DR3 Haplotype Research Articles

Effect of human leukocyte antigen class II genes on acute-onset and slow-onset type 1 diabetes in the Japanese population

The contribution of the human leukocyte antigen (HLA) subtype to slow-onset type 1 diabetes (T1D), which includes latent autoimmune diabetes in adults (LADA), remains unclear in the Japanese population. We compared the frequencies of HLA DR-DQ haplotypes and genotypes of 72 acute-onset T1D patients, 100 slow-onset T1D patients, and 292 control subjects. The frequencies of DRB1*0405-DQB1*0401 (DR4) and DRB1*1302-DQB1*0604 (DR13) haplotypes were significantly higher in acute-onset patients, whereas that of the DRB1*1502-DQB1*0601 haplotype was significantly lower than those in slow-onset diabetes patients and controls. In contrast, DRB1*0802-DQB1*0302 (DR8) and DRB1*0901-DQB1*0303 (DR9) haplotypes were significantly more frequent, and the DRB1*1501-DQB1*0602 haplotype was extremely rare, in acute-onset patients and slow-onset diabetes patients. Genotype analysis revealed that DR4/9, DR4/13, and DR9/13 in acute-onset patients indicated high odds ratios (6.81, 12.0, and 15.6, respectively), whereas DR4/8 was significantly more frequent in slow-onset diabetes patients, but not in acute-onset patients. Our study demonstrated for the first time that the DR8 haplotype confers susceptibility to slow-onset T1D in the Japanese population. Moreover, there potentially are hierarchies for predisposing haplotypes, namely, DR13 > DR4 > DR9 > DR8 and for protective haplotypes, namely, DRB1*1501-DQB1*0602 > DRB1*1502-DQB1*0601.

CORRELATION OF DRβ1*1501, DQβ1*0602 DONOR ALLELIC HAPLOTYPE WITH HUMORAL ANTIBODY EPISODES OF ACUTE RENAL ALLOGRAFT REJECTION

The present investigation was designed to show the effect of molecular HLA class II DR and DQ allelic differences between donor and recipient on humoral antibody rejection identified by C4d peritubular capillary staining. The hypothesis is that expression of the DRβ1*1501, DQβ1*0602 allele in the donor kidney increases the likelihood of humoral antibody rejection. We found that 67 %(n=18) of DR15 and/or DQ6 haplotype donor kidneys induce humoral antibody renal allograft rejection; 35% (n=40) of DR15 and/orDQ6 haplotype donor kidneys failed to induce humoral antibody renal allograft rejection. 41% of C4d+ recipients had donors with DR15; 15% of C4d− recipients had donors with HLA‐DR15. We compared donor haplotype alleles of 4 C4d+ with 6 C4d− recipients by high resolution molecular typing; 3 of 4 C4d+ recipients had a donor with the DRβ1*1501/DQβ1*0602 allele. This allele was absent in all C4d− donors. 35% of C4d+ recipients had 2 DR mismatches when compared to 33% of C4d− recipients. Our results, suggest that the DRβ1*1501, DQβ1*0602 allele in the donor kidney increases the risk of humoral antibody episodes of acute rejection, and signals the need for C4d staining. Future analysis of additional donor and recipient haplotypes will establish whether or not this is a useful predictor of humoral rejection episodes.

HLA-A, -B, -DR haplotype frequencies in the Thai Stem Cell Donor Registry

This study aimed to report antigen and haplotype frequencies (HFs) in the Thai Stem Cell Donor Registry (TSCDR). From 16,807 human leukocyte antigen (HLA)-A, -B, and -DR typed donors, 19 HLA-A, 41 HLA-B, and 13 HLA-DR antigens were found. HLA-A43, A80, B78, B82, B83, and DR18 were not observed. A total of 1921 haplotypes were estimated and 245 haplotypes were reliable and their cumulative HF was 75.74%. Similar to previous Thai subpopulation studies, the most common haplotypes were HLA-A33-B58-DR17 (4.54%), A2-B46-DR9 (4.11%), A33-B44-DR7 (2.85%), and A11-B75-DR12 (2.00%). To evaluate the probability in finding matched donors, from April 2002 to August 2008, 793 Thai patients were requested for unrelated stem cell donor searching. The number of patients with HLA-A, -B, -DR split matched donor found were 49%. Only 8% of the patients found matched donor within 1 month. However, high-resolution HLA-A, -B, -DR typing in TSCDR is suggested to accurately estimate HFs and evaluate the probability in finding a matched donor for patients in the future.

