Contribution of DRB1*04 variants to predisposition to or protection from insulin dependent diabetes mellitus is independent of dq

Certain DQ alpha/beta dimeric molecules have been shown to play a major role in determining susceptibility or resistance to IDDM. Whether or not predisposition associated with DR4 haplotypes is exclusively due to linkage to DQB1*0302 and DQA1*0301 alleles is still a controversial issue. A modifying effect of certain DRB1*04 subtypes on the susceptibility encoded by DQ alleles is possible, since not all DRB1*04-DQB1*0302 haplotypes are associated with the disease. The distribution of DRB1*04 subtypes was analysed in 240 DR4-positive Caucasian IDDM patients and 110 DR4-positive healthy controls using allele-specific hybridization after genomic amplification. Although an important contribution to IDDM predisposition was encoded by the DQB1*0302 allele which was found in the majority of patients (94.2% vs 64.7% in controls, Odd's ratio OR = 8.8, P < 0.0001), differences between DRB1*04 variants persisted after the effect of the DQB1 locus was removed by matching patients and controls for DQB1*0302. Thus, the DRB1*0402 allele conferred a strong IDDM-predisposing effect (OR = 3.1, P < 0.02) which was highly significant in the absence of DR3 on the second haplotype (OR = 5.6, P < 0.0001) but was not visible among DR3/4 heterozygote individuals. Conversely, the DRB1*0404 allele conferred a strong protective effect (OR = 0.26, P < 0.0001) which was dominant even in the presence of the associated high risk DR3 haplotype (OR = 0.21, P < 0.03). These data indicate that DQ molecules are not the sole contributors to the DR4-associated IDDM predisposition, and that peculiar DR4 subtypes play a significant role in susceptibility to or protection from the disease. DRB1*0402 differs from DRB1*0404 by only two acidic residues at positions 70 and 71 within the peptide binding groove, instead of amide and basic amino acids. This might induce changes of peptide binding specificity that correlate with the genetic linkage of IDDM predisposition.     

Shared epitope homozygosity' is strongly associated with rheumatoid arthritis in Turkey. Istanbul Rheumatology Study Group

OBJECTIVE: Associations with HLA-DRB alleles, implicated in the aetiopathogenesis of rheumatoid arthritis (RA), are found to be different in various ethnic groups. This study aimed to investigate DRB1 alleles in RA patients in Turkey. METHODS: The DRB region of the MHC was screened by polymerase chain reaction/sequence-specific oligonucleotide (PCR/SSO) hybridizations in 101 seropositive RA patients and compared with 101 healthy controls. RESULTS: Significant differences were in the frequencies of DRB1*0404 (12 vs 1, P = 0.003, OR = 13.5), *0401 (19 vs 4, P = 0.001, OR = 5.6) and *0408 (5 vs 0, P = 0.06, OR = 11.6) between RA patients and controls. The shared epitope (SE) was present in 70.2% of RA patients compared to 31.6% of controls (P < 0.0001, OR = 5.1). A double dose of SE was considerably more frequent in the RA group (21 vs 1, P < 0.0001, OR = 26.5). CONCLUSION: These results support the reported positive association of RA with SE in seropositive patients in Turkey, and emphasize 'SE homozygosity' as the most strongly associated genetic susceptibility marker for RA.     

Characterization of self-glutamic acid decarboxylase 65-reactive CD4+ T-cell clones established from Japanese patients with insulin-dependent diabetes mellitus

