DQB1 Genes Research Articles

Typing of a Polymorphic Human Gene Conferring Susceptibility to Insulin-Dependent Diabetes Mellitus by Picosecond-Resolved FRET on Non-Purified/Non-Amplified Genomic DNA

This work concerns the identification of the alleles of the polymorphic DQB1 gene of the human leukocyte antigen system, conferring susceptibility to the development of insulin-dependent diabetes mellitus (IDDM) in non-PCR amplified DNA samples and, more importantly, in crude cell extracts. Our method is based on the time-resolved analysis of a Förster energy-transfer mechanism that occurs in a dual-labelled fluorescent probe specific for the IDDM-associated DQB1-0201 allele. Such an oligonucleotide probe is labelled, at the two ends, by a pair of chromophores that operate as donor and acceptor in a Förster resonant energy transfer. The donor fluorescence is quenched with an efficiency that is strongly dependent on the donor-to-acceptor distance, hence on the configuration of the probe after hybridization with the various DQB1 alleles. By time-correlated single-photon counting, performed with an excitation/detection system endowed with 30-ps resolution, we measure the time-resolved fluorescence decay of the donor and discriminate, by means of the decay–time value, the DNA bearing the ‘susceptible’ allele from the DNAs bearing any other sequence in the same region of the DQB1 gene. We could also distinguish the presence of the DQB1-0201 allele in a homozygous versus a heterozygous condition.

Association Between HLA-DQ Genotypes and Haplotypes vs Helicobacter pylori Infection in an Indonesian Population

Helicobacter pylori is an important gastrointestinal pathogen related to the development of not only atrophic gastritis and peptic ulcer, but also gastric cancer. Human leukocyte antigens (HLA) may play particular roles in host immune responses to bacterial antigens. This study aimed to investigate the association between HLA-DQA1 and DQB1 genotypes and haplotypes vs H. pylori infection in an Indonesian population. We selected 294 healthy participants in Mataram, Lombok Island, Indonesia. H. pylori infection was determined by urea breath test (UBT). We analyzed HLA-DQA1 and DQB1 genotypes by PCR-RFLP and constructed haplotypes of HLA-DQA1 and DQB1 genes. Multiple comparisons were conducted according to the Bonferroni method. The H. pylori infection rate was 11.2% in this Indonesian population. The DQB1*0401 genotype was noted to be associated with a high risk of H. pylori infection, compared with the DQB1*0301 genotype. None of the HLA-DQA1 or DQB1 haplotypes were related to the risk of H. pylori infection. The study suggests that HLADQB1 genes play important roles in H. pylori infection, but there was no statistically significant association between HLA-DQA1 or DQB1 haplotypes and H.pylori infection in our Lombok Indonesian population.

Duodenal Bulb in Celiac Adults

Celiac disease (CD)-related lesions were described in duodenal bulb of celiac patients. Our aim was to evaluate the morphology of bulb mucosa in adult celiac patients and in controls to evaluate its usefulness for CD diagnosis. We studied 43 celiac patients (10 male, median age: 35.2 y) at diagnosis and 43 gastroenterological controls (10 male, median age: 37.8 y), submitted to upper endoscopy for gastroenterological complaints. Histologic lesions were assayed by an experienced pathologist according to the Marsh modified classification. Antiendomysium antibodies and antitransglutaminase antibodies-tTGAb (ELISA and/or RIA) have been tested. In selected patients, DNA was typed for DRB1, DQA1, and DQB1 genes by sequence-specific primer polymerase chain reaction. In all celiac patients lesions were present in the bulb mucosa. One female with thyroiditis, who had a CD daughter, showed lesions only in the duodenal bulb. Patchy villous atrophy was found in another patient. All celiacs were antiendomysium and/or tTGAb positive. DQ2 heterodimer was present in 5 CD patients. The gastroenterological controls showed normal mucosa in the duodenum. This study demonstrates that CD-related histologic lesions are present in duodenal bulb of adult patients. Moreover, the normal aspect of this mucosa in gastroenterological controls implies the high negative predictive value of this finding. Therefore, we suggest taking at least 1 biopsy on the bulb area and 1 from the distal duodenum for CD diagnosis, in all the patients submitted to upper endoscopy, to avoid missed or delayed diagnosis.