CD4+ T Cells Specific for a Single Alder (Aln g 1) Epitope Exhibit Different Effector Functions Dependent on their HLA-DR Restrictions

RATIONALE: The HLA-DR15 haplotype expresses similar levels of DRB1 and DRB5 gene products. We tested the hypothesis that allergen-specific T cells responding to the same epitope restricted by the two different DR molecules on the DR15 haplotype can have different effector functions.

Genetic variation within the HLA class III influences T1D susceptibility conferred by high-risk HLA haplotypes

HLA class II DRB1 and DQB1 represent the major type 1 diabetes (T1D) genetic susceptibility loci; however, other genes in the HLA region are also involved in T1D risk. We analyzed 1411 pedigrees (2865 affected individuals) from the type 1 diabetes genetics consortium (T1DGC) genotyped for HLA classical loci and for 12 SNPs in the class III region previously shown to be associated with T1D in a subset of 886 pedigrees. Using the transmission disequilibrium test, we compared the proportion of SNP alleles transmitted from within the high risk DR3 and DR4 haplotypes to affected offspring. Markers rs4151659 (mapping to CFB) and rs7762619 (mapping 5′ of LTA) were the most strongly associated with T1D on DR3 (p=1.2 × 10−9 and p=2 × 10−12 respectively) and DR4 (p=4 × 10−15 and p= 8 × 10−8 respectively) haplotypes. They remained significantly associated after stratifying individuals in analyses for B*1801, A*0101-B*0801, DPB1*0301, DPB1*0202, DPB1*0401 or DPB1*0402. Rs7762619 and rs4151659 are in strong linkage disequilibrium (LD) (r2=0.82) with each other, but a joint analysis showed that the association for each SNP was not solely due to LD. Our data support a role for more than one locus in the class III region contributing to risk of T1D.

IgA deficiency and the MHC: assessment of relative risk and microheterogeneity within the HLA A1 B8, DR3 (8.1) haplotype.

Selective IgA deficiency (IgAD; serum IgA concentration of <0.07 g/l) is the most common primary immunodeficiency in Caucasians with an estimated prevalence of 1/600. The frequency of the extended major histocompatibility complex haplotype HLA A1, B8, DR3, DQ2 (the "8.1" haplotype) is increased among patients with IgAD. We carried out a direct measurement of the relative risk of homozygosity of the 8.1 haplotype for IgA deficiency in a population-based sample of 117 B8, DR3 homozygous individuals. IgA deficiency was found to be present in 2 of 117 (1.7%) of these subjects, a figure that is concordant with estimates of relative risk from large case-control studies in the Swedish population. These data are consistent with a multiplicative model for the 8.1 haplotype contribution to IgA deficiency and contrasts with prior studies, suggesting a much higher risk for 8.1 homozygosity. Using a dense single nucleotide polymorphism marker analysis of the MHC region in HLA B8, DR3, DQ2 homozygous individuals, we did not observe consistent differences between cases (n = 26) and controls (n = 24). Overall, our results do not support the hypothesis that IgA deficiency is associated with a distinct subgroup of 8.1 related haplotypes, but rather indicate that risk is conferred by the common 8.1 haplotype acting in multiplicative manner.

HLA‐B8, DR3: a new risk factor for graft failure after renal transplantation in patients with underlying immunoglobulin A nephropathy

The HLA-B8, DR3 haplotype has been associated with high immune reactivity. In this study, we have tested whether this haplotype has differential effect on graft survival in patients with IgAN compared with control patients. From the Eurotransplant Registry we analyzed graft survival of 1207 recipients with IgAN and 7935 control patients with non-glomerular diseases. Death-censored graft loss according to the HLA-B8, DR3 haplotype was calculated with Kaplan-Meier analysis and Cox-regression model was used to correct for various risk factors. The frequency of the HLA-B8, DR3 haplotype was significantly lower in IgAN patients compared with controls (10.3% vs. 15.4%, p < 0.001). Ten-year graft survival was identical in the control group with and without the HLA-B8, DR3 haplotype (71.1% and 70.2%, respectively), but significantly worse in IgAN patients carrying the HLA-B8, DR3 haplotype compared with patients without it (52.5% vs. 69.1%, respectively, p = 0.009). The risk of graft loss was increased by 66% (HR 1.6, 95% CI 1.14, 2.29) in IgAN with the HLA-B8, DR3 haplotype and independent of well-known risk factors. We have identified a new risk factor for graft loss unique to patients with IgAN. This finding emphasizes the exclusive immune characteristics of IgAN patients after transplantation.

