Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 Diabetes

We assessed the prevalence of families with both type 1 and type 2 diabetes in Finland; and we studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, glutamic acid decarboxylase (GAD) antibodies (GADab), and type 1 diabetes-associated human leukocyte antigen (HLA) DQB1-genotypes. Further, in mixed type 1/type 2 diabetes families, we investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families ascertained through the presence of more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families had, more often, GADab (18% vs. 8%, P < 0.0001) and DQB1*0302/X genotype (25% vs. 12%, P = 0.005) than patients from families with only type 2 diabetes; but they had a lower frequency of DQB1*02/0302 genotype, compared with adult-onset type 1 patients (4% vs. 27%, P < 0.0001). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes (P = 0.016). This finding was independent of the presence of GADab. We conclude that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. The findings support a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus.     

Genetic screening for individuals at high risk for type 1 diabetes in the general population using HLA Class II alleles as disease markers. A comparison between three European populations with variable rates of disease incidence

BACKGROUND: To develop screening strategies for identification of individuals at increased genetic risk for type 1 diabetes in three populations with variable disease incidence rates and distinct ethnic origin. METHODS: A stepwise HLA DQB1-DQA1-DRB1-based screening approach was evaluated. Patients with childhood-onset type 1 diabetes were recruited from Finland (n = 1739), Hungary (n = 149), and Greece (n = 119). Consecutive newborns (2568 from Finland and 1047 from Greece) or healthy schoolchildren (n = 177 from Hungary) served as controls. RESULTS: The DQB1*02/0302 genotype conferred the highest disease risk in all populations. The DQB1*02/y (y not equal DQB1*0301,*0302,*0602,*0603, *0604) genotypes were more common and conferred a higher disease risk in the Greek population (OR 4.9) compared to the Finns (OR 1.2). DQB1*0302/x (x not equal DQB1*02, *0301, *0602, *0603, *0604) genotypes were, in contrast, more prevalent among Finnish cases (32.7%) as compared to Hungarians (18.1%) or Greeks (13.5%). The protective DQB1*0602 or *0603 positive genotypes were most common in the Finns, while DQB1*0301 was more common in Hungarians and Greeks. In all groups, DQA1 and DRB1*04 typing considerably increased the sensitivity of the DQB1-based screening. The different high-risk genotype combinations present in about 10% of the background population had a diagnostic sensitivity of 60% in Finland and 80% in Hungary and Greece. CONCLUSIONS: HLA DR-DQ-based screening is a feasible tool for the identification of individuals at increased genetic risk for type 1 diabetes in populations with diverse genetic background. The risk markers should, however, be individually selected for the target population since the screening efficiency of various markers is highly dependent on the ethnic group studied.     

Rare human leukocyte antigen genotype in two siblings with type 1 diabetes in a Japanese family clustered with type 1 diabetes

Multiplex families with type 1 diabetes are important for identification of rare variants that cannot be identified in case–control association studies. The very low incidence of type 1 diabetes in the Japanese population, however, makes identification of such families difficult. We identified a Japanese family in which three members developed type 1 diabetes, and studied the genotype of the human leukocyte antigen. All three members with type 1 diabetes had the DRB1*08:02‐DQB1*03:02 haplotype, which is specific to the Asian population and strongly susceptible for type 1 diabetes. In particular, a proband and his sister had the same genotype, DRB1*08:02‐DQB1*03:02/DRB1*08:02‐DQB1*03:02, which is extremely rare even in the Japanese population. Both parents also had DRB1*08:02‐DQB1*03:02, but in combination with different human leukocyte antigen haplotypes. Weakly susceptible DRB1*13:02‐DQB1*06:04 was present in the affected mother, and resistant DRB1*15:01‐DQB1*06:02 in the unaffected father. These data suggest DRB1*08:02‐DQB1*03:02 to be a contributing factor for familial clustering of type 1 diabetes in this family.     

Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome

Tumor necrosis factor (TNF) production and non-Hodgkin lymphoma (NHL) outcome was found to be related to the TNF(-308) polymorphism. To explore whether this could be linked to neighboring polymorphisms, we genotyped the TNF(-376,-308,-238,-163), lymphotoxin alpha (LTalpha)(+252), and HLA DRB1 alleles in 204 patients with NHL and 120 controls. TNF(-308A) was the only allele associated with higher TNF and its p55 and p75 receptors' levels (P =.009, P =.03, and P =.007) and lower complete remission rates (P =.006). Freedom from progression (FFP) and overall survival (OS) were shorter in patients with TNF(-308A) (P =.009 and P =.02), null HLA DRB1*02 allele (P =.007 and P =.14), or both genetic markers (P =.004 and P =.005). Multivariate analysis incorporating International Prognostic Index (IPI) identified TNF(-308A) (P <.0001, relative risk [RR] = 1.63; P <.0001, RR = 1.51) and null HLA DRB1*02 alleles (P =.015, RR = 1.18; P <.0001, RR = 1.25) as independent factors for FFP and OS. These results indicate the existence of at least 2 inherited factors involved in NHL outcome.     

Tumour necrosis factor-alpha single nucleotide polymorphisms are not independent of HLA class I in UK Caucasians with adult onset idiopathic inflammatory myopathies

OBJECTIVE: To investigate haplotype tagging single nucleotide polymorphisms (SNPs) in the tumour necrosis factor alpha (TNF-alpha) gene, in UK Caucasian idiopathic inflammatory myopathy (IIM) patients. METHODS: A cross-sectional, case-control study of four TNF-alpha SNPs was undertaken, comparing cases of polymyositis (PM) (n = 121), dermatomyositis (DM) (n = 109) and myositis overlapping with other connective tissue diseases (CTD-overlap) (n = 73) with normal subjects (n = 177). Subgroup analyses were undertaken after stratifying for myositis specific/associated antibodies. RESULTS: The TNF-308A allele demonstrated a strong association with each myositis disease subgroup vs controls [PM, odds ratio (OR) 2.8, 95% confidence interval 1.9-4.3; DM, OR 2.5, 1.6-3.8; CTD-overlap, OR 3.3, 2.1-5.1]. The TNF-308GA/AA genotype frequency was significantly increased vs controls (PM, OR 3.7, 2.1-6.3; DM, OR 3.2, 1.8-5.5; CTD-overlap, OR 5.0, 2.6-9.6) suggesting a dominant model. The association was strongest in patients possessing anti-aminoacyl transfer RNA synthetase (anti-synthetase) (OR 5.1, 3.3-8.0) or -PM-Scl (OR 5.0, 2.7-8.9) antibodies. The -1031T allele was also a significant risk factor in DM (OR 2.2, 1.4-3.6), anti-synthetase (OR 2.9, 1.6-5.3) and -PM-Scl (OR 5.6, 1.9-6.4) antibody positive patients. The TNF-308A association was lost after adjusting for HLA-B*08, but remained independent of HLA-DQB1*02 (both are alleles forming part of the common ancestral haplotype). The HLA-B*08/TNF-308A/DRB1*03/DQA1*05/DQB1*02 haplotype was a risk factor in all myositis subgroups vs controls (OR 3.0, 1.8-5.3). CONCLUSIONS: TNF-308A and -1031T alleles are significant risk factors in the IIMs. In the IIMs, the TNF-308A allele is part of the common ancestral haplotype, but is not independent of HLA-B*08.     

Class II HLA genotype in fulminant type 1 diabetes: A nationwide survey with reference to glutamic acid decarboxylase antibodies