Structural and Functional Studies of trans-Encoded HLA-DQ2.3 (DQA1*03:01/DQB1*02:01) Protein Molecule

MHC class II molecules are composed of one α-chain and one β-chain whose membrane distal interface forms the peptide binding groove. Most of the existing knowledge on MHC class II molecules comes from the cis-encoded variants where the α- and β-chain are encoded on the same chromosome. However, trans-encoded class II MHC molecules, where the α- and β-chain are encoded on opposite chromosomes, can also be expressed. We have studied the trans-encoded class II HLA molecule DQ2.3 (DQA1*03:01/DQB1*02:01) that has received particular attention as it may explain the increased risk of certain individuals to type 1 diabetes. We report the x-ray crystal structure of this HLA molecule complexed with a gluten epitope at 3.05 Å resolution. The gluten epitope, which is the only known HLA-DQ2.3-restricted epitope, is preferentially recognized in the context of the DQ2.3 molecule by T-cell clones of a DQ8/DQ2.5 heterozygous celiac disease patient. This preferential recognition can be explained by improved HLA binding as the epitope combines the peptide-binding motif of DQ2.5 (negative charge at P4) and DQ8 (negative charge at P1). The analysis of the structure of DQ2.3 together with all other available DQ crystal structures and sequences led us to categorize DQA1 and DQB1 genes into two groups where any α-chain and β-chain belonging to the same group are expected to form a stable heterodimer.

What have genome-wide association studies contributed to the understanding of the pathogenesis and future management of Type 1 diabetes?

77 ISSN 1758-1907 10.2217/DMT.11.77 © 2012 Future Medicine Ltd Diabetes Manage. (2012) 2(2), 77–80 Diabetes is a major health problem and its prevalence is increasing worldwide. It is estimated that by 2030, there will be 439 million adults affected by diabetes [101]. Today diabetes impacts the lives of approximately 200 million people. Approximately 10% of all cases are Type 1 diabetes (T1D) with around a 3% increase in the incidence of T1D globally per year [1]. T1D is a complex trait that results from the interplay between environmental and genetic factors. Much evidence supports a strong genetic component associated to T1D. The epidemiological data for geographic prevalence differences is one clear indicator, with populations of European ancestry having the highest presentation rate. T1D runs strongly in families, with the sibling risk being approximately ten-times greater than in the general population [2]. It has been a challenge to isolate the susceptibility genes for diabetes. Historically, before the introduction of genome-wide association studies (GWAS), the genetic determinants of T1D consisted of five loci. The first GWAS locus was reported in 2006 [3] and the current tally of T1D GWAS loci stands at 53 [4], including rediscovery of the first five candidate gene loci. Approximately half of the genetic risk for T1D is conferred by the genomic region harboring the HLA class II genes (primarily HLA-DRB1, -DQA1 and -DQB1 genes), which encode the highly polymorphic antigen-presenting proteins. Recent fine mapping efforts of the MHC addressed why the class II genes HLA-DQB1 and HLA-DRB1 cannot completely explain the association between T1D and the MHC region [5]. It turned out that most of the remaining association that could be detected was due to signals in HLA-B and HLA-A, and that the existence of other major T1D genes in the extended MHC was unlikely. Other loci established prior to GWAS are the genes encoding insulin [6], cytotoxic T-lymphocyte-associated protein 4 [7], protein tyrosine phosphatase, nonreceptor type 22 gene [8] and IL-2 receptor a [9]. However, the majority of other reported associations in the pre-GWAS era

Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.

