华南地区汉族胰岛素依赖型糖尿病易感性与HLA—DR9相关性的初步 …

应用套式ＰＣＲ检测华南地区汉族６４例Ｉ型糖尿病病人（ＩＤＤＭ）（包括１５岁前起病组１７例，１５￣３０岁起病组３０例和３０岁后起病组１７例）和７２例健康对照者的ＨＬＡ－ＤＲ９等位基因。结果：ＩＤＤＭ组和对照组ＨＬＡ－ＤＲ９等位基因频率分别为４６．９％和３３．３％，无显著性差异（Ｐ〉０．０５）。１５岁前起病组、１５￣３０岁起病组和３０岁后起病组中ＨＬＡ－ＤＲ９频率分别为５８．８％、４６．７％和３５．３     

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—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-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。     

糖尿病患者谷氨酸脱羧酶自身抗体测定的临床意义

应用间接ＥＬＩＳＡ法测定３７例胰岛素依赖型糖尿病（ＩＤＤＭ）患者血清谷氨酸脱羧酶（ＧＡＤ）自身抗体，并以非胰岛素依赖型糖尿病（ＮＩＤＤＭ）、及其它自身免疫性疾病、正常人各３０例作对照，同时用间接免疫荧光法测定胰岛细胞浆抗体（ＩＣＡ）作比较。结果：ＩＤＤＭ患者的阳性率高达８３．８％（３１／３７），ＮＩＤＤＭ患者为１６．７％（５／３０），而其它自身免疫性疾病及正常人无１例阳性。在ＩＤＤＭ患者中，ＧＡＤ     

139例胰岛依赖型糖尿病发病方式的分析

对１３９例胰岛素依赖型糖尿病（ＩＤＤＭ）病人进行回顾性研究。男性５４例，女性８５例。平均年龄３１．７４±１２．２０岁。平均病程１３．４６±９．１５年。４８例在发病前有明确病毒感染史（占３４．５％），其中以上呼吸道和肠道感染占绝大多数（８３％），２例在接种卡介苗后发生ＩＤＤＭ。病毒感染与是否首发为糖尿病酮症酸中毒（ＤＫＡ）无关。有病毒感染组平均发病年龄１５．５８±１０．０４岁，显低于无病毒感染组平     

HLA—DR2,DRB1＊0301,DQA1＊0501基因频率与肌炎及其临床表现的 …

目的：观察人类白细胞相关抗原ＨＬＡ－ＤＲ２，ＤＲＢ１＊０３０１，ＤＱＡ１＊０５０１基因频率为多发性肌炎／皮肌炎（ＰＭ／ＤＭ）发病及其临床表现的关系，方法：特异性引物聚合酶链式反应（ＰＣＲ－ＳＳＰ）方法分别测定了３１例ＰＭ／ＤＭ患者及５０例正常人的ＨＬＡ－ＤＲ２，ＤＲＢ１＊０３０１及ＨＬＡ－ＤＡＱ１＊０５０１的基因频率，结果：三种基因型在３１例肌炎患得中基频率分别为：６．４５％，９．６８％和７７．４     

139例胰岛素依赖型糖尿病发病方式的分析

对１３９例胰岛素依赖型糖尿病（ＩＤＤＭ）病人进行回顾性研究。男性５４例，女性８５例。平均年龄３１．７４±１２．２０岁。平均病程１３．４６±９．１５年。４８例在发病前有明确病毒感染史（占３４．５％），其中以上呼吸道和肠道感染占绝大多数（８３％），２例在接种卡介苗后发生ＩＤＤＭ。病毒感染与是否首发为糖尿病酮症酸中毒（ＤＫＡ）无关。有病毒感染组平均发病年龄１５．５８±１０．０４岁，显著低于无病毒感染组平均发病年龄１９．６９±８．９８岁（Ｐ＜００２）。所有病例中大约四分之一的病人有糖尿病家族史，明显高于国外类似报道。     

