HLA class II antigens in South African Blacks with type I diabetes

Type 1 diabetes mellitus is poorly characterised in many African communities, including South Africa, where little is known of the disease epidemiology. This study aimed to identify the HLA class II alleles associated with type 1 diabetes in a group of Zulu subjects in Durban, KwaZulu-Natal by PCR-SSP. The HLA alleles associated with type 1 diabetes included HLA-DQB*0302 (P<0.0001), DRB1*O9 (P<0.0001), DRB1*04 (P=0.002), DRB1*0301 (P=0.003), DQB*02 (P=0.004) and DQA*03 (P=0.035). Estimated haplotypes positively associated with type 1 diabetes included HLA-DRB1 *0301-DQA*0501, DRB1*04-DQA*03, DRB1*04-DQB*0302, DRB1*0301-DQB*0201, DQA*0501-DQB*0201 and DQA*03-DQB*0302. These findings are similar to those reported from Zimbabwe and other populations with type 1 diabetes.     

HLA DR/DQ alleles and risk of type I diabetes in childhood: a population–based case–control study

Abstract The objective was to evaluate HLA DR/DQ alleles and their risk factor for type 1 diabetes in the Abruzzo region (central Italy). Sixty incident cases from the Abruzzo region were studied together with 120 unrelated control subjects living in the same administrative areas. The relative risk of diabetes associated with the alleles under study was calculated by deriving the odds ratio (OR) maximum likelihood estimates and their 95% confidence intervals (CI) by the exponentiation of the logistic regression beta–parameter. The combination DRB1*03/DQA1*0501/DQB1*0201 was found in 20.0% of patients and 7.1% of the control subjects, conferring an OR of 4.04 and a CI of 1.97–8.49. The combination DRB1*04/DQA1*0301/DQB1*0302 was found in 23.3% of diabetic patients and 6.7% of controls, giving an OR of 5.69 and a CI of 2.77–12.05. DRB1*11/DQA1*0505/DQB1*0301 and DQA1*0505/DQB1*0301 were negatively associated with type 1 diabetes (OR=0.27, CI 0.11–0.57; OR=0.07, CI 0.02–0.19). The DQA1 genotype at risk was found to be DQA1*0301/DQA1*0501: OR=23.80, CI 2.97–190.89, as it occurred with the highest frequency in the patient group. The DQB1 genotype at risk was found to be DQB1*0201/DQB1*0302, which occurred in 13.3% of patients but in only 1.1% of the control group (OR=29.75, CI 5.36–549.25). Our results shed further light on the risk of development of this disease during a specific time period in an area where the overall incidence of type 1 diabetes is known.     

Autoimmune polyglandular syndrome type 2 shows the same HLA class II pattern as type 1 diabetes

Autoimmune polyglandular syndrome (APS) type 2 is defined by the manifestation of at least two autoimmune endocrine diseases. Only few data exist on genetic associations of APS type 2. In this controlled study, 98 patients with APS type 2, 96 patients with type 1 diabetes (T1D), and 92 patients with autoimmune thyroid disease, both as a single autoimmune endocrinopathy, were tested for association with alleles of the human leukocyte antigen (HLA) class II loci DRB1, DQA1, and DQB1. Patients with APS type 2 had significantly more often the alleles DRB1*03 (P(c) < 0.0001), DRB1*04 (P(c) < 0.000005), DQA1*03 (P(c) < 0.0001), and DQB1*02 (P(c) < 0.05), when compared with controls. Less frequent in APS were DRB1*15 (P(c) < 0.05), DQA1*01 (P(c) < 0.0005), and DQB1*05 (P(c) < 0.005). With regard to frequency and linkage of these alleles, the susceptible haplotypes DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*0401/04-DQA1*0301-DQB1*0302 were deduced. Protective haplotypes in this study were DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*0101-DQA1*0101-DQB1*0501. Comparing APS patients with vs without AD, no significant differences regarding HLA class II alleles were noted in our collective. Patients with T1D as a singular disease had the same susceptible and protective HLA alleles and haplotypes. The prevalence of DRB1*03 and DRB1*04 in APS patients was not because of the presence of diabetes, as the APS type 2 patients without diabetes had the same allele distribution. In conclusion, these data suggest a common immunogenetic pathomechanism for T1D and APS type 2, which might be different from the immunogenetic pathomechanism of other autoimmune endocrine disease.     

