HLA-DRB1*0401 IS ASSOCIATED WITH SUSCEPTIBILITY TO INSULIN-DEPENDENT DIABETES MELLITUS INDEPENDENTLY OF THE DQB1 LOCUS

The distribution of DRB1*04 alleles and DRB1/DQB1 haplotypes was analysed in 57 DR4⁺ caucasoid subjects with insulin-dependent diabetes mellitus (IDDM) and 96 DR4⁺ healthy controls selected on the basis of DR serology, and the findings were analysed in relation to age at diagnosis of IDDM. DNA samples were amplified using specific DR and DQ primers and hybridized with sequence-specific oligonucleotide probes. A significantly increased combined frequency of DRB 1*0401 and 0402 was observed in IDDM subjects aged ≤12 years at diagnosis (allele frequency 88.4% compared with 62.0% in controls, P < 0.025). There was a non-significant increase in DRB 1*0401 and 0402 in IDDM subjects ≤12 years when compared with IDDM subjects >12 years (P < 0.1). DRB 1 *0404 was decreased in the total IDDM subject group compared with controls (4.8% vs. 19.0%, P < 0.025) but did not reach statistical significance in the individual age at diagnosis groups. In contrast, the frequency of DQB1 *0302 was increased uniformly across both ages at diagnosis groups. In controls DRB 1*0401 occurred in haplotype association with DQB 1*0301 in a significantly greater frequency than with DQB 1*0302. However, 95.0% of DRB 1*0401 IDDM subjects were DQB 1*0302. DRB 1*0404, which was decreased in frequency in IDDM subjects, occurred in association significantly more frequently with DQB 1 *0302 in controls. These results imply that DRB 1 and DQB 1 have independent roles as HLA susceptibility genes in IDDM. DQB1 may have a permissive role whereas DRB1 could influence the rate at which underlying disease progresses to clinical IDDM.     

HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations

The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).     

The distribution of DR4 haplotypes in sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci

The contribution of genetic variation at HLA class II loci to the susceptibility to and protection from IDDM was investigated by analyzing the distribution of HLA-DRB1^*04 haplotypes in 630 Sardinian newborns and 155 Sardinian IDDM patients. The different RRs and ARs of the various DR4-DQB 1^*0302 haplotypes, significantly ranging from the strongly associated DRB 1^*0405, DQB 1^*0302 to the protective DRB 1^*0403, DQB 1^*0302 haplotypes, provides clearcut evidence that the DRB 1 locus is crucial in conferring IDDM predisposition or protection. Also, the DQB1 locus influences IDDM predisposition or protection by restricting the disease-positive association to DRB 1^*0405 haplotypes carrying the susceptibility DQB 1^*0302 or DQB 1^*0201 alleles but not the protective DQB 1^*0301 allele. Haplotype analysis not only suggests that the DRB 1 and DQB1 loci influence IDDM risk in the same way, but also that the HLA-linked protection is “dominant” compared with “susceptibility.” These results, obtained from a population with one of the highest IDDM incidences in the world, define more clearly the contribution of the various HLA loci to IDDM protection or susceptibility and allow a more precise calculation of AR.     

HLA-DRB1、DQB1基因与汉族人群寻常型天疱疮的相关性研究

目的　探讨 HL A- DRB1、DQB1位点基因在汉族人群寻常型天疱疮易感性中的作用。方法用序列特异性引物 -聚合酶链反应方法 ,对 6 1例寻常型天疱疮 (pemphigus vulgaris,PV)患者和 5 7名正常对照进行了 HL A- DRB1、DQB1等位基因的分型 ,并分析了 DRB1、DQB1基因在两组中的分布。结果　与正常对照组比较 ,PV组 DR4、DRB1* 14 (* 14 0 1、* 14 0 4、* 14 0 5 )基因频率明显增高 (Pc分别 <0 .0 5及P<0 .0 1) ,差异有显著性 ;PV组 DQB1* 0 5 0 3、DQB1* 0 30 2基因频率明显增高 (Pc均 <0 .0 5 ) ,差异有显著性。对 DR4阳性样本的组内基因亚型分型结果发现 ,PV组中 DRB1* 0 4 0 3、DRB1* 0 4 0 6频率显著增高(Pc<0 .0 5 ) ,差异有显著性。 PV患者组单倍型 HL A- DRB1* 0 4 ,DQB1* 0 30 2和 HL A- DRB1* 14 ,DQB1* 0 5 0 3频率明显增高 (P<0 .0 5 )。结论　HL A- DRB1* 0 4 ,DQB1* 0 30 2和 HL A- DRB1* 14 ,DQB1* 0 5 0 3可能是汉族人 PV推测的易感单倍型。     

