 with PLE, supported by phototesting and negative lupus serology. HLA typing subsequently confirmed the strong association (90%) between AP and the DR4 allele, in particular with the rare subtype DRB1*0407 which was present in 60% of these patients. No HLA association was found in PLE. In the 16 remaining cases, however, clinical overlap meant that no definite diagnosis could be made; these patients were notionally described as having persistent PLE (PPLE). Demographic and HLA data in this group suggested that PPLE was perhaps most appropriately grouped with PLE. In addition to those patients who were difficult to classify, 35% of our typical AP patients also described clinical progression from PLE to AP, AP to PLE or coexistence of both AP and PLE. In conclusion, our study suggests that while AP and PLE are clinically distinct conditions in most cases, they may perhaps share a common pathophysiological basis. The AP phenotype may be determined by HLA and perhaps other factors in patients otherwise predisposed to PLE.

Adolescent↗
PubMed2002

Gene polymorphisms, inflammatory diseases and cancer.

Genes whose products play a critical role in regulation of the immune response include the human leucocyte antigen (HLA) and cytokine families of genes. The HLA genes are the most polymorphic found in the human genome, and the bulk of this polymorphism results in functional differences in expressed HLA molecules, resulting in inter-individual differences in presentation of peptide antigens to T-cells. In addition, a considerable number of cytokine-associated gene polymorphisms have been identified, the bulk of which occur in the upstream promoter sequences of these genes, which in many cases results in differential in vitro expression of the respective pro- or anti-inflammatory gene product. Particular HLA polymorphisms result in well-defined associations with a large number of immunologically-mediated diseases, including some diseases with known dietary risk factors. For example, individuals of HLA-DQA1*0501, DQB1*0201 genotype have a greater than 200-fold increased risk of developing intolerance to dietary wheat gluten (coeliac disease), and additional HLA-related factors may influence the development of malignant lymphoma within pre-existing coeliac disease. Similarly, HLA-DRB1 alleles sharing a common sequence motif constitute the primary known genetic risk factor for rheumatoid arthritis. The influence of polymorphisms associated with differential cytokine expression on disease susceptibility is currently of much interest. Most attention has been focused on associations with susceptibility to benign immunologically-mediated diseases, including a number of gut diseases. However, recent work from our laboratory indicates that cytokine polymorphisms may influence susceptibility to and prognosis in a number of different cancers, including malignant melanoma skin cancer and solid tumours which may be influenced by diet, such as prostate cancer (collaboration with the CRC/BPG UK Familial Prostate Cancer study). In addition, preliminary work suggests that dietary modulation of expression levels of certain cytokines in healthy human subjects may be genotype dependent.

Arthritis, Rheumatoid↗
PubMed2003

Heterozygosity for MICA5.0/MICA5.1 and HLA-DR3-DQ2/DR4-DQ8 are independent genetic risk factors for latent autoimmune diabetes in adults.

Major histocompatibility complex class I chain-related gene A (MICA) encodes polymorphic, stress-inducible antigens recognized by gammadelta T cells within the intestinal epithelium. MICA microsatellite polymorphism has been implicated to be related to different autoimmune diseases. Ninety-eight patients with type 1 diabetes (median age, 35 years; range, 9-89 years and 51 patients with latent autoimmune diabetes (LADA; median age, 48 years; range, 19-79 years) were compared with 113 healthy control patients (median age, 35 years; range, 19-65 years) to study the importance of MICA-microsatellite polymorphism and HLA-DR-DQ as genetic risk factors for diabetes. The different factors were compared univariately and by logistic regression analysis. In the logistic regression model, heterozygosity for MICA5.0/5.1 was a significant risk factor for LADA (odds ratio [OR] = 12; 95% confidence interval [95%CI], 2.5-59) as well as heterozygosity for HLA-DR3-DQ2/DR4-DQ8 (OR = 15; 95%CI, 2.7-84). None of the MICA polymorphisms were related to type 1 diabetes. Heterozygosity for HLA-DR3-DQ2/DR4-DQ8 was a risk factor for type 1 diabetes (OR = 14; 95%CI, 2.9-66) as well as DR4-DQ8/x (OR = 2.8; 95%CI, 1.4-5.9). HLA-DR15-DQ6 was protective for type 1 diabetes (OR = 0.12; 95%CI, 0.015-0.96). We concluded that both heterozygosity for MICA5.0/5.1 and HLA-DR3-DQ2/DR4-DQ8 are separate risk factors for LADA, but that heterozygosity for HLA-DR3-DQ2/DR4-DQ8 and DR4-DQ8 alone are most important for type 1 diabetes.