MHC class II DQB diversity in the Japanese black bear, Ursus thibetanus japonicus

BackgroundThe major histocompatibility complex (MHC) genes are one of the most important genetic systems in the vertebrate immune response. The diversity of MHC genes may directly influence the survival of individuals against infectious disease. However, there has been no investigation of MHC diversity in the Asiatic black bear (Ursus thibetanus). Here, we analyzed 270-bp nucleotide sequences of the entire exon 2 region of the MHC DQB gene by using 188 samples from the Japanese black bear (Ursus thibetanus japonicus) from 12 local populations.ResultsAmong 185 of 188 samples, we identified 44 MHC variants that encoded 31 different amino acid sequences (allotypes) and one putative pseudogene. The phylogenetic analysis suggests that MHC variants detected from the Japanese black bear are derived from the DQB locus. One of the 31 DQB allotypes, Urth-DQB*01, was found to be common to all local populations. Moreover, this allotype was shared between the black bear on the Asian continent and the Japanese black bear, suggesting that Urth-DQB*01 might have been maintained in the ancestral black bear population for at least 300,000 years. Our findings, from calculating the ratio of non-synonymous to synonymous substitutions, indicate that balancing selection has maintained genetic variation of peptide-binding residues at the DQB locus of the Japanese black bear. From examination of genotype frequencies among local populations, we observed a considerably lower level of observed heterozygosity than expected.ConclusionsThe low level of observed heterozygosity suggests that genetic drift reduced DQB diversity in the Japanese black bear due to a bottleneck event at the population or species level. The decline of DQB diversity might have been accelerated by the loss of rare variants that have been maintained by negative frequency-dependent selection. Nevertheless, DQB diversity of the black bear appears to be relatively high compared with some other endangered mammalian species. This result suggests that the Japanese black bears may also retain more potential resistance against pathogens than other endangered mammalian species. To prevent further decline of potential resistance against pathogens, a conservation policy for the Japanese black bear should be designed to maintain MHC rare variants in each local population.

Influence of HLA-DQ2 and DQ8 on Severity in Celiac Disease

HLA-DQB1*02 homozygosity was shown to be more common in patients with complicated rather than uncomplicated celiac disease (CD). To study HLA-DQA1 and DQB1 profile in adult patients with different forms of CD, including patients with complicated and potential CD, the most affected and the most preserved histologic end of the pathologic celiac spectrum. HLA-DQA1 and DQB1 molecular typing was performed in 218 adult CD patients (169 with uncomplicated CD, 27 with complicated CD, and 22 with potential CD) and 224 healthy stem cell donors. HLA-DQA1 and DQB1 gene polymorphism was analyzed using polymerase chain reaction sequence-specific primers and/or reverse polymerase chain reaction sequence-specific oligonucleotides techniques. As expected, the frequency of HLA-DQB1*02 allele, DQB1*02 homozygosity, and DQB1*0302 gene were statistically different in the 4 groups. However, multivariate analysis demonstrated that patients with potential CD have a higher frequency of both HLA-DQB1*0302 and HLA-DQB1*0603 alleles and a reduced frequency of DQB1*02 homozygosity compared with patients with uncomplicated and complicated CD. The increased frequency of DQB1*0302 and the reduced frequency of DQB1*02 homozygosity in potential CD is consistent with the idea that different clinical/pathologic evolutions might be related to different immunogeneses. This could be clinically relevant in the future.

Human neutrophil antigen and antibody studies: a Taiwanese experience

Neutrophil alloantibodies are clinically known to cause neonatal neutropenia and transfusion‐related lung injuries. Furthermore, neutrophil autoantibodies are associated with autoimmune neutropenia. This article is a review on neutrophil alloantigen in the Taiwanese population, and case investigations related to allo/auto neutrophil antibodies over a period of 20 years in the immunohaematology reference laboratory of Mackay Memorial Hospital, Taiwan.In Taiwanese populations, HNA‐1a is more frequent than HNA‐1b (90% and 50% respectively) and HNA‐1c is not seen. Furthermore, the FcgRIIIb‐deficient individual homozygous for FCGR3B gene deletion is estimated to be approximately 1 in 180 and is not as rare as previously thought.Although mothers homozygous for either HNA‐1a or HNA‐1b are commonly found in Taiwan, the number of patients with neonatal neutropenia caused by HNA‐1 alloantibodies is seldom seen. In a search among our previous laboratory requests of neonatal cases for granulocyte antibodies testing over a 10‐year period, only four cases showed neutrophil alloantibodies in the mother and baby’s sera.Lastly, primary autoimmune neutropenia among 51 children was retrospectively investigated. The study revealed that the specificity of the autoantibody was most commonly directed against HNA‐1a. In addition, 31 cases were genotyped for HLA‐DRB1 and ‐DQB1 genes. The HLA allele HLA‐DQB1*05:03 was found to be associated with primary autoimmune neutropenia in Taiwan.