To investigate autoimmunity to glutamic acid decarboxylase (GAD) 65 in Japanese patients with insulin-dependent diabetes mellitus (IDDM, type I diabetes), we established seven CD4+ T-cell clones, by stimulating peripheral blood mononuclear cells (PBMC) of six IDDM patients, using a mixture of overlapping human GAD65 peptides. No GAD65 autoreactive T-cell clones were evidenced in four healthy controls. Specificities of T-cell clones were as follows: (a) two clones specific to GAD65 p111-131 (residue 111 to 131) + DR53 (DRB4*0103); (b) one clone specific to GAD65 p413-433 + DR1 (DRB1*0101); (c) two clones specific to GAD65 p200-217 + either DR9 (DRB1*0901) or DR8 (DRB1*0802); and (d) two clones specific to GAD65 p368-388 + DP2 (DPA1*01 or 0201-DPB1*0201). Two DR53-restricted and one DR1-restricted T-cell clones, responded to a recombinant human GAD65 protein, and showed cytotoxicity against B lymphoblastoid cell lines pre-pulsed with the peptides. Six T-cell clones exhibited the Th1-like phenotype. Interestingly, two DR53-restricted T-cell clones killed a Fas-deficient B lymphoblastoid cell line, thereby indicating that cytotoxicity was not completely dependent on a Fas-Fas ligand interaction. Thus, the T-cell epitopes were mapped in a limited portion of GAD65 protein, with a tendency to be restricted by disease-associated HLA-DR, but not DQ molecules.     

Characteristics of the innervation of the head and neck

The association of HLA-DRB1 and DQB1 genes with IDDM in Koreans was assessed using 115 IDDM patients and 140 nondiabetic controls. DQB1*0201 is the only DQB1 allele positively associated with IDDM while DQB*0602, *0601 and *0301 are negatively associated. Three DRB1 alleles (DRB1*0301, DRB1*0407 and DRB1*0901) are positively associated while four DR allele groups (DRB1*15, DRB1*12, DRB1*10 and DRB1*14) are negatively associated. However, Haplotype analyses indicated that DQB1*0302, DRB1*0405 and DRB1*0401 may confer susceptibility because the DRB1*0405-DQB*0302 and DRB1*0401-DQB1*0302 haplotypes are positively associated with the disease. The lack of association in Koreans with the DQB1*0302 allele, which appears predisposing in studies of non-Orientals, is due to its strong linkage disequilibrium (LD) with the protective DRB1*0403 and *0406 alleles, while the lack of association with DRB1*0405 is because of its strong LD with the protective DQB1*0401 allele. Nine DR/DQ genotypes confer significantly increased risk to IDDM. Seven of the nine genotypes (DR3/4s, DR1/4s, DR4s/13, DR4s/8, DR4s/7, DR9/13 and DR3/9) were also found to be at high risk to IDDM in other populations, while the two others (DR1/9 and DR9/9) are only found in Koreans. Surprisingly, DR4/4 homozygotes are not associated with high risk to IDDM in Koreans. This observation can be explained by the high frequency of protective DR4 subtypes and the protective DQ alleles (0301 and 0401) associated with the susceptible DR4 alleles. Our analyses indicate that the counterbalancing act between susceptible DRB1 and protective DQB1, and vice versa, that has already been observed in Chinese and Japanese, is the major factor responsible for the low incidence of diabetes in Koreans.     

Influence of non-inherited maternal HLA-DR antigens on susceptibility to rheumatoid arthritis

OBJECTIVE: It has recently been observed that non-inherited maternal DR4 antigens (NIMAs) of DR4 negative rheumatoid arthritis (RA) patients were increased compared with non-inherited paternal DR4 antigens (NIPAs). The aim of this study was to determine the prevalence of non-inherited DR4 antigens and DRB1 alleles in parents of RA patients. METHODS: HLA-DR serology and DRB1 typing was performed in 97 RA patients and their parents. NIMA and NIPA frequencies were compared, stratified according to the presence of DR4 and/or the shared epitope (SE). RESULTS: In DR4 negative patients, NIMA DR4 was increased compared with NIPA DR4 (OR 3.10, 95% CI 0.76, 12.70). When combined with results from a previous study this increase was significant (OR 3.65, 95% CI 1.29, 10.31). The NIMA effect of SE positive DR4 subtypes in this study (OR 4.73, 95% CI 0.94, 23.8) was stronger than the NIMA effect of combined SE positive DRB1 alleles (OR 2.19 95% CI 0.36, 13.22). CONCLUSIONS: The association between non-inherited maternal HLA-DR4 alleles and the susceptibility to RA was observed in two independent populations.     

