HLA—DQ基因与成人IDDM和成人缓慢进展型IDDM的相关性研究

目的 研究ＨＬＡ－ＤＱ基因与成人发病的ＩＤＤＭ和成人缓慢进展型ＩＤＤＭ的相关性。方法 利用ＰＣＲ／ＳＳＰ技术检测了３０例成人发病的ＩＤＤＭ患者,５２例在人缓慢进展型ＩＤＤＭ患者和５０例正常人的ＨＬＡ－ＤＱ基因频率。结果（１）ＨＬＡ－ＤＱＡ１＊０３０１,０５０１及ＤＱＢ１＊０２０１等基因与ＩＤＤＭ和缓慢ＩＤＤＭ呈显著正相关;ＤＱＢ１＊０３０１与缓慢ＩＤＤＭ呈显著正相关,而ＤＱＢ１＊０３０２与ＩＤＤＭ     

HLA-DRB1和DQ基因与胰岛素依赖型糖尿病遗传易感相关性的联合研究

用ＰＣＲ（聚合酶链反应）及序列特异性寡核苷酸探针杂交技术（ＳＳＯＰＨ）对中国北方人中ＨＬＡ－ＤＲＢ１和ＤＱ基因与ＩＤＤＭ的遗传易感相关性联合进行了研究，以５４例胰岛素依赖型糖尿病患儿为研究对象，４０例正常成年供血员为对照。结果表明：ＤＲＢ１＊０３０１、ＤＱＡ１＊０５０１、０３０１和ＤＱＢ１＊０２０１为ＩＤＤＭ易感性基因，ＤＱＡ１＊０１０３、ＤＱＢ１＊０６０１为ＩＤＤＭ保护性基因。ＤＲＢ１＊０３０１－ＤＱＡ１＊０５０１－ＤＱＢ１＊０２０１为ＩＤＤＭ易感性单倍型。ＤＲ３／ＤＲ４和ＤＲ３／ＤＲ９杂合子在病人中显著增高，表明ＤＲ３和ＤＲ４或ＤＲ３和ＤＲ９单倍型的易感性效果之间产生了协同作用。     

HLA-DR-DQ连锁基因单倍体与成人缓慢进展型和速发型1型糖尿病的相关性研究

目的探讨ＨＬＡＤＲＤＱ连锁基因单倍体与成人缓慢进展型１型糖尿病（ＳＰＩＤＤＭ）和速发型１型糖尿病（ＦＰＩＤＤＭ）的相关性。方法利用ＰＣＲ／ＳＳＰ技术检测了５２例ＳＰＩＤＤＭ患者、３０例ＦＰＩＤＤＭ患者和１３０例正常人的ＨＬＡＤＲＤＱ连锁基因频率。结果①ＨＬＡＤＱＡ１０３０１ＤＱＢ１０２０１和ＤＱＡ１０５０１ＤＱＢ１０２０１连锁基因单倍体与ＳＰＩＤＤＭ（Ｐｃ＜０．００１）和ＦＰＩＤＤＭ（Ｐｃ＜０．００１）均呈显著正相关；②ＨＬＡＤＱＡ１０３０１ＤＱＢ１０３０１和ＤＱＡ１０３０１ＤＱＢ１０６０２连锁基因单倍体与ＳＰＩＤＤＭ呈显著正相关（Ｐｃ＜０．００１）；③ＨＬＡＤＱＡ１０３０１ＤＱＢ１０３０２，ＤＱＡ１０３０１ＤＱＢ１０３０３及ＤＲＢ１０３０１ＤＱＡ１０３０１ＤＱＢ１０２０１连锁基因单倍体与ＦＰＩＤＤＭ呈显著正相关（前二者Ｐｃ＜０．０１，后者Ｐｃ＜０．００１）。结论ＳＰＩＤＤＭ和ＦＰＩＤＤＭ虽然均为自身免疫性糖尿病，但其ＨＬＡ表型并不完全相同，不同的ＨＬＡ表型可能是决定患者起病方式及病情发展不同的因素之一。     

HLA—Ⅱ类基因与狼疮性器官系统损害的相关性研究

目的 分析ＨＬＡ－Ⅱ类基因与狼疮性器官、系统损害的相关性,探讨系统性红斑狼疮（ＳＬＥ）从基因到临床表达的发病机制。方法 应用ＰＣＲ－ＳＳＯＰＨ技术检测１１３例确认ＳＬＥ病人的ＤＲ、ＤＱＡ１、ＤＱＢ１等位基因。结果 浆膜炎与ＤＱＢ１＊０６０１正相关;神经精神症状与ＤＲＢ１＊１５０１正相关;血肌同与ＤＱＢ１＊０３０２、ＤＱＢ１＊０４０１正相关;血尿素氮增高与ＤＱＢ１＊０２０１负相关;蛋白尿与ＤＱＢ１     