The HLA-DRB1*0405 haplotype is most strongly associated with IDDM in Algerians.

Insulin-dependent diabetes mellitus (IDDM) in Caucasians is strongly associated with HLA-DR3-DQ2 and DR4-DQ8. In order to investigate the HLA class II associations with IDDM in Algerians, we have used polymerase chain reaction (PCR) and sequence specific oligonucleotide analysis (SSO) to identify DQA1, DQB1, and DRB1 alleles, haplotypes and genotypes in 50 unrelated IDDM patients and 46 controls from a homogeneous population in Western Algeria. Both DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) haplotypes were found at increased frequencies among the patients compared to controls (45% vs. 13%, RR = 5.5, Pc < 10(-5) and 37% vs. 4%, RR = 12.9, Pc < 10(-4), respectively). Among the latter, in contrast to other Caucasian populations, only DRB1*0405-DQA1*0301-DQB1*0302 was significantly increased in the Algerian patients (25% vs. 1% in controls, RR = 30.3, Pc < 10(-3). Accordingly, the highest risk of disease was observed in DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0405-DQA1+ ++*0301-DQB1*0302 heterozygotes (34% in patients vs. 0% in controls; RR = 49; Pc < 10(-3). This observation and its comparison with DR-DQ haplotypes in other ethnic groups suggest that the DRB1*0405 allele which encodes an Asp57-negative beta chain may contribute to IDDM susceptibility in a similar way as Asp57-negative DQ beta chains.     

The influence of age at onset and gender on the HLA-DQA1, DQB1 association in Chinese children with insulin dependent diabetes mellitus

Certain alleles of human leukocyte antigen (HLA)-DR and -DQ genes have been strongly associated with susceptibility and resistance to insulin- dependent diabetes mellitus (IDDM). To further clarify the association of HLA DQ alleles with IDDM and the influence of age at onset and gender on the association with IDDM, we investigated the association of HLA-DQA1, -DQB1 in 54 childhood onset Chinese (21 male) IDDM patients and 65 normal controls by using polymerase chain reaction-sequence specific primer (PCR-SSP). The mean age plus or minus SD at onset of IDDM patients was 8.37+/-3.54 year old. Our results revealed that the frequencies of DQA1 *0301, *0302, DQB1 *0201, and *0302 in IDDM patients were significantly higher than that in the control group (p < 0.025, < 0.005, < 0.001, and < 0.001, respectively). The frequency of DQA1 *0301, *0302, DQB1 *0201, and *0302 were susceptible alleles to IDDM with relative risks of 2.0, 3.5, 5.0 and 4.3, respectively. The protective alleles to IDDM were DQA1 *0101, *0103, DQB1 *0301, *0503, and *0602. We divided IDDM patients into three groups according to age at onset (1-5, 6-10, and 11-15 years old). The frequency of DQA1 *0302 decreased as age increased, and the frequency of DQA1 *0501 increased as age increased. Our results also showed that male IDDM patients had higher frequencies of DQA *0501, DQB1 *0201 than female IDDM patients (p < 0.025 and < 0.025, respectively), while female IDDM patients had higher frequencies of DQB1 *0502 than male IDDM patients (p < 0.05). In our study significant susceptibility haplotypes to IDDM were DQA1 *0301-DQB1 *0302, DQA1 *0501-DQB1 *0201, DQA1 *0301-DQB1 *0201, and DQA *0302-DQB1 *0201.     

