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PubMed2006

Sequencing-based analysis of the HLA-DPB1 polymorphism in Nu ethnic group of south-west China.

In the present study, DNA typing for HLA-DPB1 was performed using polymerase chain reaction-sequencing-based typing method in 72 randomly selected Nu ethnic individuals inhabiting the Yunnan province of south-west China. Among the 12 detected DPB1 alleles, the most frequent was DPB1*1301, with the percentage of 20.83%, followed by DPB1*0501 (19.44%), DPB1*040101 (16.67%) and DPB1*2801 (9.72%). The allele DPB1*1501 was found for the first time in the Chinese population. Neighbour-joining showed that the Nu ethnic minority belonged to East Asian cluster and was most closely related to Lisu, being consistent with the historical records. In addition, the results obtained in this study will also provide useful information on organ transplantation, forensic investigations and disease association studies.

China↗
PubMed1999

Alpha-2 domain polymorphism and HLA class I peptide loading.

Diversity within the class I HLA antigen binding groove is positioned to moderate the presentation of peptide ligands. Polymorphism is widely dispersed about the peptide binding groove, and unravelling the functional significance of a given polymorphism requires comparative analysis of peptides presented by class I subtypes differing at the position(s) in question. Previous studies have demonstrated that not all class I polymorphisms act equally, and to determine the impact of substitutions specifically located in the alpha2 domain, peptides purified from B*1501, B*1512, B*1510, and B*1518 were examined by pooled Edman sequencing and comparative mass spectrometric analysis. Molecule B*1512 differs from B*1501 at residues 166 (Glu to Asp) and 167 (Trp to Gly) of the alpha2 domain. The pooled motif and ion mass ligand maps for B*1512 tightly matched those of B*1501, demonstrating that the 166/167 polymorphism between B*1501 and B*1512 has little impact upon ligand presentation. Although the 166/167 polymorphism minimally affects peptide binding preferences, this polymorphism makes B*1512 and B*1501 quite distinct by serology. We then compared the B70 molecules B*1510 and B*1518. The two are almost indistinguishable by serology and differ only by an alpha2 polymorphism at 116. Comparative peptide mapping shows that a Tyr to Ser polymorphism at 116 drastically changes the ligands bound by B*1510 and B*1518; no overlaps could be found. Polymorphisms in alpha2 therefore vary from subtle to extreme in the manner by which they moderate ligand presentation, and serologic crossreactivity did not reflect the ligands presented by these B15 subtypes.

Amino Acid Sequence↗
PubMed2005

[Analysis of HLA alleles polymorphism in Chinese patients with primary biliary cirrhosis].

OBJECTIVE: To investigate the frequencies of human leuckocyte antigens (HLA) -A, B and DRB1 alleles in Chinese patients with primary biliary cirrhosis (PBC) using polymerase chain reaction-based techniques, and to assess the correlation of HLA molecules with other clinical and laboratory profiles. METHODS: Genotyping of HLA-A, B, and DRB1 were performed in 65 well-characterized patients with primary biliary cirrhosis and 431 healthy controls with PCR amplification with sequence-specific primers (PCR-SSP). RESULTS: The frequency of DRB1*0701 was increased to 29.2% compared with 13.9% in the controls (PC < 0.05, OR = 2.55, 95% CI: 1.4 approximately 4.6). No association was found with HLA-DRB1*08 which had been constantly reported. The A*2 allele (53.8%) was more frequent in the PBC patient group but without a significant statistical difference. The frequencies for the other A, B and DRB1 alleles were similar between patients and healthy controls. There was no difference between patients with or without DRB1*0701 in some clinical and laboratory profiles. CONCLUSION: Susceptibility to primary biliary cirrhosis in Chinese is associated with DRB1*0701 allele and differs from people in North America, South America, North Europe and even in Japan, but the association is not restricted to any particular subgroup of patients. Valine at position 78 of HLA DRbeta1 may play an important role in the pathogenesis of primary biliary cirrhosis.

Adult↗
PubMed2002

HLA-G polymorphisms in couples with recurrent spontaneous abortions.