Aims/Introduction: Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin‐deficient hyperglycemia within a few days. The aim of the present study was to clarify characteristic class II HLA genotypes in a large number of patients with fulminant type 1 diabetes to date. Materials and Methods: We analyzed the HLA‐DRB1 and DQB1 genotypes, and their haplotypes in 207 patients with fulminant type 1 diabetes and 325 control subjects in the Japanese population. Results: The frequencies of the DRB1*04:05‐DQB1*04:01 and DRB1*09:01‐DQB1*03:03 haplotypes were significantly higher, and those of the DRB1*01:01‐DQB1*05:01, DRB1*15:02‐DQB1*06:01 and DRB1*08:03‐DQB1*06:01 haplotypes were significantly lower in patients with fulminant type 1 diabetes than in the control subjects. Combination analysis showed that the frequencies of homozygotes with DRB1*04:05‐DQB1*04:01 [odds ratio (OR) 7.0] and DRB1*09:01‐DQB1*03:03 (OR 9.5) were significantly higher in patients with fulminant type 1 diabetes. Within a limited portion of patients with fulminant type 1 diabetes with antibodies to glutamic acid decarboxylase (GADab; n = 25), the frequency of DRB1*09:01‐DQB1*03:03, but not DRB1*04:05‐DQB1*04:01, was significantly higher than in control subjects (44.0% vs 13.7%; Pc < 0.05, OR 5.0). [Correction to last line of Results, added after online publication 29 July 2011: “OR 5.1” is changed to “OR 5.0”.] Conclusions: Our large‐scale study showed the characteristic class II HLA genotypes in fulminant type 1 diabetes, and implicated that genetic contribution to disease susceptibility is distinct between GADab‐positive and GADab‐negative fulminant type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00139.x, 2012)     

Heterophile antibodies segregate in families and are associated with protection from type 1 diabetes

Markedly elevated levels of serum IL-4 were reported previously in 50% of a small group of type 1 diabetes nonprogessors. To determine the patterns of expression for this phenotype, a larger cohort of 58 families containing type 1 diabetic patients was examined. Analysis of the two-site ELISA assay used to measure serum IL-4 revealed evidence for heterophile antibodies, i.e., nonanalyte substances in serum capable of binding antibodies mutivalently and providing erroneous analyte (e.g., IL-4) quantification. Interestingly, relatives without type 1 diabetes were significantly more likely to have this phenotype than were patients with the disease (P = 0.003). In addition, the trait appears to have clustered within certain families and was associated with the protective MHC allele DQB1*0602 (P = 0.008). These results suggest that heterophile antibodies represent an in vivo trait associated with self-tolerance and nonprogression to diabetes.     

DR- and DQ-associated protection from type 1A diabetes: comparison of DRB1*1401 and DQA1*0102-DQB1*0602*

The transmission disequilibrium test was used to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type 1 diabetes repository (n = 1371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (n = 2441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P < 0.001, vs. the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P < 0.0001). Rare DQA1*0102-DQB1*0602 haplotypes without DRB1*1501 were never transmitted to affected offspring (n = 6). The DQA1*0101-DQB1*0503 haplotype was transmitted to 2 of 42 (4.8%) affected offspring (P < 0.001, vs. 50% expected transmission). Although DRB1*1401 is in linkage disequilibrium with DQB1*0503, neither of the two affected children who carried DQA1*0101-DQB1*0503 had DRB1*1401. However, all 13 nonaffected children who inherited DQA1*0101-DQB1*0503 had DRB1*1401. In a case-control comparison of patients from the Barbara Davis Center, DQA1*0101-DQB1*0503 was found in 5 of 110 (4.5%) controls compared with 3 of 728 (0.4%) patients (P < 0.005). Of the three patients with DQB1*0503, only one had DRB1*1401. Our data suggest that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type 1A diabetes.     

Molecular analysis of major histocompatibility complex allelic associations with systemic lupus erythematosus in Taiwan