HLA-DR Alleles in Amyloid β-Peptide Autoimmunity: A Highly Immunogenic Role for the DRB1*1501 Allele

Active amyloid beta-peptide (Abeta) immunization of patients with Alzheimer's disease (AD) caused meningoencephalitis in approximately 6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of Abeta Ab responses, which correlate with the extent of Abeta clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing Abeta T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with Abeta-specific T cell responses elicited via distinct T cell epitopes within residues 15-42 of Abeta. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of Abeta challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-gamma and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. Furthermore, following long-term therapeutic immunization of an AD mouse model bearing the DRB1*1501 allele, Abeta was effectively cleared from the brain parenchyma and brain microglial activation was reduced. The present study thus characterizes HLA-DR alleles directly associated with specific Abeta T cell epitopes and demonstrates the highly immunogenic properties of the abundant allele DRB1*1501 in a mouse model of AD. This new knowledge enables us to explore the basis for understanding the variations in naturally occurring Abeta-reactive T cells and Abeta immunogenicity among humans.

Does the DRB1⁎1501 allele confer more severe and faster progression in primary progressive multiple sclerosis patients?: HLA in primary progressive multiple sclerosis

The effect of HLA alleles on the outcome of multiple sclerosis (MS) has been widely investigated; however, results are conflicting and no consistent correlation has been established. This study evaluated the association between the HLA DR2 haplotype in patients with primary progressive MS (PPMS) and the effect of alleles on progression. An association was found between PPMS and the DR2 and DRB1⁎1501 and DQB1⁎0602 alleles. Severe morbidity was found in DRB1⁎1501-positive PPMS patients. This exploratory study raises new hypotheses for future research and emphasizes the need to investigate possible candidate genes other than HLA that may contribute towards heterogeneity in the course of the disease.

Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a german population.

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered by variations within MHC class II region on chromosome 6p as well as the CTLA4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR3) in 130 families with a type 1 diabetic offspring in order to evaluate their role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. The presence or absence of DQLTR3 was defined by a nested PCR approach and CTLA4 microsatellite polymorphisms were detected with fluorescence-labeled primer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Whereas the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not modulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmission of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibility to type 1 diabetes mellitus.

Localization of Type 1 Diabetes susceptibility in the ancestral haplotype 18.2 by high density SNP mapping

Previous studies have suggested that the ancestral haplotype 18.2 (AH18.2) carries additional susceptibility gene to Type 1 Diabetes (T1D) on the Major Histocompatibility Complex (MHC). We analyzed 10 DR3/TNFa1b5 homozygous subjects in order to establish the conservation of the AH18.2 and then compared this conserved region with other DR3 haplotype, the AH8.1. The Illumina's HumanHap550 Bead chip was used to perform an extensive genotyping of the MHC region. The AH18.2 was highly conserved between DDR1 and HLA-DQA1 genes; therefore most probably the second susceptibility gene is located within this region. We can exclude the region centromeric to HLA-DRA gene and telomeric to DDR1 gene. A comparison between the AH18.2 and AH8.1 haplotypes showed that 233 SNPs were different in the aforementioned conserved region. These data suggest that the 1.65 Mb MHC region between DDR1 and HLA-DRA genes is likely to carry additional susceptibility alleles for T1D on the AH18.2 haplotype.

Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility.

Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

Long-range linkage on chromosome 6p of VEGF, FKBP5, HLA and TNF alleles associated with transplant rejection

Polymorphisms in several genes on the short arm of chromosome 6 (6p), among them, VEGF, FKBP5, HLA-DR and TNF-α, have been associated with inflammation and transplant outcome, such as acute rejection. Independent segregation of these genes is unproven, so we investigated linkage between distant genes on 6p and the putative existence of evolutionarily conserved long-range 6p haplotypes. SNPs studied were VEGF-2578*C/A (rs69947), VEGF-1154*G/A (rs1570360) TNF-α-308*G/A (rs1800629) and FKBP5*C/T (rs1360780) in 206 random and 80 selected HLA-DR52 positive individuals. To simplify the analysis, the HLA-DR genotypes were collapsed to the five human ancestral supertypes, namely: HLA-DR51, DR52, DR53, DR1 and DR8. Gametic phase and linkage between paired genotypes were determined using Arlequin 3.01 software, and significance was determined by Chi-square and Fisher's exact test analysis. Significant allelic associations were evident across the 6p region examined. Two putative haplotypes were identified, associated with DR52 and DR1. Within the HLA-DR52 supertype, TNF-α −308*A was associated with DR3, while FKBP5*T was associated with DR6. The interval between VEGF and TNF-α is 12.31 Mb. Therefore, allelic associations are surprising considering expected recombination and the evolutionary time (c10MY) since divergence of DR supertypes. This suggests that DR1 and DR52 haplotypes may have a survival advantage. Within the DR52 supertype, VEGF*C-DR3-TNF −308*A is a ‘high inflammatory’ haplotype associated with acute and chronic rejection, while the FKBP5*T-DR6 haplotype is associated with resistance to endogenous and exogenous glucocorticoids. Conversely, the DR1 haplotype is a ‘low inflammatory’ haplotype.

The frequent and conserved DR3‐B8‐A1 extended haplotype confers less diabetes risk than other DR3 haplotypes

The goal of this study was to develop and implement methodology that would aid in the analysis of extended high-density single nucleotide polymorphism (SNP) major histocompatibility complex (MHC) haplotypes combined with human leucocyte antigen (HLA) alleles in relation to type 1 diabetes risk. High-density SNP genotype data (2918 SNPs) across the MHC from the Type 1 Diabetes Genetics Consortium (1240 families), in addition to HLA data, were processed into haplotypes using PedCheck and Merlin, and extended DR3 haplotypes were analysed. With this large dense set of SNPs, the conservation of DR3-B8-A1 (8.1) haplotypes spanned the MHC (>/=99% SNP identity). Forty-seven individuals homozygous for the 8.1 haplotype also shared the same homozygous genotype at four 'sentinel' SNPs (rs2157678 'T', rs3130380 'A', rs3094628 'C' and rs3130352 'T'). Conservation extended from HLA-DQB1 to the telomeric end of the SNP panels (3.4 Mb total). In addition, we found that the 8.1 haplotype is associated with lower risk than other DR3 haplotypes by both haplotypic and genotypic analyses [haplotype: p = 0.009, odds ratio (OR) = 0.65; genotype: p = 6.3 x 10(-5), OR = 0.27]. The 8.1 haplotype (from genotypic analyses) is associated with lower risk than the high-risk DR3-B18-A30 haplotype (p = 0.01, OR = 0.23), but the DR3-B18-A30 haplotype did not differ from other non-8.1 DR3 haplotypes relative to diabetes association. The 8.1 haplotype demonstrates extreme conservation (>3.4 Mb) and is associated with significantly lower risk for type 1 diabetes than other DR3 haplotypes.

Association of MHC SNP genotype with susceptibility to type 1 diabetes: a modified survival approach