Prevalence of human leukocyte antigen DQA1 and DQB1 alleles in Kuwaiti Arab children with type 1 diabetes mellitus

The prevalence of human leukocyte antigen (HLA) DQB1 and DQA1 alleles has been determined in 78 Kuwaiti Arab children with insulin-dependent diabetes mellitus (IDDM) and in 57 normal healthy controls with similar ethnic background. The typing of HLA-DQ alleles was carried out using an allele-specific DNA-based polymerase chain reaction (PCR) SSP method. DR typing was also performed in 212 control subjects using PCR-SSP (sequence specific primer) method. A significantly higher frequency of DQB1*0201 allele was found in IDDM cases compared to the controls (p<0.001). There was no significant difference in the prevalence of DQB1 alleles *0302, *0501, and *0602 between IDDM cases and the controls. In contrast, DQB1 alleles *0301, *0402, *0502, *0602, and *0603 were represented at a somewhat higher frequency in controls compared to the IDDM cohort. The frequency of DQA1 allele *0301, which encode for an Arg at codon 52, was significantly higher in the IDDM patients compared to the controls (p<0.001). The frequency of DQA1 allele *0302 was also higher in IDDM cases than controls (p = 0.034) but the difference was less pronounced than DQA1*0301. Amongst the Arg52 alleles, no significant difference was detected in the frequency of *0401 between IDDM cases and the controls and the allele *0501 was detected only in controls. For non-Arg52 alleles *0103, *0104, and *0201, the differences in the two groups were not significant, with the exception of allele *0104 (p = 0.024). DR3 was the most common type in the Kuwaiti general population (28%) and DRB1*0301 was detected in 41% of the individuals with DR3 specificity. Analysis of HLA-DQBI/DQA1 haplotypes from IDDM cases and controls revealed a significantly high frequency of haplotype DQA1*0301/DQB1*0201 between Kuwaiti IDDM cases (49/78, 63%) and the controls (8/57, 14%).     

HLA-DQ8 and the HLA-DQ8-DR4 haplotype are positively associated with the hevein-specific IgE immune response in health care workers with latex allergy

BACKGROUND: Hevein is one of the most important latex allergens affecting health care workers (HCWs). OBJECTIVE: Because the genetically determined susceptibility is one important factor regulating type I allergy, the association between the hevein-specific IgE immune response and HLA class II alleles of DQB1 and DRB1, DRB3, DRB4, and DRB5 was studied. METHODS: The distribution of HLA-DQB1 and DRB1, DRB3, DRB4, and DRB5 in 269 HCWs with latex allergy, 56 latex-sensitized patients with spina bifida (SB), and 90 nonatopic control subjects under special consideration for hevein-specific IgE was examined. RESULTS: Seventy percent (189/269) of the HCWs with latex allergy and 39% (22/56) of the latex-sensitized patients with SB had increased hevein-specific IgE antibody concentrations (>0.35 kU/L). HLA data analysis revealed significantly increased phenotype frequencies for DQB1*0302 (DQ8; 91/189 [48%]) and DRB1*04 (DR4; 102/189 [54%]) in hevein-positive HCWs with latex allergy compared with the 80 hevein-negative HCWs with latex allergy (DQB1*0302: 16/80 [20%], corrected P value [P (c)] = 7.1 x 10(-4); DRB1*04: 23/80 [29%], P (c) =.01) and with control subjects (DQB1*0302: 16/89 [18%], P (c) = 1 x 10(-4); DRB1*04: 22/90 [24%], P (c) = 3.2 x 10(-4)). The DQ8-DR4 haplotype frequency was significantly elevated in HCWs with hevein-specific IgE antibodies when compared with that in HCWs without hevein-specific IgE antibodies (47% vs 18%, P (c) = 5.3 x 10(-4)) or control subjects (47% vs 18%, P (c) = 9.6 x 10(-4)). In contrast, latex-sensitized patients with SB with hevein-specific IgE antibodies showed an increased but not significant DQB1*0302 frequency (7/22 [32%] vs 2/34 [6%], P =.02, P (c) = not significant) compared with that seen in those without hevein-specific IgE antibodies. CONCLUSION: The DQB1*0302 (DQ8) alone, the DQB1*0302 (DQ8)-DRB1*04 (DR4) haplotype, or both are significantly involved in the hevein-specific IgE immune response in HCWs with latex allergy.     