Objective. To investigate the association of HLA class II alleles/haplotypes, type I C2 deficiency gene, and tumor necrosis factor α gene promoter allele (TNF2) with systemic lupus erythematosus (SLE) in the Chinese population in Taiwan. Methods. The HLA-DRB1 and DQB1 alleles were studied in 105 SLE patients and 115 controls by the polymerase chain reaction (PCR)/sequence-specific oligonucleotide probe method, the subtyping of DRB1*15/16 and DRB5 by PCR with sequence-specific primers, type I C2 deficiency gene by PCR, and TNF2 by PCR-Nco I restriction fragment length polymorphism. Results. The frequencies of the HLA class II alleles DRB1*02, DRB1*1502, DRB5*0102, DQB1*0501, and DQB1*0602 and DR2-associated haplotypes DRB1* 1501,DRB5*0101,DQB1*0602 and DRB1*1502,DRB5* 0102,DQB1*0501 were higher among SLE patients than among controls; however, only DQB1*0501 was statistically significantly associated with SLE. No specific allele/haplotype was significantly associated with lupus nephritis. No subject had type I C2 deficiency. SLE patients had a marginally higher percentage of TNF2, which was in linkage disequilibrium with DR3. Since DR3 was not associated with SLE in this Taiwanese Chinese population, TNF2 might play a role in the immunopathogenesis of SLE. Conclusion. Although no HLA-DRB1 allele was found to be significantly associated with SLE, the associations with DQB1*0501 and TNF2 suggest that DQB1 and tumor necrosis factor α may be important genetic factors in SLE susceptibility in the Chinese population in Taiwan.     

Relationship between HLA-DQ and -DR genotypes and clinical characteristics in a French population of Type 1 diabetic patients.

AIMS: The present study was designed to look for a heterogeneity in the association between Type 1 diabetes mellitus (DM) and class II alleles of major histocompatibility complex (MHC) according to clinical presentation and C-peptide secretion during the first year of the disease, in a population living in south of France. METHODS: HLA DRB1 and DQB1 genotypes were determined in 129 Caucasoid patients with Type 1 DM and compared to a control group (n = 88). In a subgroup of 46 young adult diabetic patients, basal and postglucagon C-peptide secretion was followed during the first year of the disease (at 0, 1, 3, 6, 9 and 12 months). RESULTS: The two main haplotypes associated with Type 1 DM were DRB1*04DQB1*0302 and DRB1*03DQB1*02. The genotypes DRB1* 04DQB1 *0302/DRB1*04DQB1*0302 and DRB1 *03DQB1*02/DRB1*04DQB1* 0302 were associated with an early onset of diabetes, while homozygosity for DRB1*03DQB1*02 was characterized by later onset. Levels of residual insulin secretion in patients genotyped DRB1*03DQA1*0501DQB1* 02/DRB1* 04DQA1*0301DQB1*0302 were higher than in patients genotyped DRB1* 3DQA1*0501DQB1*02/DRB1*XDQA1*XDQB1*X or DRB1* XDQA1* XDQB1*X/DRB1*XDQA1*XDQB1*X. CONCLUSIONS: This study confirms some clinical heterogeneity of Type 1 DM linked to HLA DR and DQ genotypes, and leads to a paradoxical finding: DQB1*02/ DQB1*0302 combination predisposes to an early onset in the whole population but residual secretion of insulin disappears more slowly in a subgroup of young adults with recently diagnosed diabetes. These data suggest that interrelations between MHC genotype and diabetogenic process could be different at various ages of life.     

Histocompatibility leucocyte antigens and closely linked immunomodulatory genes in autoimmune thyroid disease