Evolutionary genetics of MHC class II beta genes in the brown hare, Lepus europaeus

The genes of the major histocompatibility complex (MHC) are attractive candidates for investigating the link between adaptive variation and individual fitness. High levels of diversity at the MHC are thought to be the result of parasite-mediated selection and there is growing evidence to support this theory. Most studies, however, target just a single gene within the MHC and infer any evidence of selection to be representative of the entire gene region. Here we present data from three MHC class II beta genes (DPB, DQB, and DRB) for brown hares in two geographic regions and compare them against previous results from a class II alpha-chain gene (DQA). We report moderate levels of diversity and high levels of population differentiation in the DQB and DRB genes (Na = 11, D est = 0.071 and Na = 15, D est = 0.409, respectively), but not for the DPB gene (Na = 4, D est = 0.00). We also detected evidence of positive selection within the peptide binding region of the DQB and DRB genes (95% CI, ω > 1.0) but found no signature of selection for DPB. Mutation and recombination were both found to be important processes shaping the evolution of the class II genes. Our findings suggest that while diversifying selection is a significant contributor to the generally high levels of MHC diversity, it does not act in a uniform manner across the entire MHC class II region. The beta-chain genes that we have characterized provide a valuable set of MHC class II markers for future studies of the evolution of adaptive variation in Leporids.

Genetic characterisation of buffalo MHC (Bubu)-DQB cDNA molecule

A 771 nucleotide long cDNA molecule corresponding to major histocompatibility complex (MHC)-DQB gene was amplified, cloned and sequenced from water buffalo (Bubalus bubalis). Open reading frame of the Bubu-DQB sequence was short by three nucleotides from the DQB genes of the other ruminants. Nucleotide similarity of Bubu-DQB was highest with cattle DQB alleles (84–97%), followed by goat (88.8%) and sheep (87.5%). The sequence comparison revealed that the DQB gene was highly variable in buffalo particularly, in exon 2 (β1 domain). A total of 45 amino acid substitutions were identified in Bubu-DQB compared to cattle DQB*0101 sequence, with a maximum (27) in β1 domain. The residues involved in antigen binding and heterodimer formation were found to be different in buffalo DQB sequence compared to other species. Phylogenetic study showed that the Bubu-DQB has evolved prior to the diversification of common DQB alleles in ruminants. Our study revealed the high genetic variation in the DQB gene in buffalo, which might have generated to recognise species specific antigens.

Trans heterodimer between two non-arthritis-associated HLA alleles can predispose to arthritis in humanized mice