The Major Histocompatibility Complex (MHC) is a highly polymorphic region on chromosome 6 encompassing the human leucocyte antigen (HLA)-DQ/DR loci most predictive of susceptibility to type 1 diabetes (T1D). To assess the contribution of other MHC genes, in this exploratory analysis of Type 1 Diabetes Genetics Consortium (T1DGC) family data we characterize association between susceptibility and MHC single nucleotide polymorphism (SNP) genotype, with an emphasis on effects of genetic variation additional to carriage of predisposing or protective MHC haplotypes. We use Cox regression analyses of age of onset, stratified by family, to jointly test both linkage and association. Analysis is restricted to children from families having both affected and unaffected siblings and is conducted with and without adjustment for known HLA class I and II effects. Model fits provide scores for each individual that are based on estimates of the probability of being affected by the age of 35, given the individual's SNP genotype. The mean within-family variation in these scores provides a measure that closely reflects the relative size of the likelihood ratio test statistics, and their covariation provides a means of mapping patterns of association that incorporate both effect size and commonality of effect that is attributable to the strong linkage disequilibrium (LD) extending across the region. Univariate analyses yielded strong associations with T1D susceptibility that are dominated by SNPs in the class II HLA-DR/DQ region but extend across the MHC. Similar effects are frequently observed across SNPs within multiple genes, sometimes spanning hundreds of kilobases. SNPs within a region at the telomeric end of the class II gene HLA-DRA yielded significant associations with and without adjustment for carriage of the predictive DR3, DR4, DR2 and DR7 HLA haplotypes, and remained highly prominent in a secondary analysis that was restricted to 66 families in whom at least one of the affected siblings carried neither the DR3 nor DR4 haplotype. While many of the associations can be attributed to LD between the SNPs and the dominant HLA-DRB/DQA/DQB loci, there is also evidence of additional modifying effects.

Mating in parents of type 1 diabetes families as a function of the HLA DR‐DQ haplotype

The Major Histocompatibility Complex (MHC) region on chromosome 6p21 (IDDM1) contributes about half of the familial clustering of type 1 diabetes (T1D). Several studies have revealed that highly polymorphic genes within the MHC may associate with the mating choice. Our study should determine whether a specific mating effect is detectable in T1D families as a function of human leucocyte antigen (HLA) DR-DQ, which could contribute to disease susceptibility. We analysed the parental HLA-DR genotypes in 829 diabetic families. The families derive from the Type 1 Diabetes Genetics Consortium (T1DGC) in addition to those of our own centre and the original UK, US and SCAND diabetic families. A total of 307 of 829 parental couples (37.0%) were matched for at least one known T1D risk haplotype (DR3 or DR4), which is significantly less than the expected 374.9 (45.2%), derived from population genotype frequencies (p < 0.0009). Parents share less susceptibility haplotypes and rather complement each other as both carry one different risk haplotype (DR3 or DR4). The number of such parental couples was significantly higher than expected (293 vs. 223.4; p < 0.0003). All non-transmitted DR haplotype pairs were also analysed. More often than expected, both parents did not transmit DR1 (94 vs. 59.1; p < 0.003) and DRy (y: not DR1, not DR3, not DR4; 63 vs. 30.3; p < 0.0005). In contrast, the parental non-transmitted pair of haplotypes DR1-DRy was observed to a far lesser extent than expected (26 vs. 84.7; p < 10(-8)). These observations were only made in multiplex families, whereas in simplex families, no deviation from the expected frequencies was observed. Our data are consistent with the conclusion that genes in the HLA region may influence the mating choice in parents of T1D patients, thus contributing to familial clustering of T1D in multiplex families. This may indicate a different parental background of multiplex compared with simplex T1D families.

Allotyping human complement factor B in Asian Indian type 1 diabetic patients

Human complement factor B (BF) is an essential component of the alternate complement pathway and therefore important in innate immune and autoimmune responses. The BF gene is located in the central region of major histocompatibility complex (MHC) and is known to encode more than 30 protein variants that can be resolved by isoelectric focusing and gel electrophoresis. There are three BF alleles - BF*S, BF*FB and BF*FA - that differ in codon 7 at nucleotide positions 94 and 95. These alleles have CGG, TGG or CAG triplets at their codon 7, respectively, that code for Arg, Trp or Gln residues. We have developed a novel polymerase chain reaction using sequence-specific primers-based allotyping assay that can identify nucleotide substitutions in codon 7 in all the three BF alleles. The assay was validated by sequencing and amplified fragment length polymorphism. Using this SSP assay, we report the BF alleles located on the multiple human leukocyte antigen (HLA)-DR3 haplotypes that are unique in the Indian population and are associated with autoimmunity. The common type 1 diabetes (T1D)-favoring Caucasian haplotype HLA-A1-B8-DR3 (ancestral haplotype AH8.1) carries BF*S. However, in the North Indian T1D patients, the most common haplotype is HLA-A26-B8-DR3 (AH8.2) and this carried BF*FB. Because of its association with AH8.2, the BF*FB was overrepresented in the patients (51.03%) compared with healthy controls (32.7%, OR = 2.148, 95% CI = 1.34-3.44, P = 0.002). Similar studies on allotyping BF alleles in different haplotypes in various populations could have important implications in understanding mechanisms of MHC haplotypic diversifications and disease associations and designing future therapeutic approaches.