The etiology of a fraction of recurrent spontaneous abortions (RSA) may involve immunological mechanisms. Aberrant profiles of Th1 and Th2 cytokines have been observed which are not present in uncomplicated pregnancies. Studies of classical HLA class I and II antigens in relation to RSA have not been conclusive. Furthermore, these antigens are not expressed in the placenta with the exception of HLA-C. However, HLA-G is expressed on especially invasive cytotrophoblasts and exists in both membrane and soluble forms. HLA-G may be involved in materno-fetal tolerance. Therefore, 61 RSA couples (with three or more spontaneous abortions) and 47 fertile control couples were HLA-G genotyped by direct DNA sequencing and analyzed for specific polymorphisms. No statistically significant differences were observed in the distribution of HLA-G alleles between controls and RSA couples, however, 15% of the RSA women carried the HLA-G*0106 allele compared to 2% of the control women. The 14 bp deletion polymorphism in exon 8 was investigated separately. There were a greater number of heterozygotes for the 14 bp polymorphism in the group of fertile control women than expected, according to Hardy-Weinberg equilibrium. Furthermore, the HLA-G alleles without the 14 bp sequence were prominent in the RSA males in contrast to the RSA women in whom alleles including the 14 bp sequence were frequently observed, especially as homozygotes. These results are discussed in relation to two hypotheses concerning HLA-G and RSA. A hypothesis of HLA-G histo-incompatibility between fetus/placenta and the mother was not supported by the data. Another hypothesis concerned certain HLA-G alleles associated with an altered expression profile of HLA-G isoforms or reduced expression of certain HLA-G isoforms.

Abortion, Habitual↗
PubMed2006

Polymorphism of HLA class II genes in Miao and Yao nationalities of Southwest China.

In the present study, the polymorphism of human leucocyte antigen class II genes was investigated by the sequence-based typing method in two Chinese populations: the Miaos (n = 85) from Guizhou province and the Yaos (n = 66) from Yunnan province. These two populations exhibited certain similarity in their allelic distributions. Among 24 DRB1 alleles detected, DRB1*150101, DRB1*140101, DRB1*160201 and DRB1*090102 in Miao and DRB1*120201, DRB1*140101, DRB1*150101 and DRB1*090102 in Yao were highly predominant. Sixteen DQB1 alleles in total were found in these two populations among which DQB1*050201, DQB1*060101/060103 and DQB1*030101/0309 in both Miao and Yao and DQB1*050301 in Yao were commonly observed. In the 13 DPB1 alleles detected, the most frequent allele was DPB1*0501 in Miao and Yao followed by DPB1*02 and DPB1*1301. Frequent comparisons with other Chinese populations suggested the southern Chinese feature for both the Miao and Yao nationalities.

Alleles↗
PubMed2004

[The study on HLA-Cw polymorphism from Xi'an Han population by PCR-sequence specific oligonucleotide probe].

OBJECTIVE: To determine the HLA-Cw allele and genotype frequencies from Xi'an Han population and obtain genetic data. METHODS: The results of HLA-Cw typing for 130 randomly selected from Xi'an Han population were obtained by using the PCR-Sequence Specific Oligonucleotide Probes (SSOP). RESULTS: In this investigation, 16 alleles were detected among 130 unrelated individuals with frequencies from 0.0077 to 0.1588 and HLA-Cw*01,03,07 were the most common HLA-Cw alleles. We have made a survey of HLA-Cw alleles frequencies in Xi'an Han Population, with blank frequency being lowered to 0.018 2. CONCLUSION: The distribution of genotype frequencies met the law of Hardy-Weinberg equilibrium by Hi-square test. The frequency data can be used in forensic and paternity tests, transplant matching and anthropology.

Alleles↗
PubMed1989

Biochemically detected HLA-DQ polymorphism in DR-matched donors and recipients of renal allografts.

We performed a retrospective biochemical analysis of HLA-D-region antigens of serologically DR-compatible donors and recipients of renal allografts. No incompatible D-region antigens were detected in grafts with a stable clinical course--i.e., there were no rejection episodes--whereas incompatibility for one or more D-region antigens was found in all 13 grafts with rejection. Thus, mismatched D-region antigens may provide a stimulus for early rejection in these grafts.

Cell Line↗
PubMed1998

Analysis of HLA-DPB1 polymorphisms in African-Americans with sarcoidosis.

Several studies have found weak associations between certain human leukocyte antigen (HLA) alleles and sarcoidosis, but none have been conclusive. Glutamic acid at position 69 in HLA-DPB1 has been reported to be strongly associated with chronic beryllium disease. The immunopathologic and clinical similarities between chronic beryllium disease (CBD) and sarcoidosis suggest that similar immune-response genes may be involved in susceptibility in both diseases. We analyzed the DNA sequence of HLA-DPB1 exon 2, which contains the hypervariable regions involved in binding antigens, in blood samples from African-American sarcoidosis patients and healthy controls. Results indicate that Val36 (odds ratio [OR] = 2.30) and Asp55 (OR = 2.03) are associated with increased risk for sarcoidosis, but no association with Glu69 was found. These results suggest that although HLA-DPB1 Glu69 is not associated with sarcoidosis, other alleles may make some contribution to susceptibility to sarcoidosis in African-Americans.

Adult↗
PubMed1995

Modulation of peptide binding by HLA-B27 polymorphism in pockets A and B, and peptide specificity of B*2703.