POLYMORPHISMS OF TAP1 AND TAP2 GENES IN GERMAN PATIENTS WITH TYPE 1 DIABETES MELLITUS

Type 1 diabetes mellitus (IDDM) is an autoimmune disorder in which the alleles HLA DQA1*0501–DQB1*0201 and DQA1*0301–DQB1*0302 confer strong susceptibility. The genes for transporters associated with antigen processing (TAP1 and TAP2) are located near HLA DQ and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to IDDM possibly by selection of different antigen peptides, we investigated sequence variants of TAP1 and TAP2 genes in 120 German patients with IDDM and 218 random healthy German controls by polymerase chain reaction (PCR) followed by sequence-specific oligonucleotide analysis (SSO), single-strand conformation polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*02011 (16% vs. 4% in controls, P = 0.001, RR = 5.0) and TAP2*0101 (96% vs. 69% in controls, P < 0.0001, RR = 10.6) showed a positive association with IDDM. However, these associations disappeared when patients and controls were matched for predisposing HLA DQA1 or DQB1 alleles as well as for DRB1*0401. In conclusion, our findings indicate that the observed association of TAP variants with IDDM in German patients is due to linkage disequilibrium with HLA DQ alleles/DRB1*04 subtypes.     

Complex interaction between HLA DR and DQ in conferring risk for childhood type 1 diabetes.

Type 1 (insulin-dependent) diabetes mellitus is associated with HLA DR and DQ factors, but the primary risk alleles are difficult to identify because recombination events are rare in the DQ-DR region. The risk of HLA genotypes for type 1 diabetes was therefore studied in more than 420 incident new onset, population-based type 1 diabetes children and 340 age, sex and geographically matched controls from Sweden. A stepwise approach was used to analyse risk by relative and absolute risks, stratification analysis and the predispositional allele test. The strongest relative and absolute risks were observed for DQB1*02-DQA1*0501/DQB1*0302-DQA1*0301 heterozygotes (AR 1/46, P < 0.001) or the simultaneous presence of both DRB1*03 and DQB1*0302 (AR 1/52, P < 0.001). Stratification analysis showed that DQB1*0302 was more frequent among DRB1*04 patients than DRB1*04 controls (P < 0.001), while DRB1*03 was more frequent among both DQA1*0501 (P < 0.001) and DQB1*02 (P < 0.001) patients than respective controls. The predispositional allele test indicated that DRB1*03 (P < 0.001) would be the predominant risk factor on the DRB1*03-DQA1*0501-DQB1*02 haplotype. In contrast, although DQB1*0302 (P < 0.001) would be the predominant risk factor on the DRB1*04-DQA1*0301-DQB1*0302 haplotype, the predispositional allele test also showed that DRB1*0401, but no other DRB1*04 subtype, had an additive risk to that of DQB1*0302 (P < 0.002). It is concluded that the association between type 1 diabetes and HLA is due to a complex interaction between DR and DQ since (1) DRB1*03 was more strongly associated with the disease than DQA1*0501-DQB1*02 and (2) DRB1*0401 had an additive effect to DQB1*0302. The data from this population-based investigation suggest an independent role of DR in the risk of developing type 1 diabetes, perhaps by providing diseases-promoting transcomplementation molecules.     