Certain HLA class II alleles are associated with susceptibility to the development of arthritis. However, the development of arthritis in some persons carrying non-rheumatoid arthritis (RA)-associated alleles remains unexplained. An individual who is heterozygous for the DQA1 and DQB1 genes can express the DQ molecule in cis or trans heterodimers. In a cis heterodimer, the α-chain interacts with the β-chain coded by the same chromosome, while in a trans heterodimer it interacts with the β-chain on the other chromosome. In this study, we used a humanized mouse model of arthritis in an attempt to determine whether a trans heterodimer of 2 nonassociated alleles, DQB1*0601 and DQB1*0604, can predispose to arthritis. DQB1*0601 and *0604 occur in linkage with DQA1*0103 and *0102, respectively. To understand the role of trans heterodimers, we generated DQB1*0604/DQA1*0103-transgenic mice lacking endogenous HLA class II molecules. Severe arthritis developed in the DQB1*0604/A1*0103-trangenic mice, and an antigen-specific response was generated in vitro. DQB1*0604/DQA1*0103 presented type II collagen-derived peptides that were not presented by the arthritis-resistant DQB1*0601 allele, suggesting that trans heterodimer molecules between 2 DQB1 and DQA1 molecules may result in the presentation of unique antigens and susceptibility to the development of arthritis. Molecular modeling of type II collagen peptides showed that DQB1*0604/DQA1*0103 shares a p4 pocket with the arthritis-susceptible DQB1*0302 allele, suggesting a critical role of the p4 and p9 pockets in susceptibility to arthritis. These results provide a possible explanation for the parental inheritance of nonsusceptibility alleles in some patients with RA and a mechanism by which they can predispose to the development of arthritis.

Dog Leukocyte Antigen Class II–Associated Genetic Risk Testing for Immune Disorders of Dogs: Simplified Approaches Using Pug Dog Necrotizing Meningoencephalitis as a Model

A significantly increased risk for a number of autoimmune and infectious diseases in purebred and mixed-breed dogs has been associated with certain alleles or allele combinations of the dog leukocyte antigen (DLA) class II complex containing the DRB1, DQA1, and DQB1 genes. The exact level of risk depends on the specific disease, the alleles in question, and whether alleles exist in a homozygous or heterozygous state. The gold standard for identifying high-risk alleles and their zygosity has involved direct sequencing of the exon 2 regions of each of the 3 genes. However, sequencing and identification of specific alleles at each of the 3 loci are relatively expensive and sequencing techniques are not ideal for additional parentage or identity determination. However, it is often possible to get the same information from sequencing only 1 gene given the small number of possible alleles at each locus in purebred dogs, extensive homozygosity, and tendency for disease-causing alleles at each of the 3 loci to be strongly linked to each other into haplotypes. Therefore, genetic testing in purebred dogs with immune diseases can be often simplified by sequencing alleles at 1 rather than 3 loci. Further simplification of genetic tests for canine immune diseases can be achieved by the use of alternative genetic markers in the DLA class II region that are also strongly linked with the disease genotype. These markers consist of either simple tandem repeats or single nucleotide polymorphisms that are also in strong linkage with specific DLA class II genotypes and/or haplotypes. The current study uses necrotizing meningoencephalitis of Pug dogs as a paradigm to assess simple alternative genetic tests for disease risk. It was possible to attain identical necrotizing meningoencephalitis risk assessments to 3-locus DLA class II sequencing by sequencing only the DQB1 gene, using 3 DLA class II-linked simple tandem repeat markers, or with a small single nucleotide polymorphism array designed to identify breed-specific DQB1 alleles.

Geographic variation of the major histocompatibility complex in Eastern Atlantic grey seals (Halichoerus grypus)

Pathogen-driven balancing selection maintains high genetic diversity in many vertebrates, particularly in the major histocompatibility complex (MHC) immune system gene family, which is often associated with disease susceptibility. In large natural populations where subpopulations face different pathogen pressures, the MHC should show greater genetic differentiation within a species than neutral markers. We examined genetic diversity at the MHC-DQB locus and nine putatively neutral microsatellite markers in grey seals (Halichoerus grypus) from eight United Kingdom (UK) colonies, the Faeroe Islands and Sable Island, Canada. Five DQB alleles were identified in grey seals, which varied in prevalence across the grey seal range. Among the seal colonies, significant differences in DQB allele and haplotype frequencies and in average DQB heterozygosity were observed. Additionally, the DQB gene exhibited greater differentiation among colonies compared with neutral markers, yet a weaker pattern of isolation by distance (IBD). After correcting for the underlying IBD pattern, subpopulations breeding in similar habitats were more similar to one another in DQB allele frequencies than populations breeding in different habitats, but the same did not hold true for microsatellites, suggesting that habitat-specific pathogen pressure influences MHC evolution. Overall, the data are consistent with selection at MHC-DQB loci in grey seals with both varying selective pressures and geographic population structure appearing to influence the DQB genetic composition of breeding colonies.