78-P: HLA-A, -B, -DR gene and haplotype frequencies in 27,951 bone marrow donors from Sichuan Province marrow donor registry of China

78-P: HLA-A, -B, -DR gene and haplotype frequencies in 27,951 bone marrow donors from Sichuan Province marrow donor registry of China

What Is the Prevalence of Celiac Disease Among U.S. Patients with Autoimmune Hepatitis?

Purpose: Autoimmune hepatitis (AIH) is an insidious disorder of unknown etiology, characterized by elevated serum aminotransferase and immunoglobulin G concentrations, circulating autoantibodies, lymphoplasmacytic portal and interface hepatitis and responsiveness to prednisone. Most affected European and North American AIH patients possess either the DR3 or DR4 haplotype. The hallmarks of celiac disease (CD) are gluten intolerance, and the presence of either the DR3 and/or DQ2 haplotypes. The estimated prevalence of CD in the general U.S. population is 1:100, whereas the prevalence of CD in European subjects with AIH has been estimated at between 1:16 and 1:36 in two separate studies. Therefore, we proposed to determine the prevalence of CD among patients with AIH in the U.S. Methods: We studied patients aged ≥ 18 years with a diagnosis of AIH conforming to International Autoimmune Hepatitis Group criteria, presenting at a single U.S. center between September 2003 and May 2008. Patients' sera were tested for IgA endomysial antibody (EMA) by indirect immunofluorescence; their serum IgA concentration was measured concomitantly. Patients with selective IgA deficiency (SIgAD) were tested for serum IgG gliadin antibody (AGA) by enzyme immunoassay. Results: The sample comprised 153 patients of whom 22 were male (14.4%), with a median age of 50 years (range 18–81). The ethnic distribution was: 115 (75.2%) Caucasian, 33 (21.6%) African American non-Hispanic, two (1.3%) native American, two (1.3%) Asian, and one (0.6%) Caucasian Hispanic. One patient had a positive EMA result (duodenal mucosal biopsies were consistent with CD). One man had selective IgA deficiency, but his AGA IgG titer was normal (5.1 units: normal 0–25). Five women underwent endoscopic duodenal mucosal biopsy despite negative EMA results (four had iron deficiency anemia, the other loose stools and weight loss). One patient demonstrated histological findings consistent with CD, whereas the other four demonstrated normal histology. Conclusion: Although the prevalence of CD in these U.S. patients with AIH (1:76 [1.3%]) is considerably less than reported among European AIH patients, it is slightly greater than in the general U.S. population. This suggests the possibility of increased risk for CD among U.S. patients with AIH, and therefore appropriate serologic screening. Conversely, the study sample may have been underpowered, thereby resulting in findings which suggest a difference that does not truly exist. In either case, it appears that EMA may not be the most appropriate screening test for CD in AIH patients: only one of the two patients identified with CD in this group yielded a positive antibody result.

Dissection of the multiple sclerosis associated DR2 haplotype

Epidemiological and genetic data have consistently identified associations with HLA class II alleles in many autoimmune diseases. In multiple sclerosis (MS), an autoimmune disease targeting central nervous system (CNS) myelin, the DR2 haplotype ( DRB1*1501, DRB5*0101 and DQB1*0602) remains the strongest identified genetic risk factor in Caucasians. However, it is hard to tease apart the precise contributions of its constituent individual alleles and their modes of action remain poorly understood, due in part to the strong linkage disequilibrium in this region. Recent work in humanized mice indicates functional epistatic interactions whereby DRB5*0101 directly modulates the severity of the ensuing disease through activation-induced cell death (AICD) of encephalitogenic T cells which are restricted by DRB1*1501. Complementary structural studies help to explain how these alleles may facilitate thymic escape of autoreactive T cells and contribute to peripheral T cell activation via suboptimal binding interactions and mechanisms of molecular mimicry. Here we discuss the emerging role of the constituent alleles of the DR2 haplotype and our ongoing efforts to uncover the mechanisms by which they influence MS pathogenesis.