HLA-DR and -DQ associations with insulin-dependent diabetes mellitus in a population of Turkey

Genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) has been shown to be associated with MHC in many studies. To extend this data with a population with relatively low IDDM incidence, MHC DRB, DQA, and DQB have been investigated by polymerase chain reaction and sequence specific oligonucleotide probe hybridization (PCR/SSO) in 178 IDDM patients from Turkey and compared to 248 healthy controls. Significant differences are detected between IDDM and control groups in the frequencies of DRB1*0402 DQA1*03 DQB1*0302 (28.1% vs. 5.2%, p < 0.0001, OR: 7.1) and DRB1*0301 DQA1*0501 DQB1*02 (57% vs. 18.1%, p < 0.0001, OR: 6.1). Among the negative associations, the most strong ones are with DRB1*1401 DQA1*0101 DQB1*0503 (0.6% vs. 8.9%, p < 0.0001, OR: 0.1), DRB1*1502 DQA1*0103 DQB1*0601 (1.1% vs. 7.7%, p = 0.0023, OR: 0.1), DRB1*1301 DQA1*0103 DQB1*0603 (0.6% vs. 6.9%, p = 0.0039, OR: 0.2) and DRB1*1101 DQA1*0501 DQB1*0301 (3.9% vs. 12.1%, p < 0.0001, OR: 0.2). When the DRB, DQA or DQB genotypes of the susceptible alleles are compared, the most strong susceptibility marker of the disease is found to be DRB1*0301/*04 (31.4% vs. 2.8%, p < 0.0001, OR: 15.8) and among these, heterozygote genotype DRB1*0301/*0401 (4.5% vs. 0, p = 0.0008, OR: 24.8).These results confirm the positive associations with IDDM previously observed in other Caucasian populations and reveal many negative and strong associations which maybe underlining several characteristics that distinguish Turkish diabetics form other Caucasians.     

HLA-DR4 SUBTYPE AND -B ALLELES IN DQB1*0302-POSITIVE HAPLOTYPES ASSOCIATED WITH IDDM

We determined the distribution of DR4 subtypes in 309 DQB1*0302-positive haplotypes found in insulin-dependent diabetes mellitus (IDDM) patients and 70 control haplotypes present only in healthy family members. An increased frequency of DRB1*0401 allele (74.4% vs. 55.7%, P = 0.003) and a decrease of DRB1*0404 allele (23.6% vs. 40.0%, P = 0.0064) was revealed. A further analysis of extended haplotypes demonstrated strong linkages between various B alleles and DRB1*04 subtypes. HLA-B39 was more frequent in DRB1*0404–DQB1*0302-positive IDDM haplotypes compared with control ones (37.0% vs. 14.3%, P = 0.049), suggesting an involvement of the region telomeric to HLA-DRB1 in the susceptibility to IDDM.     

Diabetes mellitus in adults: association of HLA DRB1 and DQB1 diabetes risk alleles with GADab presence and C-peptide secretion

In our study, we investigated the relationship of HLA class II alleles to antibody production against glutamic acid decarboxylase (GADab) and to C-peptide secretion (CP) in diabetic patients. A group of 334 patients (190 women) diagnosed after 35 years of age and 99 control subjects were studied. Patients were divided into four groups according to concentrations of CP and GADab, respectively (CP high/low, GADab positive/negative). HLA DQB1 and DRB1 alleles were genotyped by SSP-PCR. The significance of DQB1 and DRB1 risk alleles was evaluated by examination of their odds ratios computed by testing 2x2 tables considering Bonferonis' corrected P<0.05 as significant. We found strong association between the HLA DRB1*03 risk allele and presence of GADab, and close relationship of the HLA DRB1*04 and HLA DQB1*0302 risk alleles with decreased CP level. Taken together we conclude that the DRB1*04 and DQB1*0302 alleles are associated with progressive decrease of CP level, while DRB1*03 is a significant genetic marker of autoantibody (GADab) development.     