HLA-DQB1 基因与中国湖北汉族人 SLE 及其自身抗体的相关性研究

目的：探讨ＨＬＡＤＱＢ１等位基因与系统性红斑狼疮（ＳＬＥ）及其自身抗体的相关性。方法：采用ＰＣＲ／ＳＳＰ技术对５２例中国湖北地区汉族ＳＬＥ患者及１４３例正常对照者进行了ＨＬＡＤＱＢ１基因分型，并采用免疫印迹技术检测患者血清中自身抗体。结果：ＳＬＥ患者ＤＱＢ１０６０８（９６２％，χ２＝１０５１，Ｐ＜０００５）基因频率显著升高，ＤＱＢ１０３０２（５７７％，ＲＲ＝０２６Ｐ＜００５，ＰＦ＝０１４）和ＤＱＢ１０５０１（１９２％，ＲＲ＝０１１，Ｐ＜００１，ＰＦ＝０１３）基因频率显著降低，与正常对照组比较，ＤＱＢ１０６０８在伴抗Ｓｍ（１０３４％，Ｐ＜０００５）、抗ＲＮＰ（１１５４％，Ｐ＜０００５）、抗ｄｓＤＮＡ（２２２２％，Ｐ＜０００５）抗体阳性的ＳＬＥ患者中频率显著升高。结论：ＤＱＢ１０６０８与ＳＬＥ关联，并分别与抗Ｓｍ、抗ＲＮＰ、抗ｄｓＤＮＡ抗体的产生有相关性。而ＤＱＢ１０３０２、ＤＱＢ１０５０１等位基因对ＳＬＥ可能具有保护性。     

HLA—DR—DQ连锁基因单倍体与成人缓慢进展型和速发型1型 …

目的 探讨ＨＬＡ－ＤＲ－ＤＱ连锁基因单倍体与成人缓慢进展型１型糖尿病（ＳＰＩＤＤＭ）和速发型１型糖尿病（ＦＰＩＤＤＭ）的相关性。方法 利用ＰＣＲ／ＳＳＰ技术检测了５２例ＳＰＩＤＤＭ患者、３０例ＦＰＩＤＤＭ患者和１３０例正常人的ＨＬＡ－ＤＲ－ＤＱ连锁基因频率。结果 ①ＨＬＡ－ＤＱＡ１＊０３０１－ＤＱＢ１＊０２０１和ＤＱＡ１＊０５０１－ＤＱＢ１＊０２０１连锁基因单倍体与ＳＰＩＤＤＭ（Ｐｃ〈０．００１）     

HLA－DQ基因和中国人胰岛素依赖型糖尿病易感性的相关分析

对４２例无亲属关系的ＩＤＤＭ患者和４０例健康对照者采用ＰＣＲ方法对ＨＬＡ－ＤＱ基因进行了分析，４２例皆为曾在本院诊断和住院患者，并一直用胰岛素注射治疗。结果：ＤＱＡ＿１５２位精氨酸０２０１和０３０１等位基因在患者组显著性增高，ＤＱＢ１－５７非门冬氨酸等位基因０３０２在患者中显著增多，ＤＱＢ１＊０５０３５７－门冬氨酸等位基因在患者中显著减少，Ｐ＜０．０１。ＤＱＡ１基因型５２－精氨酸同合子患者显著增加，ｐ＜０．００１。５２－精氨酸阴性同合子在患者中显著减少，Ｐ＜０．００１。说明ＨＬＡ－ＤＱＡ１５２－精氨酸为易感性基因。ＨＬＡ－ＤＱ５７－非门冬氨酸同合子在患者中显著增多，说明ＤＱＢ１５７－非门冬氨酸为易感性基因，门冬氨酸为保护性基因。中国患者和健康对照者携带一个门冬氨酸的基因频率分别为７９％和８７．５％，由于门冬氨酸基因频率高，可解释中国人ＩＤＤＭ患病率低的原因之一。     