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-DRB1, DQA1 and DQB1 DNA polymorphisms in healthy Algerian and genetic relationships with other populations

Abstract: This study presents the results of HLA-DRB1, -DQA1, and -DQB1 sequence-specific oligonucleotide probe (SSOP) typings for a population sample of 47 individuals originating from Western Algeria. Allele and haplotype frequencies, as well as linkage disequilibria are computed by the standard methods used for the XIth International Histocompatibility Workshop data. A total of 24 alleles are detected at the DRB1 locus, where a very high heterozygosity level (0.914) is found. The highest DRB1 frequencies are 0.160, DRB1*1101, and 0.138, for DRB1*0301 and DRB1*0701. The DQA1 and DQB1 loci are less polymorphic. Among the 8 DQA1 alleles detected, DQA1*0501 is highly predominant with a frequency of 0.383. Thirteen DQB1 alleles are observed among which DQB1*0301 and DQB1*0201 are the most frequent (0.351 and 0.245, respectively). Three haplotypes predominate clearly: DRB1*1101-DQA1*0501-DQB1*0301 (0.138), DRB1*0701-DQA1*0201-DQB1*0201 (0.128) and DRB1*0301-DQA1*0501-DQB1*0201 (0.117). The two latter are among the most frequent haplotypes found in European and North American Caucasoid populations, but the DQA1*0501-DQB1*0201 association is not significant in Algerians. The genetic distances computed for each locus among a set of populations from different continents are significantly correlated to geography. They indicate that the Algerians are very close to South European populations, particularly to Sardinians, Italians, Romanians and French, with some intermediate characteristics between Europeans and sub-Saharan Africans. These results may serve as reference for future studies of HLA and disease in the Algerian population.     

HLA-DQA1、DQB1、DRB1 02,07,09等位基因及单倍型在华东地区汉族人群的分布

应用ＰＣＲ－ＳＳＯ方法，对华东地区汉族人群进行了ＨＬＡ－ＤＱＡ１、－ＤＱＢ１和ＤＲＢ１＊０２，０７，０９基因分型。ＤＱＡ１中以ＤＱＡ１＊０３０１基因频率最高（０．３８４４），其次为＊０５０１（０．１４０６）和０１０２（０．１２１９），＊０４０１最低（０．０２８１）；ＤＱＢ１中以ＤＱＢ１＊０３０３基因频率最高（０．２３４２），其次为＊０３０１（０．１８９９）、＊０６０１（０．１２０３）和＊０２０１（０．１１０８），＊０５０１、＊０６０４和＊０６０５最低（均为０．０１２７）；ＤＲ９基因频率较高（０．２３１０），ＤＲ２中ＤＲＢ１＊１５０１占７３％，基因频率为０．０８５４，未见＊１６０１。ＤＱＡ１、ＤＱＢ１及ＤＲＢ１等位基因之间存在显著的连锁不平衡。ＤＲＢ１＊０９０１－ＤＱＡ１＊０３０１－ＤＱＢ１＊０３０３、ＤＱＡ１＊０１０３－ＤＱＢ１＊０６０１等为常见单倍型。本资料与我国其他汉族人群资料有可比性，也存在一定差异。     

Associations of HLA class II alleles with pulmonary tuberculosis in Thais

Tuberculosis is an important infectious disease in Thailand. Susceptibility to tuberculosis is influenced not only by the environment but also by host genetic factors. In this study, we investigated HLA alleles in 82 patients with tuberculosis from Bangkok and in 160 normal controls. HLA‐DRB1, DQA1 and DQB1 genotyping was performed by the PCR‐SSO method. The frequency of HLA‐DQB1*0502 was increased in tuberculosis patients compared to the normal controls (P = 0.01, OR = 2.06). In contrast, the frequencies of DQA1*0601 and DQB1*0301 were decreased in tuberculosis patients compared to the controls (P = 0.02 and P = 0.01, respect­ively). Our results suggest that HLA‐DQB1*0502 may be involved in the development of pulmonary tuberculosis, whereas HLA‐DQA1*0601 and DQB1*0301 may be associated with protection against tuberculosis.     