Characterization of the major histocompatibility complex class II DOB, DPB1, and DQB1 alleles in cynomolgus macaques of Vietnamese origin

Major histocompatibility complex (MHC) molecules play an important role in the susceptibility and/or resistance to many diseases. To gain an insight into the MHC background and to facilitate the experimental use of cynomolgus macaques, the second exon of the MhcMafa-DOB, -DPB1, and -DQB1 genes from 143 cynomolgus macaques were characterized by cloning to sequencing. A total of 16 Mafa-DOB, 16 Mafa-DPB1, and 34 Mafa-DQB1 alleles were identified, which revealed limited, moderate, and marked allelic polymorphism at DOB, DPB1, and DQB1, respectively, in a cohort of cynomolgus macaques of Vietnamese origin. In addition, 16 Mafa-DOB, 5 Mafa-DPB1, and 8 Mafa-DQB1 alleles represented novel sequences that had not been reported in earlier studies. Almost of the sequences detected at the DOB and DQB1 locus in the present study belonged to DOB*01 (100%) and DQB1*06 (62%) lineages, respectively. Interestingly, four, three, and one high-frequency alleles were detected at Mafa-DOB, -DPB1, and -DQB1, respectively, in this monkeys. The alleles with the highest frequency among these monkeys were Mafa-DOB*010102, Mafa-DPB1*13, and Mafa-DQB1*0616, and these were found in 33 (25.6%) of 129 monkeys, 32 (31.37%) of 102 monkeys, and 30 (31%) of 143 monkeys, respectively. The high-frequency alleles may represent high priority targets for additional characterization of immune function. We also carried out evolutionary and population analyses using these sequences to reveal population-specific alleles. This information will not only promote the understanding of MHC diversity and polymorphism in the cynomolgus macaque but will also increase the value of this species as a model for biomedical research.

Genetic variation in the odorant receptors family 13 and the mhc loci influence mate selection in a multiple sclerosis dataset

BackgroundWhen selecting mates, many vertebrate species seek partners with major histocompatibility complex (MHC) genes different from their own, presumably in response to selective pressure against inbreeding and towards MHC diversity. Attempts at replication of these genetic results in human studies, however, have reached conflicting conclusions.ResultsUsing a multi-analytical strategy, we report validated genome-wide relationships between genetic identity and human mate choice in 930 couples of European ancestry. We found significant similarity between spouses in the MHC at class I region in chromosome 6p21, and at the odorant receptor family 13 locus in chromosome 9. Conversely, there was significant dissimilarity in the MHC class II region, near the HLA-DQA1 and -DQB1 genes. We also found that genomic regions with significant similarity between spouses show excessive homozygosity in the general population (assessed in the HapMap CEU dataset). Conversely, loci that were significantly dissimilar among spouses were more likely to show excessive heterozygosity in the general population.ConclusionsThis study highlights complex patterns of genomic identity among partners in unrelated couples, consistent with a multi-faceted role for genetic factors in mate choice behavior in human populations.

Sequence analysis of the grey mouse lemur (Microcebus murinus) MHC class II DQ and DR region

We here report the genomic organisation of the grey mouse lemur (Microcebus murinus) MHC class II DQ and DR region based on BAC clone analysis. The sequenced Mimu-MHC haplotype spans 343kb and encompasses the genes TAP2, DOB, DQB, DQA, DRB, DRA, BTNL2 and a further BTNL gene. The DQ and DR genes of this haplotype are not duplicated. Mimu-DOB is not transcribed and represents a pseudogene due to deletions and premature stop codons. Analysis of BAC clone DNA, a cDNA sample and eight genomic DNA samples suggests that Mimu-DRB, Mimu-DQA and Mimu-DQB are highly polymorphic with the majority of peptide-binding residues being affected by polymorphisms. In contrast, Mimu-DRA is moderately polymorphic, and the variable amino acid positions are not part of the peptide-binding region. Phylogenetic analysis of Mimu-DQA and Mimu-DQB and other primate DQA and DQB genes indicates that duplication of DQA and DQB loci occurred in Anthropoidea after the split from Strepsirrhini.