HLA—DRB1和DQ基因与胰岛素依赖型糖尿病遗传易感相关性的联合研究

用ＰＣＲ及序列特异性寡核苷酸针杂交技术对中国北方人中ＨＬＡ－ＤＲＢ１和ＤＱ基因与ＩＤＤＭ的遗传易感相关性联合进行了研究。以５４例胰岛素依赖型糖尿病患儿为研究对象，４０例正常成年供血员为对照，结果表明：ＤＲＢ１＊０３０１、ＤＱＡ１＊０５０１、０３０１和ＤＱＢ１＊０２０１为ＩＤＤＭ易感性基因，ＤＱＡ１＊０１０３、ＤＱＢ１＊ＤＱＢ１＊０６０１为ＩＤＤＭ保护性基因。ＤＲＢ１＊０３０１－ＤＱＡ１＊０５０１－     

氧化修饰低密度脂蛋白及抗氧化剂在糖尿病血管病变中的作用

为探讨氧化修饰低密度脂蛋白（ＯＸＬＤＬ）及抗氧化剂在糖尿病血管病变中的作用，采用酶联免疫吸附双抗体夹心法（ＥＬＡＳＡ法），测定了６０例非胰岛素依赖型糖尿病（ＮＩＤＤＭ）病人及３０例正常对照者血浆ＯＸＬＤＬ水平。结果显示：（１）ＮＩＤＤＭ组与正常对照组比较，血浆ＯＸＬＤＬ水平显著增高（Ｐ＜０．０１）。ＮＩＤＤＭ有血管病变组与无血管病变组比较，血浆ＯＸＬＤＬ水平显著增高（Ｐ＜０．０５）。（２）２０例ＮＩＤＤＭ病人用维生素Ｃ及维生素Ｅ治疗后，血浆ＯＸＬＤＬ水平显著下降（Ｐ＜０．０５）。（３）血浆ＯＸＬＤＬ水平与ＬＤＬ－Ｃ、ＨＤＬ、ＴＧ、ＴＣ、ＡｐｏＡ１及ＡｐｏＢ均无显著相关性。提示ＯＸＬＤＬ可能与糖尿病血管病变的发生和发展有关。抗氧化治疗可能对预防血管病变的发生有一定的作用。     

扩张型心肌病HLA－DRB_1基因多态性的研究

借助聚合酶链反应（ＰＣＲ）／序列特异性引物（ＳＳＰ）技术对４２例扩张型心肌病（ＤＣＭ）患者和１６８例正常对照者进行人类白细胞抗原（ＨＬＡ）－ＤＲＢ１基因型分析。结果发现ＤＣＭ组ＨＬＡ－ＤＲＢ１＊１１基因频率与对照组比较明显增高（２６．１９％对１３．１％，Ｐ＜０．０５），其ＲＲ＝２．３６。其他等位基因频率在ＤＣＭ组与对照组间差异无显著性。提示ＨＬＡ－ＤＲＢ１＊１１基因可能与ＤＣＭ有关联。     

DQA1 and DQB1 HLA genes as markers of insulin-dependent diabetes mellitus in the Polish population

The second-generation screen of human genome has confirmed that HLA region genes play a key role in the susceptibility to insulin-dependent diabetes mellitus. The aim of the present study was to estimate the frequency of chosen alleles of DQA1 and DQB1 genes in the patients with insulin-dependent diabetes mellitus and their first degree relatives in comparison to the healthy population in the north-eastern region of Poland. HLA typing of DQA1 and DQB1 alleles of the HLA region was performed by "phototyping" PCR-SSP method. The highest predisposition to IDDM in the population of the north-eastern region of Poland was associated with DQB1*0302 allele and DQB1*02-DQA1*0301 or DQB1*0302-DQA1*0301 haplotypes, while the dominant protection was connected with DQB1*0602, DQB1*0603 and DQB1*0301 alleles. The high frequency of protective DQB1*0602 and DQB1*0603 alleles and the low percentage of "diabetogenic" DQB1*0302 genes in the healthy control population of north-estern region of Poland may suggest their dominant influence on the relatively low incidence of IDDM in this region. The relatively high percentage of the first degree relatives of IDDM patients with pancreatic autoantibodies but with protective alleles observed in our study, which significantly decreases the risk of IDDM, suggests the necessity of DQB1*0602-03 measurements in such subjects for the better IDDM risk assessment.     

Analysis by the polymerase chain reaction of histocompatibility leucocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus.