OBJECTIVES: Associations between autoimmune thyroid disease and antigens of the major histocompatibility complex (MHC) have long been recognized. Graves' disease (GD) is associated with the histocompatibility leucocyte antigen (HLA) haplotype A*01-B*0801-DRB1*0301-DQA1*0501-DQB1*0201 (or B8/DR3) whereas autoimmune hypothyroidism (AIH) has been weakly associated with HLA DRB1*03, *04 and *11/*12 alleles (or DR3, DR4 and DR5). However, the presence of important immunoregulatory genes within the HLA Class II and III regions raises the possibility that these genes harbour the primary susceptibility locus. This study examines genetic variation across the MHC in UK Caucasoid subjects with autoimmune thyroid disease. PATIENTS AND METHODS: DNA extracted from venous blood samples from 215 patients with autoimmune thyroid disease (GD 135, AIH 77) and 267 control subjects was analysed. Genotyping was performed using polymerase chain reaction and sequence specific primers for HLA Class I and II alleles and polymorphisms within the TAP1, TAP2, tumour necrosis factor (TNF), lymphotoxin alpha (LTalpha), heat shock protein (HSP)70-1, HSP70-2 and HSP70-Hom genes. RESULTS: For GD, the strongest association was with DRB1*03 [56% patients positive vs. 24% controls, P = 2 x 10(-10), odds ratio (OR) 4.0]. Positive associations were also seen for DRB1*03 linked alleles, B*0801, DRB3*01/02, DQA1*05, DQB1*02 and DPB1*0101 (OR 2.3-3.4). Specific TNF and LTalpha alleles were strongly associated with GD (Pc = 3 x 10(-5) and 0.001) and weak associations were seen for HSP70-1 + 190C and HSP70-2 + 1267G polymorphisms (Pc = 0.05 and 0.01). These associations were not significant when DRB1*03 status was considered. Patients with AIH showed only a weak association with DQB1*03 (P = 0.02). CONCLUSIONS: These results show that, of the polymorphisms tested within the MHC, GD is most strongly associated with DRB1*03, and associations with other immunoregulatory genes previously described in Caucasian subjects most likely reflect linkage disequilibrium. AIH differs from GD, being less influenced by the MHC region.     

Polymorphism of stress protein HSP70-2 gene in Tunisians: susceptibility implications in type 2 diabetes and obesity

OBJECTIVES: Tumor necrosis factor alpha (TNFalpha) is expressed primarily in adipocytes and elevated levels of this cytokine have been linked to obesity and insulin resistance. Several studies have shown statistical evidence of linkage between obesity and the chromosomal region encompassing the TNFalpha gene, suggesting that TNF alpha and/or a nearby gene is involved in the pathogenesis of obesity. Recently we analyzed the -308 TNFalpha polymorphism and that of HSP70-2 gene in Tunisian patients with obesity and no significant difference in allele frequencies of the -308 TNFalpha polymorphism was found between obese patients and controls. In contrast, polymorphism in HSP70-2 gene was found to be highly associated with obesity. Both TNFalpha and HSP70-2 genes have been mapped within the major histocompatibility complex (MHC). We designated a case-controlled study to investigate a potential association of genetic variation of the TNFalpha and that of the heat shock protein 70-2 (HSP70-2) with type 2 diabetes. METHODS: We used the polymerase chain reaction and restriction enzyme to characterize the variation of the TNFalpha promoter region and that of the HSP70-2 gene in 280 unrelated Tunisian patients with type2 diabetes and 274 healthy control subjects. RESULTS: Analysis of the -308 TNFalpha polymorphism in patients with type 2 diabetes and in control subjects revealed that the heterozygous TNF1/TNF2 genotype was significantly less frequent in the patient group (p=0.003), suggesting that TNF1/TNF2 may be considered as a protective marker against type 2 diabetes (OR=0.58). In contrast, a significant relative risk of type 2 diabetes was found associated with the P2-HSP70-2 homozygous genotype in non obese diabetic subjects (OR=1.97; p=0.0012). CONCLUSION: These results along with those showing high frequency of P2-HSP70-2 genotype in obese Tunisians, suggest that HSP70-2 polymorphism has susceptibility implications in both obesity and diabetes.     

The presence or absence of a retroviral long terminal repeat influences the genetic risk for type 1 diabetes conferred by human leukocyte antigen DQ haplotypes. Belgian Diabetes Registry