HLA associations with multiple sclerosis in the Canary Islands

The study of small island populations has proved informative with respect to the epidemiology and genetics of many complex traits including multiple sclerosis. The class II major histocompatibility antigen DR15 is associated with multiple sclerosis in all groups except Sardinians, where the primary association is with DR4. We compared HLA-DR and -DQ allele frequencies in a representative sample of patients with multiple sclerosis from the Canary Islands with appropriate controls. There was a significant association with DR15 (patients 21/53: 40%: controls 11/55; 20%: chi2=4.09; pc=0.04; relative risk [RR]=1.98). DRB1*1501-DRB5*0101 was present in 17/53 (32%) patients in whom sub-types could be identified compared with 6/55 (11%) controls (chi2=7.21; pc=< 0.01; RR=2.94). All DR15 positive controls carried the DQA1*0102, DQB1*0602 haplotype whereas this was only present in 26/30 patients, suggesting that the primary association is with HLA-DR and not -DQ. We also found a significant increase in HLA-DR4 (16/53 [30%] in patients compared with 7/55 [13%] in controls; pc=0.05). This study contributes a new point on the immunogenetic map of multiple sclerosis in Europe, confirming the primary DR15 association with multiple sclerosis in a previously unstudied population but again highlighting the importance of DR4 in Mediterranean peoples.     

Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients

Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class II-matched normal individuals. Our data reveal that (a) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; (b) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and (c) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected.     

Induction of autoimmune arthritis in HLA-DR4 (DRB1*0401) transgenic mice by immunization with human and bovine type II collagen

Although associations between the expression of particular HLA genes and the susceptibility to specific autoimmune diseases has been known for some time, the role that these HLA molecules play in the autoimmune response is unclear. Through the establishment of a chimeric HLA-DR/I-E transgene, we have examined the function of the rheumatoid arthritis (RA) susceptibility allele HLA-DR4 (DRB1*0401) in presenting antigenic peptides derived from the model Ag, type II collagen (CII), and in mediating an autoimmune response. As a transgene, the chimeric DR4 molecule conferred susceptibility to an autoimmune arthritis induced by immunization with human CII or bovine CII. These mice developed an inflammatory, autoimmune arthritis that was similar both histologically and in severity to that previously described for the collagen-induced arthritis model. The DR4-mediated autoimmune arthritis was accompanied by T cell and B cell responses to both the immunogen and the autoantigen, murine CII. The DR4-restricted T cell response to human CII was focused on an immunodominant determinant within CII263-270 and a minor determinant within CII286-300, the same CII determinants recently identified for yet another RA susceptibility allele, HLA-DR1 (DRB1*0101). Thus these data demonstrate that, like HLA-DR1, HLA-DR4 is capable of binding peptides derived from human CII and therefore probably plays a role in the autoimmune response to human CII observed in RA patients.     

Analysis of a genetic factor of metal allergy--polymorphism of HLA-DR, -DQ gene

To reveal immunogenetic factors involved in the pathogenesis of metal allergy, 30 unrelated Japanese patients with histories of metal allergy were typed for HLA. They were confirmed by an unequivocal positive patch-test reaction to mercury, nickel or palladium. The HLA-DR and -DQ DNA were typed by using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSO) method. The frequency of each allele in the patient groups was compared to that in normal Japanese subjects. In mercury sensitive patients, there was no significant HLA association. In nickel sensitive patients, there was a significant increase of DRB4 (p < 0.05) but no significant association of DRB1 nor DQ locus, although there was an increase of DRB1*0405 (R.R = 2.36). In palladium sensitive patients, there were significant increases of DRB4 (R.R. = 15.48, p < 0.05), DR4(R.R. = 13.27, p < 0.005), DRB1*0405(R.R. = 4.43, p < 0.05), and DQB1*0401 (R.R. = 4.59, p < 0.05), and significant decreases of DRB5 (R.R. = 0.09, p < 0.05), and DQA1*0103 (R.R. = 0, p < 0.05).     