DNA sequence analysis of class II HLA from Caucasian and black patients with type 1 (insulin-dependent) diabetes mellitus has suggested that aspartic acid at position 57 (Asp 57) of the DQ beta chain provides protection against insulin-dependent diabetes mellitus (IDDM). In contrast, most Japanese patients with IDDM have Asp 57-positive alleles. To determine the reason for the differences and to localize the HLA-linked diabetogenic gene in Japanese, we studied the DQA1 and DQB1 genes of Japanese patients with IDDM and control subjects by the polymerase chain reaction in combination with restriction fragment length polymorphism analysis. Associations of DQA1*0301 and DQB1*0303 with IDDM were observed. DQA1*01 was associated negatively with IDDM. The HLA-DR9 haplotype, which is associated positively with IDDM in Japanese, was associated with DQA1*0301 and DQB1*0303, indicating that the Japanese DR9 haplotype is the same as that in caucasians but different from that in blacks. Of the loci on Japanese DR9 haplotypes, the DQA1*0301 allele showed the highest association with IDDM. DQB1*0303 was also positively associated with IDDM. Since DQB1*0303 is identical to DQB1*0302 except that it contains Asp 57, the data suggests that an Asp 57-positive allele confers susceptibility to IDDM when the whole molecule of the DQ beta chain is similar to other susceptible DQ beta chains. DQA1*0301 appears to be a marker of IDDM in all these populations: Japanese, caucasian, and black.     

HLA DRB1/DQA1/DQB1 haplotype determines thyroid autoimmunity in patients with insulin-dependent diabetes mellitus

OBJECTIVE  Thyroid autoimmunity is frequently associated with insulin-dependent diabetes mellitus (IDDM). The genetic factors which contribute to thyroid autoimmunity and IDDM have been described but vary between different races. We have therefore investigated the effect of class II HLA genes at both loci and the HLA haplotypes on the presence of autoimmunity in patients with IDDM in Taiwan.
SUBJECTS AND MEASUREMENTS  Eighty-three patients with IDDM and 105 unrelated normal controls were recruited for the measurement of thyroid autoantibodies and for genotyping of HLA DRB1, DQA1 and DQB1 by polymerase chain reaction-based DNA typing techniques.
RESULTS  Among 83 patients with IDDM, 23 (27.7%) were positive for antithyroid autoantibodies. Compared to those without thyroid autoimmunity, there was a female preponderance for IDDM with thyroid autoimmunity (female: male, 3:20 vs 29:31). Among the DR specificities, DR6 was associated with a weak protective effect against thyroid autoimmunity in IDDM patients. Upon detailed analysis of class II HLA haplotypes, the DRB1*0301/DQA1*0501/DQB1*0201 haplotype was found to be associated with an increased risk of IDDM regardless of thyroid autoimmunity, while DRB1*0405/DQA1*0301/DQB1*0401 was significantly increased only in the IDDM patients with thyroid autoimmunity. IDDM individuals with the HLA DRB1*0405/DQA1*0301/DQB1*0302 haplotype were not at risk of thyroid autoimmunity.
CONCLUSIONS  Our data indicated that there was a generalized genetic factor within or associated with the DRB1*0301/DQA1*0501/DQB1*0201 haplotype, and a more restricted effect with the DRB1*0405/DQA1*0301/DQB1*0401 haplotype which led to thyroid autoimmunity in patients with insulin-dependent diabetes mellitus.     

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.     

Similarity of HLA-DQ profiles in adult-onset type 1 insulin-dependent diabetic patients with and without extra-pancreatic auto-immune disease.

Some insulin-dependent diabetic patients present with auto-immune diseases involving extra pancreatic tissues (type 1b diabetes mellitus). The genetic specificity of this syndrome, as opposed to insulin dependent diabetes mellitus (IDDM) free of such associations (Type 1a IDDM) is not clearly established. We have analyzed the HLA-DQB1 and DQA1, loci, after PCR amplification of genomic DNA, in 44 Type 1b IDDM patients, 78 Type 1a IDDM patients and 105 control subjects. No essential difference in HLA-DQ profiles appeared between Type 1b and Type 1a IDDM patients. Both diabetic groups displayed a significant enrichment in DQB1 alleles negative for aspartate at position 57 (Type 1b: 83%; Type 1a: 89%; controls 48%; p < 0.001 vs both patient groups) and in DQB1 Asp 57 negative homozygosity: 71% of Type 1b; 80% of Type 1a; 25% of controls (p < 0.01). This enrichment in DQB1 Asp 57 negative alleles was accounted for by DQB1* 0201 in the Type 1b group, and by DQB1 % 0201 and 0302 in the Type 1a patients. Conversely, alleles DQB1* 0602 and 0301 (DQB1 Asp 57 positive) were protective. Both diabetic groups also displayed a significant enrichment in DQA1 alleles positives for arginine at position 52 (65% of Type 1b; 76% of Type 1a; 50% of control subjects; p < 0.01 and 0.001, respectively, vs controls), and in DQA1 Arg 52 positive homozygotes (48% of Type 1b, 58% of Type 1a, 22% of control subjects; p < 0.01). All differences between diabetic groups and the control group were more pronounced in the case of Type 1a than of Type 1b patients. The HLA-DQ genes shared by Type 1a and Type 1b patients must therefore be closely associated with islet autoimmunity. Genetic differences between Type 1a and Type 1b syndromes, if any, must be investigated in other MHC and non-MHC regions of the genome.     