Major genetic susceptibility to type 1 diabetes mellitus maps to the human leukocyte antigen (HLA) region on chromosome 6p. During evolution, endogenous retroviral long terminal repeats (LTR) have been integrated at several sites within this region. We analyzed the presence of a solitary HERV-K LTR in the HLA DQ region (DQ-LTR3) and its linkage to DRB1, DQA1, and DQB1 haplotypes derived from 246 German and Belgian families with a patient suffering from type 1 diabetes mellitus. Segregation analysis of 984 HLA DQA1/B1 haplotypes showed that DQ-LTR3 is linked to distinct DQA1 and DQB1 haplotypes but is absent in others. The presence of DQ-LTR3 on HLA DQB1*0302 haplotypes was preferentially transmitted to patients from heterozygous parents (82%; P < 10(-6)), in contrast to only 2 of 7 DQB1*0302 haplotypes without DQ-LTR3. Also, the extended HLA DRB1*0401, DQB1*0302 DQ-LTR3-positive haplotypes were preferentially transmitted (84%; P < 10(-6)) compared with 1 of 6 DR-DQ matched DQ-LTR3 negative haplotypes. DQ-LTR3 is missing on most DQB1*0201 haplotypes, and those LTR3 negative haplotypes were also preferentially transmitted to patients (80%; P < 10(-6)), whereas DQB1*0201 DQ-LTR3-positive haplotypes were less often transmitted to patients (36%). Other DQA1/B1 haplotypes did not differ for DQ-LTR3 between transmitted and nontransmitted haplotypes. Thus, the presence of DQLTR3 on HLA DQB1*0302 and its absence on DQB1*0201 haplotypes are independent genetic risk markers for type 1 diabetes.     

Genetic heterogeneity in susceptibility to autoimmune hepatitis types 1 and 2

OBJECTIVE: Susceptibility to autoimmune hepatitis (AIH) type 1 has been associated with DRB1*03, DRB1*04, and DRB3 alleles in European and North-American whites, with DRB1*04 in Japan, and with DRB1*04 and DRB1*13 in Latin America. Very few studies have been performed on AIH type 2. The aim of the present study was to evaluate the association of AIH types 1 and 2 with HLA-DR and DQ loci. METHODS: We performed HLA-DRB and -DQB1 typing by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) in 139 AIH patients. Most had AIH type 1 associated with circulating anti-smooth muscle antibody with F-actin specificity or antinuclear antibody. Twenty-eight patients presented AIH type 2 with anti-liver/kidney microsome type 1 or anti-liver cytosol type 1 antibodies. RESULTS: We observed a significant increase of DRB1*13 (70% vs 26% of controls, p < 0.00001) and DRB3 (93% vs 69% of controls, p < 0.00001) in AIH type 1 patients. Analysis of patients without DRB1*13 disclosed a secondary association with DRB1*03 (70% vs 30% of controls, p = 0.0001) and either the DRB1*13 or the DRB1*03 alleles were present in the majority of these patients (91% vs 48% of controls, p = 0.001). Comparison of DRB1*13- and DRB1*03-positive subjects revealed that the former alleles conferred susceptibility to younger patients with AIH type 1. DQB1 typing showed a significant increase in DQB1*06 (68% vs 41% of controls, p = 0.00007) in strong linkage disequilibrium with DRB1*13, and a decrease in DQB1*0301 (8% vs 47% of controls, p(c) = 0.0003). On the other hand, HLA typing of patients with AIH type 2 disclosed a significant increase in the DRB1*07 (68% vs 20% of controls, p(c) < 0.00014), DRB4 (79% vs 43% of controls, p(c) = 0.004), and DQB1*02 (86% vs 42%, p = 0.00002) alleles. After exclusion of DRB1*07, a secondary association with HLA-DRB1*03 was further observed in these patients (78% vs 30%, p = 0.007) and most of them had either DRB1*07 or DRB1*03 (93% vs 44% of controls, p(c) < 0.0001). CONCLUSIONS: Our data indicate that predisposition to AIH types 1 and 2 is associated, respectively, with the DRB1*13 or DRB1*03 and DRB1*07 or DRB1*03 alleles, and suggest that protection against type 1 disease may be conferred by DQB1*0301. In addition, the cluster of DRB1*13 in children with AIH type 1 also supports the concept that different HLA alleles might influence the onset of the disease.     

Sequence analysis of the diabetes-protective human leukocyte antigen-DQB1*0602 allele in unaffected, islet cell antibody-positive first degree relatives and in rare patients with type 1 diabetes.