The results in this study address three aspects of peptide binding to the disease-associated antigen HLA-B27 and its modulation by polymorphism: the contribution of major anchor residues 2 and 9, the role of pocket B polymorphism in modulating peptide specificity, and the binding properties of B*2703, a subtype not found to be associated with spondyloarthropathy. Synthetic analogs of peptides naturally presented by B*2705 were used to demonstrate that residue 2 is essential, since Ala2 analogs bound marginally to B*2705, but the specificity of B*2705 for Arg2 is not absolute, and show that the contribution of basic residue 9 to binding was significant, but less than Arg2. The effect of single mutations in the B pocket was to decrease or--with the Glu > Met-45 mutation--totally shift pocket B specificity for Arg2 towards other residues at this position. This was shown by quantitating the relative binding of Gln2 and Ala2 analogs, and by pool-sequencing of the peptides bound in vivo to these mutants. Peptides naturally presented by B*2705 apparently bound with a lower affinity to pocket A variants with altered hydrogen bonding to the peptide N terminus, including B*2703. Binding of peptide analogs with changes at positions 2 or 9 suggested that in B*2703 pocket A, interactions are weaker and pocket B interactions are stronger than in B*2705. This can be explained by the effect of the unique His59 change in B*2703 in both pockets. Thus, B*2703 is probably the HLA-B27 sub-type with the most stringent specificity for the Arg2 peptide motif.

Amino Acid Sequence↗
PubMed2001

Stratification analysis of MICA triplet repeat polymorphisms and HLA antigens associated with ulcerative colitis in Japanese.

We previously reported a conserved haplotype of HLA B52-DR2 and a significantly high frequency of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) transmembrane-short tandem repeat (TM-STR) 6 allele in Japanese patients with ulcerative colitis (UC). To examine the predominance of the MICA TM-STR 6 allele as a marker of the susceptibility to UC within the susceptible haplotype, the association of each allele with UC was estimated following stratification of the patients to control for any possible confounding effects of other alleles positively associated with UC. Sixty-four patients with UC and 236 unrelated healthy controls were included in this study. All subjects were Japanese. HLA-A, -B, -C, and -DR antigens were determined serologically. A triplet repeat polymorphism of the MICA was determined by direct sequencing. To control for the effect of linkage disequilibrium, Mantel-Haenszel weighed odds ratios were calculated. Significantly higher phenotype frequencies of B52, MICA TM-STR 6, and DR2 were observed in patients with UC. Linkage disequilibria among alleles associated with UC revealed that a B52 - MICA TM-STR 6 - DR2 haplotype was conserved in patients with UC, as in controls. When the association of HLA-B52 was estimated after patient stratification for the possible confounding effect of MICA TM-STR 6 or DR2, a strong significant association of B52 with UC was still observed. In contrast, no association with UC was observed for MICA TM-STR 6 or DR2, after stratification of the possible confounding effect of HLA-B52. These results imply that the significant increase in MICA TM-STR 6 in Japanese patients with UC is attributable to linkage disequilibrium with HLA-B52.

Colitis, Ulcerative↗
PubMed2002

Association between two tumour necrosis factor intronic polymorphisms and HLA alleles.

The gene for tumour necrosis factor (TNF) lies at the telomeric end of the class III region of the major histocompatibility complex (MHC). Polymorphisms within this gene have been implicated in the genetic background of a large number of common human diseases. Recently two polymorphisms, TNF +489 and +691, have been described in the first intron of TNF (+489, G to A transition; +691, G deletion) and disease associations have been reported; however, the pattern of linkage disequilibrium with other MHC alleles has not been studied. We have therefore studied the association of TNF alleles with HLA-DR, -DQ and -B alleles in 216 healthy individuals from the north of England. The frequencies of the uncommon alleles were 0.08 (+489A) and 0.05 (+691Gdel). The +489A allele is associated with carriage of DRB1*1104, DQB1*0301, B18 and B35. The +691Gdel allele is associated with carriage of DRB1*13 *11, DQB1*0301 and B44. Knowledge of the pattern of association, indicating probable linkage disequilibrium, between these TNF alleles may be useful in studies aimed at determining the role of this locus in the genetic background of the large number of diseases which show genetic associations with MHC haplotypes.

England↗
PubMed1998

HLA-DR/DQ transgenic, class II deficient mice as a novel model to select for HSP T cell epitopes with immunotherapeutic or preventative vaccine potential.