Celiac disease among Ashkenazi Jews from Israel: A study of the HLA class II alleles and their associations with disease susceptibility

The immunogenetics of celiac disease demonstrates a highly significant association with the HLA class II alleles DQA1*0501 DQB1*0201 encoded in either a cis- or trans-configuration. In Northern Europe, these alleles are found in linkage disequilibrium with DRB1*0301 while in Southern Europe an additional secondary association through linkage disequilibrium is seen with the combination DRB1*1101/0701. This study examines 34 Ashkenazi Jews with celiac disease and 36 ethnically matched controls to determine alleles at the DRB, DQA1, DQB1, and DPB1 loci using SSO probes in conjunction with gene amplification by the PCR. The results confirm a highly significant association with the DQA1*0501 DQB1*0201 allelic combination (71% celiac vs 8% control individuals; p = 0.00005; χ² = 21.4). Of celiac subjects, 29% were negative for the proposed DQ susceptibility alleles, the majority of whom were DRB1*0402 positive (20% overall celiac group). No additional susceptibility was associated at the DRB3 and DPB loci. This study confirms that the MHC-linked celiac disease susceptibility among Ashkenazi Jews is closely associated with the presence of the combination of alleles DQA1*0501 DQB1*0201. However, within this population of relatively high-prevalence celiac disease, 30% of celiac patients do not carry these alleles and are therefore not covered by a single “unifying” hypothesis.     

系统性红斑狼疮临床表现与HLA Ⅱ类单倍型关联的研究

目的 探讨系统性红斑狼疮（ＳＬＥ）易感基因致病的模式。方法 利用多聚酶链反应／特异寡核控针杂交（ＰＣＲ／ＳＳＯＰＨ）方法检测１１３例确诊ＳＬＥ病人的ＨＬＡⅡ基因型并进行单倍型分析。结果 ＳＬＦ病人的单倍型具有特定的结构特征,即以２个或３个重型ＳＬＥ相关基因共同组成１个单倍型;反之,２个或３个轻型ＳＬＥ相关基因组成另１个单倍型;重型基因和轻型基因之间很少有强连锁不平衡。ＤＱＡ１＊０３０１－ＤＱＢ１＊     

HLA class II allele and haplotype distribution in a population from central Poland

We have studied the distribution of HLA DRB1, DQA1, DQB1 alleles and haplotypes in a sample of 103 unrelated healthy individuals from the region of Lodz in central Poland by the polymerase chain reaction and hybridization with allele-specific oligonucleotide probes (PCR-SSO). DRB1*0101, DRB1*07, DRB1*1501, DRB1*03 and DRB1*11 were the most frequent alleles at the DRB1 locus. The DRB1*04 group was observed at a high frequency, but only five out of the 19 DR4 subtypes tested were observed. The most frequent was DRB1*0401, followed by DRB1*0403, DRB1*0402, DRB1*0407 and DRB1*0417. Eight DQA1 alleles were found in this Polish population, among which DQA1*0501, DQA1*0101 and DQA1*0102 were the most frequent. At the DQB1 locus 13 alleles were found. Among them, four were present with frequencies above 10%: DQB1*0201, DQB1*0301, DQB1*0501 and DQB1*0602. Our results underline significant differences between the population of central Poland and populations of neighbouring countries such as Germany, Ukraine and the Czech Republic. This study will serve as a reference for further anthropological studies, as well as studies of associations between HLA and disease.     

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.     

Variation of HLA class II genes in the Nganasan and Ket,two aboriginal Siberian populations

Allelic frequencies at the three most polymorphic loci of the HLA class II region (DRB1, DQA1 and DQB1) were determined in the Nganasan and Ket, the remnants of the two most ancient groups in the Lower Yenisey River/Taimyr Peninsula region in northern Siberia. By single‐stranded conformational polymorphism typing, verified by sequencing, 19 HLA‐DRB1‐DQA1‐DQB1 haplotypes and 15 HLA‐DRB1, seven DQA1 and 11 DQB1 alleles were found. The most frequent alleles were DRB1*1301 (23.5%), DQA1*0103 (29.4%), *0501/03/05 (29.4%), and DQB1*0301/09 (32.4%) in the Ket, and DRB1*0901 (25%), DQA1*0301 (39.6%), and DQB1*0301/09 (37.5%) in the Nganasan. The distribution patterns and comprehensive phylogenic analysis based on the haplotype frequencies of 17 Siberian populations suggest that the founders of both the Ket and the Nganasan came from Palaeolithic populations in the Altai‐Sayan Upland.     

Human leukocyte antigen class II allele frequencies and haplotype association in Iranian normal population.