Effectiveness of inactivated influenza vaccine among nursing home residents during an influenza type A (H3N2) epidemic

We performed serological phenotyping of HLA antigens in 175 patients with rheumatoid arthritis (RA) with (n = 41) and without (n = 134) renal involvement (RI), and DNA typing of HLA class II alleles in 75 patients. Among the patients with RA, the frequency of serologically determined HLA-DR4 was found to be significantly increased (odds ratio: 1.8, confidence interval: 1.3-2.5, p = 2.4x10(-4)). In the patients without RI, the frequency of serological DR4 significantly increased (odds ratio: 2.2, confidence interval: 1.6-3.3, p = 2. 6x10(-5)). On the other hand, among the patients with RI, a serological determinant, DR15, did significantly increase (odds ratio: 2.7, confidence interval: 0.9-8.4, p = 1.2x10(-3)) in comparison to the controls. At the DNA level, we found that the association of Japanese RA patients with serological HLA-DR4 was based on that with a genotype of HLA-DRB1*0405 (odds ratio: 2.4, confidence interval: 1.5-4.0, p = 4.4x10(-4)) and also found an association of HLA-DRB1*1501 (odds ratio: 2.8, confidence interval: 1.2-6.6, p = 0.017) with RA patients having RI. Our results confirmed the association of HLA-DRB1*04 with RA over the ethnic barrier at the DNA level. Our results also suggested a distinct genetic effect of HLA-DRB1*1501 in the aspect of the susceptibility of RI in RA.     

MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P < 0.0001), DQA1*0101 (P = 0.001), and DQB1*0503 (P < 0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB1*1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p < 0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB1*0302 (p = 0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67-74 of the beta domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles.     

Linoleate impairs collagen synthesis in primary cultures of avian chondrocytes

Several extended major histocompatability complex (MHC) haplotypes are associated with susceptibility to autoimmune disease in Caucasian populations. It is known that African Americans and Afro-Caribbeans are ethnic groups descended from west, central and southern black African populations which are admixed with Caucasians. To examine the possible association of some marker of Caucasian MHC genes and susceptibility to rheumatoid arthritis (RA) in African Americans, we studied extended MHC haplotypes (HLA-B, complement and DR) in a sample of 18 African American and Afro-Caribbean probands with RA, their first degree relatives and in 15 non-RA families. We defined 36 disease-associated RA haplotypes among the probands and 96 normal haplotypes in normal individuals. To obtain the most conservative estimate, we excluded recognized Caucasian, DR4-bearing, extended MHC haplotypes from the analysis. Admixture proportions for non-HLA-DR4 extended MHC haplotypes of known Caucasian origin among RA-associated and normal haplotypes were computed (0.40 versus 0.163 respectively). When we compared the difference in proportions between RA and normal haplotypes, the proportion of extended MHC haplotypes of known Caucasian origin was significantly increased among RA-associated haplotypes (Z = 3.16, p (one sided) < 0.001, p (adjusted) < 0.008). Our results suggest that racial admixture with Caucasian MHC genes may augment RA susceptibility and thus may be one mechanism to explain the higher prevalence of RA in African Americans and Afro-Caribbeans than in black African populations.     

Multiple epitopes of HLA-DRB1*0411 are recognized by T-cell clones originated from individuals carrying other DR4 subtypes

HLA polymorphism dictates the binding and recognition of specific peptides, leading to variations in individual immune responses and may contribute to autoimmune disorders and outcome in organ transplantation. We have studied the molecular basis for the cellular recognition of DRB1*0411 in individuals carrying other sequence-related DR4-alleles by characterization of T-cell clones (TLC). A set of 166 TLC were raised by priming cells from DRB1*0401,0402 and DRB1*0405,0901 individuals and 52 of them recognized DRB1*0411. Five distinct patterns of T-cell allorecognition were found: DRB1*0411 alone, DRB1*0411 and 0405, DRB1*0411 and 0406, DRB1*0411 and 0407 and DRB1*0411, 0406 and 0407, depending on responder phenotypes and epitopes recognized by their T cells. A stretch of 30 amino acids on DRB1*0411 from positions 57 to 86 behaves as a functional domain and residues S57, R71, E74 and V86 seem to be crucial in forming immunogenic determinants recognized by these TLC. The knowledge of shared amino acid residues between closely related DR4 alleles, which show similar patterns of recognition by T cells could also be useful in the selection of prospective donors for clinical transplantation of solid organs or bone marrow.     