Adolescent↗
PubMed2003

Advantage of rare HLA supertype in HIV disease progression.

The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.

Amino Acid Motifs↗
PubMed1993

Detection of established and novel alleles of the HLA-DPB1 locus by PCR-SSO.

The polymorphism at the HLA-DPB1 locus was investigated in 490 Austrian individuals. Exon 2 sequences of the HLA-DPB1 genes were amplified by polymerase chain reaction and probed with a panel of sequence-specific oligonucleotide probes. HLA-DPB1 genotypes were deduced from the hybridization pattern of the probes. HLA-DPB1 allele frequencies and Hardy-Weinberg equilibrium were calculated. Linkage disequilibria between HLA-DPB1 and HLA-DQA1 alleles were determined. Four novel hybridization patterns indicating new alleles were found.

Alleles↗
PubMed1991

Ten HLA-DR4 alleles defined by sequence polymorphisms within the DRB1 first domain.

We have studied DRB1 sequence polymorphisms associated with DR4 subtypes using DR4-specific DNA amplification and sequence-specific oligonucleotide probe (SSOP) hybridization. The 5' amplification primer was designed to hybridize with a unique sequence in the first hypervariable region (HVR) of the DRB1 second exon of all known DR4 alleles; the 3' primer was designed to hybridize with an intron sequence common to all DRB1 The specificity of the amplification step was demonstrated by double-blind testing of 105 selected DNA samples. Prospective SSOP typing of DR4 alleles was performed in 104 unrelated individuals known to be DR4-positive, including 13 who were DR4-homozygous. A DRB1 subtype corresponding with the previously defined DR4-associated specificities Dw4, Dw10, Dw13.1, Dw13.2, Dw14.1, Dw14.2, Dw15, and DwKT2 could be assigned for each of the 117 DR4 haplotypes tested. In most cases, DR4-homozygous, DRB1-heterozygous individuals could be genotyped with the panel of probes. In the course of our analysis, we identified two new DR4-related alleles, DRB1*04.CB (DRB1*0410)1 and DRB1*04.EC (DRB1*, 0411)2 which were recognized by their novel hybridization patterns. The DRB1 second exon sequence of DRB1*04.CB is identical to DRB1*0405 except at codon 86 where GTG encodes valine instead of GGT encoding glycine. DRB1*04.EC is identical to DRB1*04.CB except at codon 74 where GAG encodes glutamic acid instead of GCG encoding alanine. Our results provide further evidence that SSOP hybridization is the most effective approach available for subtyping DR4 haplotypes and identifying unrecognized variants. A similar approach should be equally informative for subtyping other DR alleles.

Alleles↗
PubMed1992

A new approach to HLA-DPB1 typing combining DNA heteroduplex analysis with allele-specific amplification and enzyme restriction.

Allelic polymorphism of HLA-class II antigens plays a key role in the regulation of the immune response and in transplantation immunity. The allelic diversity of these antigens can now be analyzed at the DNA level after amplification by polymerase chain reaction. In this study we apply a simple technique based on the electrophoretic analysis of DNA heteroduplexes to the typing of HLA-DPB1 alleles. In order to increase its resolution, a group-specific amplification was used which subdivides the 19 HLA-DPB1 alleles in two non-overlapping families. A separate analysis was then performed within each group of alleles. This approach allowed an unequivocal one-step typing of the alleles belonging to group 1 which comprises few alleles of high frequency. Some group 2 alleles require, as a further step, the test with a restriction enzyme. The combination of more than one technique represents, in our opinion, the easiest way to solve the micropolymorphism of class II alleles. We conclude that this method, which is very simple, quick, and accurate and does not require probes, may become the method of choice for HLA-DPB1 typing.

Alleles↗
PubMed1991

HLA DQ alpha typing of forensic specimens by amplification restriction fragment polymorphism (ARFP) analysis.

The alleles present at the HLA DQ alpha locus may be typed by either allele specific oligonucleotide (ASO) probing or by restriction mapping, referred to here as amplification restriction fragment polymorphism (ARFP) analysis. ASO typing relies upon hybridization principles, whereas ARFP typing relies upon restriction site analysis. Dot-blot ASO typings which are of doubtful interpretation may be directly checked by ARFP analysis. Aliquots of the PCR products amplified using the commercial Amplitype HLA DQ alpha system are digested with suitable restriction endonucleases. Electrophoresis, blotting and detection of biotin-labelled restriction fragments provides a sensitive and robust typing method suited to forensic analysis.

Alleles↗
PubMed1999

Human leukocyte antigen polymorphisms in the Taiwanese population.