The human leukocyte antigen (HLA)-DQA1*0102/DQB1*0602/DRB1*1501 (DR2) haplotype confers strong protection from type 1 diabetes. Growing evidence suggests that such protection may be mostly encoded by the DQB1*0602 allele, and we reported that even first degree relatives with islet cell antibodies (ICA) have an extremely low diabetes risk if they carry DQB1*0602. Recently, novel variants of the DQB1*0602 and *0603 alleles were reported in four patients with type 1 diabetes originally typed as DQB1*0602 with conventional techniques. One inference from this observation is that DQB1*0602 may confer absolute protection and may never occur in type 1 diabetes. By this hypothesis, all patients typed as DQB1*0602 positive with conventional techniques should carry one of the above diabetes-permissive variants instead of the protective DQB1*0602. Such variants could also occur in ICA/DQB1*0602-positive relatives, with the implication that their diabetes risk could be significantly higher than previously estimated. We therefore sequenced the DQB1*0602 and DQA1*0102 alleles in all ICA/DQB1*0602-positive relatives (n = 8) previously described and in six rare patients with type 1 diabetes and DQB1*0602. We found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them has the mtDNA A3243G mutation associated with late-onset diabetes in ICA-positive individuals. These findings suggest that diabetes-permissive DQB1*0602/3 variants may be very rare. Thus, although the protective effect associated with DQB1*0602 is extremely powerful, it is not absolute. Nonetheless, the development of diabetes in individuals with DQB1*0602 remains extremely unlikely, even in the presence of ICA, as confirmed by our further evaluation of ICA/DQB1*0602-positive relatives, none of whom has yet developed diabetes.     

HLA class II is a factor in cardiovascular morbidity and mortality rates in patients with type 1 diabetes

Aims/hypothesis

Patients with type 1 diabetes and kidney disease have a higher risk of cardiovascular events. HLA class II genes are expressed on infiltrated inflammatory cells and smooth-muscle cells in atherosclerotic plaques. We hypothesised that HLA class II haplotypes or genotypes might influence the risk of cardiovascular complications and death in Finnish type 1 diabetic patients.

Methods

We included 3,082 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. We analysed the 12 and ten most common HLA II haplo- and genotypes, respectively, using χ ² tests. The positive findings were analysed with three differently adjusted regression models with cardiovascular morbidity and death as endpoints. Different kidney status groups were analysed separately.

Results

At baseline, the common (DR1/10)-DQB1*05:01 haplotype (20.4%) and the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype (8.7%) were independently associated with cardiovascular disease in all kidney status groups, except in patients with normal AER. At follow-up (9.45?years; range 0.1–16.1?years), the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype was associated with cardiovascular mortality rates in patients with normal AER and microalbuminuria.

Conclusions/interpretation

The (DR1/10)-DQB1*05:01 haplotype and the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype are independently associated with cardiovascular events and death in Finnish type 1 diabetic patients.     

Susceptibility markers in Tunisian first-degree relatives of patients with type 1 diabetes

To identify the profile of anti-pancreas autoantibodies and elucidate the HLA DRB1, DQB1 polymorphism in Tunisian first-degree relatives of patients with type 1 diabetes, we recruited 96 relatives from 21 families with at least one diabetic child. Islet cell antibodies (ICA) were detected by immunofluorescence on monkey pancreas; glutamate decarboxylase (GADA), IA2 (IA2-A) and insulin (IAA) antibodies were measured by RIA. HLA class II DRB1 and DQB1 alleles were typed by PCR-SSP. ICA, GADA, IA2-A and IAA were found in respectively 11.5, 4.2, 5.2 and 8.3% of relatives. Twenty-two out of 96 had at least one antibody and 20 out of these 22 had a susceptibility allele (DRB1*03, DRB1*04, DQB1*02 or DQB1*0302) with or without protective allele (DRB1*11, DRB1*13, DRB1*15 or DQB1*06). All of the 5 relatives having 2 autoantibodies or more carried the DRB1*04-DQB1*0302 susceptible haplotype. In conclusion, this observational study confirms in a Tunisian population known epidemiological data and demonstrates the usefulness of follow-up to determine the predictive value of studied markers.     