Significance of the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy

OBJECTIVE: Genetic oxidation polymorphisms of debrisoquine (CYP2D6) and proguanil (CYP2C19) were studied in unrelated healthy South Pacific Polynesian volunteers recruited in the South Island of New Zealand. METHODS: Phenotyping for CYP2D6 and CYP2C19 activities was determined using debrisoquine and proguanil, respectively, as probe drugs by measuring the urinary metabolic ratio of parent drug and its metabolite. RESULTS: Of 100 Polynesian subjects phenotyped, the metabolic ratio of debrisoquine ranged from 0.01 to 9.94. Therefore, all South Pacific Polynesians were classified as extensive metabolizers of debrisoquine according to previously established criteria of the antimode. The prevalence of poor metabolizers of debrisoquine (CYP2D6) in this Polynesian population is 0% (95% confidence interval of 0-3.6%). Oxidation polymorphism of CYP2C19 using proguanil as a probe was also studied in 59 Polynesian volunteers. The frequency distribution of the proguanil/cycloguanil ratio was bimodal. The proguanil/cycloguanil ratios for these subjects ranged from 0.09 to 34.4. Using a recommended proguanil/cycloguanil ratio cut-off point of 10 established in Caucasian populations, eight Polynesian subjects were identified as poor metabolizers of proguanil (CYP2C19), which corresponds to a poor metabolizer phenotype frequency of 13.6% (a 95% confidence interval of 5.9-24.6%). CONCLUSION: The incidence of poor metabolizer phenotypes for debrisoquine (CYP2D6) in South Pacific Polynesians appears to lower than in Caucasian populations, while the prevalence of poor metabolizers for proguanil (CYP2C19) in this ethnic population is higher. The frequencies of the poor metabolizer phenotype for debrisoquine and also for proguanil in South Pacific Polynesians are similar to those reported in Asian populations.     

Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study

Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.     

HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese

It has previously been demonstrated that susceptibility to pemphigus vulgaris is associated with human leukocyte antigen (HLA)-DR4 serologic specificity among Ashkenase Jews, and with DR4 as well as DR6 (DR14) in other ethnic groups. We genotyped HLA-DRB1, DQA1, DQB1, and DPB1 alleles in 16 patients with pemphigus by polymerase chain reaction-restriction fragment length polymorphism, to find evidence of potential HLA class II allele associations with pemphigus in Japanese patients who have a relatively homogeneous ethnic background. All nine patients with pemphigus vulgaris and five of seven patients with pemphigus foliaceus carried one or two alleles of HLA-DRB1*04 (*0403, *0406) and HLA-DRB1*14 (*1401, *1405, *1406) subtypes. Sequence analysis of these DRB1*04 and DRB1*14 alleles revealed the amino acid homology of phenylalanine at position 26 and valine at position 86 with the DRB1*0402 allele that reportedly confers a strong susceptibility to pemphigus vulgaris in Ashkenazi Jews. Thus our findings, together with previous HLA studies on pemphigus vulgaris patients of different ethnic groups, suggest that HLA-DRB1*04 and DRB1*14 alleles are commonly associated with pemphigus vulgaris across racial barriers. These HLA-DRB1 alleles are likely to be also associated with pemphigus foliaceus. Further studies on more diverse ethnic populations will be helpful in determining the significance of the association between certain amino acid residues of the class II molecules and disease susceptibility to pemphigus vulgaris as well as pemphigus foliaceus.     