HLA DQA1-DQB1-TAP2 haplotypes in IDDM families: no evidence for an additional contribution to disease risk by the TAP2 locus

Summary The TAP2 gene, located in the HLA class II region, encodes a subunit of a transporter involved in the endogenous antigen-processing pathway, and has been suggested to contribute to the genetic risk for insulin-dependent diabetes (IDDM). In order to determine whether the TAP2 locus modulates the risk conferred by HLA DQ loci, HLA DQA1-DQB1-TAP2 haplotypes were analysed in 48 IDDM probands, their first degree relatives, and in 62 normal control subjects. A decreased frequency of the TAP2B allele was confirmed in this IDDM cohort (12 vs 28% in control subjects, p _c <0.05). Analysis of 73 informative meiotic events in IDDM and control families demonstrated a recombination fraction between HLA DQB1 and TAP2 loci of 0.041 (Log of the odds score=16.5; p<10^–8) indicating strong linkage between these loci. Family haplotype analysis demonstrated linkage disequilibrium between TAP2 and HLA DQA1-DQB1, and showed that the reduced frequency of TAP2B was associated with its absence on the IDDM susceptible DQA1*0301-DQB1*0302 haplotype, its low frequency on DQA1*0501-DQB1*0201, and the association of TAP2B with DQA1*0101-DQB1*0501 haplotypes which were less frequent in IDDM patients. Comparison of transmitted with non-transmitted haplotypes in IDDM families showed a slight but not significant decrease in TAP2B allele frequency on transmitted (3 of 37) vs non-transmitted (2 of 9) HLA DQA1*0501-DQB1*0201 haplotypes. No other differences were observed. Twenty-four unrelated DQA1*0501-DQB1*0201 haplotypes from non-diabetic families had a TAP2B allele frequency (4%) similar to that in IDDM haplotypes. These findings suggest that the decreased TAP2B allele frequency in Italian IDDM patients is due to HLA DQ haplotype differences between IDDM patients and control subjects, and do not support a contribution to IDDM risk by the TAP2 locus.Abbreviations ARMS Amplificatory refractory mutation system - IDDM insulin-dependent diabetes mellitus - MHC major histocompatibility complex - PCR polymerase chain reaction - TAP transporter associated with antigen processing     

Association of HLA Class II Genes with Idiopathic Pulmonary Arterial Hypertension in Koreans

The aim of this study was to compare the frequency of the HLA-DRB1 and HLA-DQB1 alleles in Korean patients with idiopathic pulmonary arterial hypertension (IPAH) and in normal controls and to determine any association that may exist between clinical characteristics of IPAH and specific HLA alleles. IPAH patients seen between October 1998 and September 2001 were retrospectively assessed, and 19 patients and 193 controls were HLA typed at the HLA-DRB1 and DQB1 loci. Clinical characteristics and hemodynamic parameters were reviewed. The patients with IPAH had a significantly higher frequency of the HLA-DRB1*0406 allele (18% vs. 6%, p = 0.004) and the HLA-DQB1*0302 allele (24% vs. 12%, p = 0.034), as well as a significantly higher frequency of haplotype DRB1*0406-DQB1*0302 (p = 0.0006). All 6 patients with haplotype DRB1*0406-DQB1*0302 (H+ group) were women, compared with 8 of the 13 patients lacking the DRB1*0406-DQB1*0302 haplotype (H- group), but without statistical significance. Three of 19 patients showed a positive short-term hemodynamic response to NO inhalation, all 3 of whom had the DRB1*0406-DQB1*0302 haplotype. There were no other significant differences in clinical characteristics and hemodynamic parameters between the H+ and H- groups. We conclude from this study that the HLA-DRB1*0406-DQB1*0302 haplotype is associated with IPAH in Korean patients. These results suggest that certain clinical characteristics of IPAH may be controlled in part by patients' HLA alleles.     

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.     

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.