The polymorphism of the HLA class II genes DRB1, DQA1, and DQB1 was investigated in 100 unrelated Iranian individuals from Fars province in Southern Iran, using the restriction fragment length polymorphism (RFLP) method. Subtyping of DRB1*04, *15, and *16 alleles was performed using PCR amplification with sequence specific primes (PCR-SSP). The allele and the haplotype frequencies were calculated. The most common DRB1 alleles were DRB1*11, DRB1*15, and DRB1*04 with a frequency of 25.0%, 14.5%, and 10.5%, respectively. In contrast, the allelic frequency of DRB1*12 and DRB1*08 was very low (1.5% for each). In the DR15 group DRB1*1501 was the most prevalent variant (6.0%). Concerning DR4, the most common alleles were DRB1*0405 and DRB1*0402 (3.5% for each). Interestingly, DRB1*0402 was associated with DQB1*0302 and DRB1*0405 was associated with DQB1*0302 and DQB1*02, the latter being a rare DRB1/DQB1 haplotype in Caucasian individuals. The most frequent DQB1 alleles were DQB1*0301 (31.0%), and DQB1*05 (22.0%). The most frequent DQA1 variants were DQA1*0501 (39.0%) and DQA1*0102 (14.5%). The most common haplotype was DRB1*11-DQB1*0301-DQA1*0501 (25.0%) followed by DRB1*0301-DQB1*02-DQA1*0501 (10%) and DRB1*0701- DQB1*02-DQA1*0201 (6.5%). Data presented in this study suggest that the Iranian population shares some HLA components with populations resident in eastern and southern European countries.     

HLA-DR and -DQ alleles in Italian patients with melanoma

Abstract: Controversial data have been reported about HLA alleles and susceptibility to melanoma. Our investigation was undertaken to analyze the relationship between HLA alleles distribution in patients with melanoma and susceptibility to the tumor, in order to study the possible correlation between HLA class II DQA1, DQB1 and DRB1 genes involved in immune recognition, and melanoma, usually considered a highly immunogenic tumor. We therefore typed by means of PCR-SSP (sequence-specific primers) 53 Italian patients and 53 healthy random controls coming from the same geographic area. We observed a decrease of all haplotypes bearing DQB1*0301, DQB1*0302 and DQB1*0303 alleles but not of haplotype DRB1*11;DQA1*0501;DQB1*0301. Our results seem to support the hypothesis of a protective role of some DQ3-bearing haplotypic combinations in melanoma.     

A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan

To investigate the correlation between clinical features and HLA DR/DQ genetic variability in myasthenia gravis (MG), we evaluated HLA DR/DQ allele frequencies in 87 Japanese patients with childhood-onset disease. HLA genotypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303 were significantly higher in patients than in healthy controls (P(c) < 0.0001, RR = 5.5; P(c) < 0.0001, RR = 8.5, for two genotypes, respectively). Patients who had a significantly higher likelihood of the HLA types DRB1*1302/DQA1*0102/DQB1*0604 or DRB1*0901/DQA1*0301/DQB1*0303 belonged to the latent general type (LG) of MG; this is clinically ocular type, but shows myasthenic electromyographic findings in extremity muscles. The LG type of MG was observed in 78% of patients exhibiting the clinically ocular type; this group comprised approximately 75% of patients with childhood-onset MG. These date suggest that LG type of MG may present a particular subset of childhood-onset MG, which is associated with the specific HLA subtypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303.     

Molecular characterization of HLA class II genes in celiac disease patients of Latin American caucasian origin

Abstract: In the present study, the polymorphic domain of HLA class II genes present in a pediatric population of Argentinian celiac disease patients was analyzed by hybridization to sequence-specific oligonucleotides and DNA sequencing. Sixteen out of 16 DR5/7 heterozygous patients bore the DQA1*0501 and DQB1*0201 alleles implicated in the DQ2 risk specificity. The second exon of DQA1, DQB1 and DRB1 genes from 2 DR5/7 patients was characterized by DNA sequencing. The following alleles were found in both patients: DRB1*1101 and DRB1*0701; DQB1*0301 and DQB1*0201; DQA1*0501 and DQA1*0201. Previous serological analysis in this population had shown the presence of DQ2 in 95% of the patients (40% in controls) and a negative association with DQ1 haplotypes, suggesting the presence of other "permissive" or neutral alleles. The following HLA-DQB1 alleles, besides DQB1*0201, were identified in 31 CD patients: DQB1*0301, 0302, 0401 and 0402. All these alleles share a common pattern of residues between positions 84 and 90, and distinct from that present in DQ1-related alleles.     