Polymorphisms of human leukocyte antigens (HLA) are important in transplantation medicine, anthropologic studies, and paternity testing. We investigated the polymorphisms of HLA classes I and II in the Taiwanese population by means of serologic typing and polymerase chain reaction (PCR) analysis with sequence-specific primers. We calculated the HLA-A, -B, and -C gene frequencies in 673 Taiwanese subjects and the HLA-DRB1, and HLA-DQB1 gene frequencies in 204 subjects with available DNA samples. Haplotype frequencies and linkage-disequilibrium were analyzed on the basis of these data. The common HLA class I antigens were A11 (gene frequency, 34.9%), A2 (29.3%), A24 (15.8%), and A33 (9.8%); B60 (21.9%), B46 (13.1%), B58 (9.7%), and B13 (8.5%); and Cw1 (18.8%), Cw7 (15.3%), and Cw10 (10.7%). The common HLA-DRB1 and HLA-DQB1 alleles were DRB1*12 (15.2%), DRB1*09 (15.2%), DRB1*08 (12.0%), and DRB1*04 (12.0%); and DQB1*0301 (23.5%), DQB1*0303 (15.2%), DQB1*0601 (14.5%), and DQB1*02 (10.8%). The common two-locus haplotypes were A2-B46 (frequency, 9. 7%), A11-B60 (9.6%), and A33-B58 (6.8%); DRB1*09-DQB1*0303 (14.9%), DRB1*12-DQB1*0301 (14.2%), and DRB1*08-DQB1*0601 (10.7%). This study is the first to report the gene frequencies of HLA-DQB1 alleles and the common HLA-DR-DQ haplotypes among Taiwanese. Comparison of our results with those from two other Chinese populations in mainland China reveals that Taiwanese are more closely related to southern Han than to northern Han Chinese.

China↗
PubMed2005

TAP1 and TAP2 polymorphisms and their linkage disequilibrium with HLA-DR, -DP, and -DQ in an eastern Andalusian population.

Transporter associated with antigen processing (TAP) molecules are involved in the processing of endogenous peptides that bind to major histocompatibility complex (MHC) class I molecules. The possible functional significance of TAP polymorphisms for antigenic peptide transport is an unresolved issue. Population genetics is a tool for investigating the evolutionary and functional significance of genetic polymorphisms. We studied 105 unrelated individuals from Eastern Andalusia in Southern Spain for TAP1 and TAP2 polymorphisms and to detect linkage disequilibrium between TAP1 and TAP2 and between TAP1/TAP2 and human lymphocyte antigen (HLA) DR, DP, and DQ genes. HLA-DR, -DQ, -DP, and TAP1 loci were genotyped with the polymerase chain reaction (PCR)-sequence-specific oligonucleotide method, and TAP2 genes were typed by using the amplification-refractory mutation system-PCR technique. The alleles TAP1*D (3.3%), TAP2*D (2.4%), and TAP2*E (2.9%) were present in the Eastern Andalusian population but not in the general Spanish population. No evidence of linkage disequilibrium was found between TAP1 and TAP2 or between the TAP genes and HLA-DR, -DP, and -DQ in the Eastern Andalusian population. These results are consistent with the absence of coevolution between TAP and MHC class II genes and the hypothesis of selective neutrality.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Complete characterization of the DQB1 first exon polymorphism.

Here we report an additional source of variation resulting from genetic polymorphism in HLA-DQbeta1 genes, namely, allelic diversity in the first exon of the HLA-DQB1 locus, which encodes the leader peptide sequence. Six different variants, including a novel polymorphic site, were detected among the DBQ1 haplotypes.

Exons↗
PubMedDate not supplied

HLA haplotypes and hormonal studies in 25 Italian families of patients with classical and non-classical 21-OH deficiency.

To investigate the genetic polymorphisms of the HLA region and the molecular defect of the P450c21B gene in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, we studied 89 individuals from 25 families of CAH patients (14 classical forms, 11 non-classical forms). The following immunogenetic and hormonal investigations were performed: HLA-A and B typing, restriction fragment length polymorphism (RFLP) analysis of 21-hydroxylase A and B genes, and serum 17-OH-progesterone values determined basally and 60 min after ACTH stimulation. In the patients affected by the classical form, RFLP analysis revealed 5 deletions and 1 gene conversion in 6 haplotypes and no molecular defect in the others, who probably carry point mutations. In the patients with non-classical form we found P450c21A duplication in 11/18 haplotypes; 9 of the 11 patients shared the HLA-B14 allele. Utilizing both hormonal and genetic data we identified two cryptic forms; hormonal data alone failed to differentiate heterozygous from normal individuals.

17-alpha-Hydroxyprogesterone↗