HLA-C Antigen Mismatch Is Associated with Worse Outcome in Unrelated Donor Peripheral Blood Stem Cell Transplantation

The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated donor-recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA-matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk [RR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA-matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen-mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA-matched donors. The study's limited power due to small sample size precludesconclusions about other mismatches.

Association between human leukocyte antigen DQB1 gene polymorphisms and bronchial asthma among Mongolia and Han nationalities

Objective To investigate association between human leukocyte antigen DQB1 (HLADQB1 ) gene polymorphisms and bronchial asthma among Mongolian and Han nationalities. Methods Sequence-specific primer polymerase chain reaction (PCR-SSP) was used to detect frequencies of HLA DQB1 genotypes and alleles in 50 cases of Han and 68 Mongolian asthmatic patients, and 50 Han and 54 Mongolian healthy controls, respectively. Difference in gene frequencies between the two nationalities was estimated by odds ratio (OR) and chi-square test. Results Frequency of the HLA-DQB1 0602 allele was significantly higher in Han patients with bronchial asthma than that in healthy Han nationality (OR = 6.163,P ＜0.01 ). Frequency of the HLA-DQB1 0603/0608 allele decreased in Mongolian asthmatic patients, as compared to that in healthy Mongolians ( OR = 0.199, P ＜ 0.05 ). Frequency of the HLA-DQB1 0301/4 allele was significantly higher in Mongolian asthmatic patients as compared to that in healthy Mongolians ( OR =2.074,P ＜0.05). Frequency of the HLA-DQB1 0301/4 allele was significantly higher in Mongolian than that in Han asthmatic patients ( OR = 2.482 ,P =0.05). Frequency of the HLA- DQB1 0602 allele was significantly higher in healthy Mongolians than that in healthy Han nationality ( OR = 3.341, P ＜ 0.05 ), in contrast, frequency of the HLA-DQB1 0402 allele was significantly lower in healthy Mongolians than that in healthy Han nationality ( OR = 0.209, P ＜ 0.05 ). Conclusions The HLA-DQB1 0603/0608 allele is possibly a protective gene and the HLA-DQB1 0301/4 allele a susceptible gene for bronchial asthma in Mongolians, and the HLA-DQB1 0602 allele is possibly a susceptible gene for bronchial asthma in Han nationlity. Key words: Asthma; HLA antigens; Mongolian nationality; Han nationality

Necrotizing meningoencephalitis of Pug Dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis

Necrotizing meningoencephalitis (NME) is a disorder of Pug Dogs that appears to have an immune etiology and high heritability based on population studies. The present study was undertaken to identify a genetic basis for the disease. A genome-wide association scan with single tandem repeat (STR) markers showed a single strong association near the dog leukocyte antigen (DLA) complex on CFA12. Fine resolution mapping with 27 STR markers on CFA12 further narrowed association to the region containing DLA-DRB1, -DQA1 and, -DQB1 genes. Sequencing confirmed that affected dogs were more likely to be homozygous for specific alleles at each locus and that these alleles were linked, forming a single high risk haplotype. The strong DLA class II association of NME in Pug Dogs resembles that of human multiple sclerosis (MS). Like MS, NME appears to have an autoimmune basis, involves genetic and nongenetic factors, has a relatively low incidence, is more frequent in females than males, and is associated with a vascularly orientated nonsuppurative inflammation. However, NME of Pug Dogs is more aggressive in disease course than classical human MS, appears to be relatively earlier in onset, and involves necrosis rather than demyelination as the central pathobiologic feature. Thus, Pug Dog encephalitis (PDE) shares clinical features with the less common acute variant forms of MS. Accordingly, NME of Pug Dogs may represent a naturally occurring canine model of certain idiopathic inflammatory disorders of the human central nervous system.