HLA-C genes and susceptibility to type 1 autoimmune hepatitis

Susceptibility to autoimmune hepatitis (AIH) is associated with the HLA A1-B8-DR3 haplotype, DR4 antigen, and, more specifically, the HLA DRB3*0101, DRB1*0301, and DRB1*0401 alleles. Few investigators, however, have examined the HLA C locus in AIH, which warrants detailed study in view of its recently described roles in immunoregulation. Eighty-seven adult, white patients with well-characterized type 1 AIH and 100 controls were studied. HLA C and HLA DRB1 alleles were assigned by polymerase chain reaction (PCR)-based genotyping. HLA A and B antigens were determined by standard microlymphocytotoxicity assay. Extended haplotypes were constructed according to known patterns of linkage disequilibrium. Only one HLA C locus allele, Cw*0701, which was present in 54% of patients versus 34% of controls (P = .006; relative risk [RR] = 1.54) was associated with AIH. The overall increase in the frequency of the Cw*07 gene (70.1% of patients vs. 54% of controls; P = .024; RR = 1.3) was due entirely to inheritance of the Cw*0701 allele rather than the other Cw*07 alleles, Cw*0702, *0703, and *0704. The RR for Cw*0701 (RR = 1.54) is greater than that for HLA A1 (RR = 1.33) and DRB1*0301 (RR = 1.49), but less than that for HLA-B8 (RR = 1.75). The present findings suggest that the gene or genes conferring susceptibility to AIH lie in the region centromeric to the HLA A locus between HLA C and DRB1. Although linkage disequilibrium with both B8 and DRB1*0301 may account for our finding of an increased frequency of Cw*0701, it is also possible that this allele contributes to disease susceptibility, perhaps by interaction with natural killer cells or cytotoxic T lymphocytes.     

Associations of GAD65- and IA-2- autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. The Belgian Diabetes Registry

OBJECTIVE: To investigate the association of GAD (65-kDa) autoantibodies (GAD65-Abs) and IA-2 autoantibodies (IA-2-Abs) with human leukocyte antigen (HLA)-DQ and insulin gene (INS) risk markers in patients with recent-onset IDDM and their siblings. RESEARCH DESIGN AND METHODS: Blood was sampled from 608 recent-onset IDDM patients and 480 siblings, aged 0-39 years and consecutively recruited by the Belgian Diabetes Registry, to determine GAD65- and IA-2-Ab (radiobinding assay), HLA-DQ- (allele-specific oligonucleotyping), and INS-genotypes (restriction fragment length polymorphism analysis; siblings, n = 439). RESULTS: At the onset of IDDM, GAD65-Abs were preferentially associated with two populations at genetic risk but only in the 20- to 39-year age-group: 1) their prevalence was higher in carriers of DQA1*0301-DQB1*0302 (88 vs. 73% in non[DQA1*0301-DQB1*0302], P = 0.001), and 2) an association was found in patients lacking this haplotype but carrying DQA1*0501-DQB1*0201, together with INS I/I (87 vs. 54% vs. non[INS I/I], P = 0.003). Siblings of IDDM patients also presented the association of GAD65-Abs with DQA1*0301-DQB1*0302 (13 vs. 2% non[DQA1*0301-DQB1*0302], P < 0.001), while associations with the second genetic risk group could not yet be assessed. At the onset of IDDM, IA-2-Ab prevalence was higher in carriers of DQA1*0301-DQB1*0302 (69 vs. 39% non[DQA1*0301-DQB1*0302], P < 0.001) but not of DQA1*0501-DQB1*0201 or INS I/I. This association was present in both the 0- to 19- and the 20- to 39-year age-groups. It was also found in siblings of IDDM patients (4 vs. 0% non[DQA1*0301-DQB1*0302], P < 0.001). CONCLUSIONS: Both GAD65- and IA-2-Abs exhibit higher prevalences in presence of HLA-DQ- and/or INS-genetic risk markers. Their respective associations differ with age at clinical onset, suggesting a possible usefulness in the identification of subgroups in this heterogeneous disease.     

A new DRB1*15 allele (DRB1*1506) identified by sequence-based typing

A new DRB1*15 allele (DRB1*1506) was detected during the studies of the 12th International Histocompatibility Workshop within the Allele and Haplotype Society #11 which studied the DR2 and DR51 antigens. The new allele was found in four unrelated Asian Indian individuals by sequence-based typing. It has a base substitution from T to C in codon 50 at a previously considered conserved position.