Human leukocyte antigen class II allele association to disease progression in Iranian patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in Western countries, but its incidence is low in Asian populations. In the present study we determined the frequency of DRB1 and DQB1 alleles in 87 Iranian CLL patients and 100 healthy controls using a polymerase chain reaction (PCR) technique. An increased frequency of DRB1*07 (p = 0.04), DQB1*06 (p = 0.01) alleles, and DRB1*13/DQB1*03 haplotype (p = 0.01) and decreased frequency of the DQB1*03 (p = 0.01) allele were observed in our patients compared with healthy controls. Comparison between patients with indolent (n = 42) and progressive (n = 38) disease revealed a significant increase in DRB1*04 and DRB5 alleles in progressive patients. Similarly, a higher frequency of DRB5 (p = 0.01) allele was observed in CD38(+) compared with CD38(-) patients. Classification of the patients into immunoglobulin variable region heavy-chain genes mutated and unmutated subtypes did not reveal significant differences for the expression of any of the HLA alleles or haplotypes between these two subtypes. Our findings observed in an Iranian population indicate that CLL could be associated with distinct HLA class II alleles and haplotypes of which the DQB1*06 allele and DRB1*13/DQB1*03 haplotype have not already been reported in CLL patients from other ethnic backgrounds. Some HLA class II alleles may contribute to disease progression in CLL.     

Immunogenetics of HLA class II in Israeli patients with adult-onset type 1 diabetes mellitus

The distribution of HLA class II alleles and genotypes in Israelis of different ethnic origin with adult-onset type 1 diabetes (T1D) was examined. The results were compared with published findings in healthy Israelis and childhood-onset T1D Israelis. An additional comparison was made between subgroups of patients with rapidly and slowly progressive adult-onset T1D (LADA). A DNA-based low-resolution analysis was performed for DRB1* and DQB1* alleles and a high-resolution analysis for DRB1*04 and DQB1*1 alleles. In all, 87% of the study group was positive for DRB1*03 or DRB1*04 compared with 36% of the healthy controls. The main alleles accounting for susceptibility to T1D were DRB1*0402, found in 77.9% of carriers of DRB1*04 and DQB1*0302, found in 74.6% of carriers of DQB1*03. The DQB1*0602 was not detected in any patient. The distribution was similar to that reported in Israeli children with T1D and significantly different from healthy Israelis. There was no significant difference in the distribution of HLA class II alleles between patients with rapidly progressive T1D or LADA. It may be concluded that the different ages of onset of T1D and its different forms of development in Israeli patients are apparently not caused by a different prevalence of HLA class II alleles.     

DR4 subtypes and their molecular properties in a population-based study of Swedish childhood diabetes

The aim of this study was to determine the association between childhood insulin-dependent diabetes mellitus (IDDM) and HLA-DR4 subtypes and to test in a population-based investigation whether the DR4 association has an effect independent to that of DQ. First, HLA genotyping identified DR4 in 337/425 (79%) patients and 148/367 (40%) controls (Odds Ratio 5.67; p<0.01). Second, a total of 14 DR4 subtypes were detected by PCR and sequence specific oligo probes. Only two DR4 subtypes, DRB1*0401 (62% patients and 25% controls; OR 4.95, p<0.01) and *0404 (16% patients and 10% controls; OR 1.67, p<0.05) were however positively associated with the disease. These two subtypes were positively associated only when linked to DQB1*0302-DQA1*0301 (DQ8) (56% patients and 14% controls; OR 7.69, p<0.01; 15% patients and 10% controls; OR 1.55, p<0.05, respectively). When DRB1*0401 was linked to DQB1*0301-DQA1*0301 (DQ7) (6% patients and 11% controls; OR 0.52, p<0.05), this DR4 subtypes was negatively associated with IDDM. Third, tests of strongest association allowed the following ranking of alleles or haplotypes: DQB1*0302-DQA1*0301 (DQ8) >DQB1*0302 > DRB1*0401 >DRB1*0404 and the association of DRB1*0401 has a significant effect in DQ8 positive IDDM patients. We conclude that the DR4 association with IDDM is secondary to DQ by linkage disequilibrium, which support the role of HLA-DQ as a primary genetic risk factor for IDDM.     