人类白细胞相关抗原HLA DQB1基因与IDDM的关联

利用ＰＣＲ／ＳＳＯ方法对ＩＤＤＭ病人，ＬＡＤＡ病人，ＮＩＤＤＭ病人以及健康对照者进行ＨＬＡ ＤＱＢ１基因分型。结果发现ＤＱＢ１＊０２０１及ＤＱＢ１＊０３０２在ＬＡＤＡ组显著增高，分别为５３．４％，６６．７％比正常组的１９．５％和３４．２％。与正常组相比，ＤＱＢ１＊０３０２在ＩＤＤＭ组显著增高，为９１．１％比３４．２％。     

AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is a rare autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22.3. This monogenic disease provides an interesting model for studies of other common and more complex autoimmune diseases. The most common components of APECED are chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease, but several other endocrine deficiencies and ectodermal dystrophies also occur and the phenotype varies widely. The AIRE genotype also varies; 42 different mutations have been reported so far. To understand the complexity of the phenotype, we studied the AIRE and human leukocyte antigen (HLA) class II genotypes in a series of patients with APECED. The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, R257X, than in those with other mutations. Addison's disease was associated with HLA-DRB1*03 (P = 0.021), alopecia with HLA-DRB1*04- DQB1*0302 (P < 0.001), whereas type 1 diabetes correlated negatively with HLA-DRB1*15-DQB1*0602 (P = 0.036). The same HLA associations have previously been established for non-APECED patients. We conclude that mutation of AIRE per se has little influence on the APECED phenotype, whereas, in contrast to earlier reports, HLA class II is a significant determinant.     

Disease-associated autoantibodies as surrogate markers of type 1 diabetes in young children at increased genetic risk. Childhood Diabetes in Finland Study Group

To evaluate the emergence of diabetes-associated autoantibodies in young children and to assess whether such antibodies can be used as surrogate markers of type 1 diabetes in young subjects at increased genetic risk, we studied 180 initially unaffected siblings (92 boys and 88 girls) of children with newly diagnosed type 1 diabetes. All siblings were younger than 6 yr of age at the initial sampling, and they were monitored for the emergence of islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) up to the age of 6 yr and for progression to clinical type 1 diabetes up to the age of 10 yr. All 160 siblings with DNA samples available were typed for susceptible (DQB1*02 and *0302) and protective (DQB1*0301 and *0602-03) HLA DQB1 alleles. Twenty-two siblings (12.2%) tested positive for ICA in their first antibody-positive sample before the age of 6 yr, 13 (7.2%) tested positive for IAA, 15 (8.3%) tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There were 16 siblings (8.9%) who had 1 detectable autoantibody, 5 (2.8%) had 2, and 12 (6.7%) had 3 or more. In the group of 82 siblings with increased human leukocyte antigen-defined genetic susceptibility [DQB1*02/*0302, *0302/x (x = other than *02 or a protective allele), *02/y (y = other than *0302 or a protective allele)], 18 (22.0%) tested positive for ICA in their first antibody-positive sample, 10 (12.2%) tested positive for IAA, 14 (17.1%) tested positive for GADA, and 12 (14.6%) tested positive for IA-2A. One antibody was detectable in 6 siblings (7.3%), 2 were detectable in 5 (6.1%), and 3 or more were detectable in 12 (14.6%). Fifteen siblings (18.3%) presented with clinical type 1 diabetes before the age of 10 yr. All of the progressors showed increased human leukocyte antigen-defined genetic susceptibility. Thirteen of those 15 siblings, who presented with clinical type 1 diabetes before the age of 10 yr, had at least 2 antibodies detectable before the age of 6 yr (disease sensitivity, 87%; 95% confidence interval, 60-98%). Thirteen of the 17 siblings who tested positive for 2 or more autoantibodies before the age of 6 yr developed type 1 diabetes before the age of 10 yr (positive predictive value, 76%; 95% confidence interval, 50-93%). These observations suggest that disease-associated autoantibodies can well be used as surrogate markers of clinical type 1 diabetes in primary prevention trials targeting young subjects with increased genetic disease susceptibility.