HLA-DRB1, -DQA1, -DQB1 and DPB1 susceptibility alleles in Cameroonian type 1 diabetes patients and controls

It is known that certain combinations of alleles within the human leucocyte antigen (HLA) complex are associated with susceptibility or resistance to type 1 diabetes. Variable associations of DR and DQ with type 1 diabetes are documented in Caucasians but rarely in African populations; however, the role of HLA-DP genes in type 1 diabetes remains uncertain. In order to investigate the HLA class II associations with type 1 diabetes in Cameroonians, we used sequence-specific oligonucleotide probing (SSOP) to identify DRB1, DQA1, DQB1 and DPB1 alleles in 10 unrelated C-peptide negative patients with type 1 diabetes and 90 controls from a homogeneous population of rural Cameroon. We found a significantly higher frequency of the alleles DRB1*03 (χ² = 17.9; P = 0.001), DRB1*1301 (χ² = 37.4; P < 0.0001), DQA1*0301 (χ² = 18.5; P = 0.001) and DQB1*0201 (χ² = 37.4; P < 0.001) in diabetes patients compared to the control group. The most frequent alleles in the control population were DQA1*01, DQB1*0602 and DRB1*15. The DRB1*04 allele was not significantly associated with type I diabetes in our study population. We observed no significant difference between patients and controls in DPB1 allele frequency. In conclusion, the data in Cameroonian diabetes patients suggest the existence of HLA class II predisposing and specific protective markers, but do not support previous reports of a primary association between HLA-DP polymorphism and development of type I diabetes .     

HLA-DRB1, -DQA1, -DQB1 and DPB1 susceptibility alleles in Cameroonian type 1 diabetes patients and controls.

It is known that certain combinations of alleles within the human leucocyte antigen (HLA) complex are associated with susceptibility or resistance to type 1 diabetes. Variable associations of DR and DQ with type 1 diabetes are documented in Caucasians but rarely in African populations; however, the role of HLA-DP genes in type 1 diabetes remains uncertain. In order to investigate the HLA class II associations with type 1 diabetes in Cameroonians, we used sequence-specific oligonucleotide probing (SSOP) to identify DRB1, DQA1, DQB1 and DPB1 alleles in 10 unrelated C-peptide negative patients with type 1 diabetes and 90 controls from a homogeneous population of rural Cameroon. We found a significantly higher frequency of the alleles DRB1*03 (chi2 = 17.9; P = 0.001), DRB1*1301 (chi2 = 37.4; P < 0.0001), DQA1*0301 (chi2 = 18.5; P = 0.001) and DQB1*0201 (chi2 = 37.4; P < 0.001) in diabetes patients compared to the control group. The most frequent alleles in the control population were DQA1*01, DQB1*0602 and DRB1*15. The DRB1*04 allele was not significantly associated with type I diabetes in our study population. We observed no significant difference between patients and controls in DPB1 allele frequency. In conclusion, the data in Cameroonian diabetes patients suggest the existence of HLA class II predisposing and specific protective markers, but do not support previous reports of a primary association between HLA-DP polymorphism and development of type I diabetes.     

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.     

DQCAR microsatellite polymorphisms in three selected HLA class II-associated diseases

Abstract: DQCAR is a very polymorphic CA repeat microsatellite located between the HLA DQA1 and DQB1 gene. Previous studies have shown that specific DQCAR alleles are in tight linkage disequilibrium with known HLA DR-DQ haplotypes. Of special interest was the fact that haplotypes containing long CA repeat alleles (DQCAR > 111) were generally more polymorphic within and across ethnic groups. In these latter cases, several DQCAR alleles were found even in haplotypes containing the same flanking DQA1 and DQB1 alleles. In this work, three HLA class II associated diseases were studied using the DQCAR microsatellite. The aim of this study was to test if DQCAR typing could distinguish haplotypes with the same DRB1, DQA1 and DQB1 alleles in control and affected individuals. To do so, patients with selected HLA DR-DQ susceptibility haplotypes were compared with HLA DR and DQ matched controls. This included: Norwegian subjects with Celiac disease and the HLA DRB1*0301, DQA1*05011, DQB1*02 haplotype; Japanese subjects with Type 1 (insulin-dependent) Diabetes Mellitus and the HLA DRB1*0405, DQA 1*0302, DQB 1*0401 haplotype; and French patients with corticosensitive Idiopathic Nephrotic Syndrome and the HLA DRB 1*0701, DQA 1*0201, DQB1*0202 haplotype. These specific haplotypes were selected from our earlier work to include one haplotype bearing a short DQCAR allele (celiac disease and DR3, DQ2-DQCAR99) and two haplotypes bearing long DQCAR alleles (Diabetes Mellitus and DR4, DQ4-DQCAR 113 or 115 Idiopathic Nephrotic syndrome and DR7, DQ2-DQCAR 111–121). Additional DQCAR diversity was found in both control and patients bearing haplotypes with long CA repeat alleles. The results indicate that DQCAR typing did not improve specificity in combination with high resolution DNA HLA typing as a marker for these three disorders.