Human leukocyte antigen non-class II determinants for type 1 diabetes in the Finnish population

We explored the contribution of non-class II HLA loci to type 1 diabetes genetic susceptibility in the Finnish population. We analyzed 11 markers covering a 4-Mb region telomeric to the DQB1 gene in Finnish nuclear families with parents carrying either the DR8-DQB1*04 (n=188) or the DRB1*0404-DQB1*0302 haplotypes (n=135). On the DRB1*0404-DQB1*0302 haplotype we found independent disease association of the D6S273 and C125 markers (p(corr) = 10(-4) and 0.0095, respectively). The C125*200 alleles on this haplotype conferred an increased disease risk (OR = 3.6; p = 0.003). The B*39 allele also showed disease association (OR = 2.6; p = 0.054). The C125*200 allele appeared at an increased frequency also on transmitted B39 positive DRB1*0404-DQB1*0302 haplotypes, suggesting an independent effect. In addition, the C143*417 allele on the DRB1*08-DQB1*04 haplotype was associated with decreased disease risk (OR = 0.48, p = 0.003). Our data confirm that non-class II HLA loci affect genetic susceptibility to type 1 diabetes. In addition to HLA B*39 the C125 locus contributes to disease risk on the Finnish DRB1*0404-DQB1*0302 haplotypes. Another locus close to D6S273 may also have an effect. For the first time we report that a locus near the C143 marker appear to affect disease association of the DRB1*08-DQB1*04 haplotype.     

Endogenous retroviral long terminal repeats of the HLA-DQ region are associated with susceptibility to insulin-dependent diabetes mellitus

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HERV-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 ^*0301 and DQB1 ^*0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 × 10^{− 5}), even after matching for the high-risk alleles DQA1 ^*0501, DQB1 ^*0201-DQA1 ^*0301, and DQB1 ^*0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 ^*04 alleles in all DQB1 ^*0302 ⁺ individuals showed 56% DRB1 ^*0401, DQB1 ^*0302 [LTR⁺ patients vs. 29% controls with the same haplotype (p < 0.002). In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 ^*0401-, DQA1 ^*0301-, and DQB1 ^*0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM. Human Immunology 50, 103–110 (1996)     

HLA in Czech adult patients with autoimmune diabetes mellitus: comparison with Czech children with type 1 diabetes and patients with type 2 diabetes.

Type 1 diabetes results from an autoimmune insulitis, associated with HLA class II alleles. The evidence about HLA allele association is not clear in patients diagnosed after 35 years of age. In this study we have analyzed HLA alleles of DQB1 and DRB1 genes by sequence specific primer (SSP)-PCR technique in adult patients with disease onset after 35 years of age. Two hundred and eighty-one patients were divided into three groups according to the insulin therapy, the level of C peptide (CP), and GAD antibodies (anti-GAD). Group 1 (type 1 diabetes in adults) was characterized by CP less than 200 pmol/L and anti-GAD more or less than 50 ng/mL (n = 80). All of them had insulin therapy within 6 months after diagnosis. Group 2 latent autoimmune diabetes mellitus in adults (LADA) was defined by a minimum 6-month-long phase after diagnosis without insulin therapy, and was characterized by CP more than 200 pmol/L and anti-GAD more than 50 ng/mL (n = 70). Group 3 (type 2 diabetes) was characterized by CP more than 200 pmol/L and anti-GAD less than 50 ng/mL (n = 131). None ever had insulin therapy. In group 1, there was increased frequency of DRB1*04 (45.0% vs. controls 14.1%, OR = 5.0, P < 0.0005) and DQB1*0302 alleles (43.3% vs. controls 11.1%, OR = 6.1, P < 0.00005). There was increased frequency of DRB1*03 and DQB1*0201, and decreased frequency of DQB1*0602 (3.3% vs. controls 20.2%), but it was not significant. In group 2, there was a significantly increased frequency of DRB1*03 only (50.0% vs. controls 21.2%, OR = 3.7, P < 0.05). Compared with children with type 1 diabetes and adults with type 2 diabetes (group 3), we conclude that the presence of predisposing DQB1 alleles in adults with type 1 diabetes decreases with the age, probably due to environmental factors. Only the DRB1*03, but not the DQB1 gene, becomes the main predisposing allele in LADA patients. These findings suggest that the presence of HLA-DQB1*0302 identifies patients at high risk of requiring insulin treatment. Type 1 diabetes mellitus (DM) in children or adults may have partly different immunogenetic etiopathogenesis than LADA.