Protective immunity against mycobacteria is dependent on antigen/MHC class II specific, CD4+ Th1 cells. HLA-DR3-restricted Th1 cells respond to a subset of mycobacterial antigens, including the immunodominant hsp65, and recognize a single epitope in hsp65, notably p1-20. Altered peptide ligands (APL) of p1-20 can inhibit p1-20/hsp65-induced proliferation of DR3-restricted T cells in an allele specific manner in vitro. In order to develop a preclinical model in which p1-20 APL can be tested in vivo in the context of HLA, we have used murine class II deficient, HLA transgenic (Ab0) mice, in which all CD4+ T cells are restricted by the tg HLA molecule. BCG-immunized DR3.Ab0 and DQ8.Ab0 mice both responded well to hsp65. Furthermore, DR3.Ab0 mice recognized precisely the same p1-20 epitope as DR3-restricted human T cells, whereas DQ8.Ab0 mice responded to a different set of hsp65 peptides. This shows that (i) the same immunodominant protein and peptide epitope are recognized by T cells from DR3.Ab0 mice and DR3+ humans and (ii) indicates the major role of HLA-polymorphism in controlling the human T cell response to mycobacterial antigens. Thus, HLA-transgenic, Ab0 mice provide a novel, preclinical model system to analyze APL and vaccines in the context of HLA polymorphism.

Animals↗
PubMedDate not supplied

Non-HLA gene polymorphisms in juvenile rheumatoid arthritis.

A substantial amount of work has gone into elucidating the non-HLA genetic associations in JRA. In this paper, we attempt to provide an overview of this body of knowledge. Direct comparison of the different studies is difficult. Different ethnic populations, different JRA/JIA subgroups, and different systems of nomenclature and classification all impose various limitations. Adding to the complexity is the polygenic nature of chronic childhood arthritis. Family based studies will be necessary to overcome ethnicity related issues. A candidate gene approach complemented by genome wide screen data will hopefully advance our knowledge of the genetics of JRA.

Arthritis, Juvenile↗
PubMed2006

Role of non-HLA genetic polymorphisms in graft-versus-host disease after haematopoietic stem cell transplantation.

Graft-versus-host disease (GvHD) is the main complication after haematopoietic stem cells transplantation (HSCT) and acute forms (aGvHD) occur in 20-40% of cases even after donor (D) and recipient (R) HLA matching, apparently because of D/R minor histocompatibility antigen (mHA) mismatches and cytokine polymorphisms. The genotype of cytokines and mHA of 77 haematological R following HSCT from HLA identical siblings were determined to detect genetic polymorphisms correlated with GvHD. We analysed TNFA (-863 C/A, -857 C/T and G/A at positions -574, -376, -308, -244, -238), IL-10 (-1082 G/A, -819 C/A, -592 C/T), IL-1B (T/C +3953), IL-1RA (VNTR), HA-1 (H/R allele) and CD-31 (C/G at codon 125, A/G at codon 563). Allele frequencies were in Hardy-Weinberg equilibrium and similar to those of 77 healthy controls. We observed positive correlations between a lower risk of clinically significant aGvHD and both the presence of -1082G -819C -592C IL-10 haplotype when both R and D are considered together and the absence of R IL-1RA allele 2. Furthermore, we observed an association between the absence of TNF-A -238 A allele and the risk of extensive chronic GvHD. mHA and cytokines genotyping would thus seem a valid source of information for the prior identification of recipients with a higher risk of aGvHD.

Adult↗
PubMed1995

Molecular analysis of HLA class II polymorphism in Croatians.

HLA-class II polymorphisms have been studied in a population of 141 unrelated healthy Croatians using PCR amplification, followed by non-radioactive oligonucleotide hybridization. Thirty one DRB1, 8 DQA1, 13 DQB1 and 16 DPB1 alleles were found in the tested population. DRB1*1601, 0701, 1501, 0101 and 1104 are the most frequent alleles at the DRB1 locus. At the DQA1 locus two alleles predominate: DQA1*0501 and 0102, while the most frequent DQB1 allele is *0301. Analysis of HLA-DPB1 polymorphism showed that, as in other Europeans, DPB1*0401 is the most frequent allele. Four different two locus haplotypic associations (DRB1-DRB3, DRB1-DRB5, DRB1-DQB1 and DQA1-DQB1) as well as three locus DRB1-DQA1-DQB1 haplotypic associations were assigned on the basis of known linkage disequilibria. Several unusual two-locus associations have been observed: DRB1*0301-DRB3*0202, DRB1*1501-DRB5*02, DRB1*1601-DRB5*0101, DRB1*1502-DRB5*0101, DQA1*0103-DQB1*0503 and DQA1*0501-DQB1*0302. Among 236 examined DRB1-DQA1-DQB1 haplotypic combinations, the most frequent was DRB1*1601-DQA1*0102-DQB1*0502 that was found with statistically significant higher frequency than in other Europeans. Twenty-eight distinct probable haplotypes were observed just once, suggesting that the main characteristic of Croatian population is great heterogeneity of haplotypes. This study will serve as a reference for further anthropology studies, HLA and disease associations studies and for donor/recipient matching in organ and bone marrow transplantation.

Alleles↗