汉族类风湿关节炎患者HLA—DR和—DQ基因分型研究

为探讨ＨＬＡ－ＤＲ和－ＤＱ等位基因与我国汉族类风湿关节炎（ＲＡ）的相关性，采用聚合酶链反应－限制性内切酶片段长度多态性分析（ＰＣＲ－ＲＦＬＰ）方法对汉族人群中３５例ＲＡ患者和１００名健康人的ＤＲ和ＤＱ位点进行ＤＮＡ定型分析。结果发现，ＤＲ４频率在正常人为２４．０％，在ＲＡ患者为５１．４％（Ｐ＜０．０１，ＲＲ＝３．３０）；ＤＲ４亚型位点分析发现２组均以ＤＲＢ１＊０４０５占多数，但ＤＲＢ１＊０４０５频率在ＲＡ组为３１．４％，高于正常人的１０．０％（Ｐ＜０．０１）。ＤＱ４频率在全部ＲＡ患者为３７．１％，在ＤＲ＋４ＲＡ患者为７２．２％，均高于全部正常人的１０．０％（Ｐ＜０．０１）和ＤＲ＋４正常人的４１．６％（Ｐ＝０．０３７６）；ＤＲ＋４－ＤＱ＋４ＲＡ患者的病情重于ＤＲ－４患者。结果提示，ＤＲ４、主要是ＤＲＢ１＊０４０５与ＲＡ相关，ＤＱ４可增加ＤＲ４对ＲＡ的易感性，ＤＲ＋４－ＤＱ＋４单倍型是ＲＡ病情严重程度的标志。     

肌糖原合成酶基因多态性与糖尿病及其合并高血压的关系

目的研究肌糖原合成酶基因与非胰岛素依赖型糖尿病（ＮＩＤＤＭ）及其合并高血压的关系。方法采用限制性内切酶Ｘｂａｌ对肌糖原合成酶基因片段的聚合酶链反应（ＰＣＲ）产物酶解的方法，观察１６４例ＮＩＤＤＭ（包括６２例合并高血压病人）的糖原合成酶基因多态性。结果肌糖原合成酶基因型（Ａ１／Ａ１，Ａ１／Ａ２）和等位基因（Ａ１，Ａ２）均与ＮＩＤＤＭ无关，而ＮＩＤＤＭ合并高血压者Ａ２等位基因频率明显高于血压正常的ＮＩＤＤＭ者（Ｐ＜０．０５）。结论糖原合成酶基因多态性作为一种标志，提示与其连锁的基因可能参与ＮＩＤＤＭ病人的高血压的发病。     

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。     

Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical onset of Type 1 (insulin-dependent) diabetes mellitus before age 10 years,but not at onset between age 10 and 40 years

Summary Demographic and biological data were collected from all Caucasian Type 1 diabetic patients (n = 279) who were recruited at clinical onset by the Belgian Diabetes Registry over 34 months. The male/female ratio was significantly higher for onset between age 20 and 40 years (2.4) than before age 20 years (1.0); no age-or sex-differences were noticed in serum fructosamine concentration. Total and high concentrations of insulin autoantibodies and islet cell antibodies were preferentially associated with the HLA DQA1*0301-DQB1*0302 susceptibility haplotype. The occurrence of both types of antibodies was also correlated, irrespective of haplotype. At onset before age 10 years, the high risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 was more prevalent than all other DQA1-DQB1 genotypes taken together, leading to a higher prevalence of the DQA1*0301-DQB1*0302 haplotype in this age group (75%) than in the 10–39 years age group (54%). Under age 10 years, the presence of DQA1*0301-DQB1*0302 was strongly associated with insulin autoantibodies (90%) and islet cell autoantibodies (92% with 85% of high titre), whereas patients without this haplotype were less frequently positive for insulin autoantibodies (31%) or islet cell autoantibodies (38% high titre). In the group with onset at age 10–39 years, the DQA1*0301-DQB1*0302 haplotype presented a lower association with insulin autoantibodies (40%) and islet cell autoantibodies (50 to 65% high titre), prevalences which no longer differed from those in subjects lacking this haplotype. The present data demonstrate that variations in prevalence of insulin autoantibodies and islet cell autoantibodies at onset of Type 1 diabetes can result from differences in age and in the fraction of patients with the HLA DQA1*0301-DQB1*0302 haplotype. The presence of this susceptibility haplotype at onset under age 10 years identifies a sub-group of patients with more than 90% positivity for insulin autoantibodies and more than 90% positivity for islet cell autoantibodies. It is conceivable that this sub-group can be recognized in the pre-diabetic phase through screening for immunological and genetic markers.     

IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of Type 1 diabetes and associated autoimmunity

AIM/HYPOTHESIS: Type 1 diabetes (T1D) is an autoimmune disease with multiple susceptibility genes. The aim of this study was to determine whether combining IDDM1/HLA and IDDM2/ insulin( INS) 5' variable number of tandem repeat locus (VNTR) genotypes improves T1D risk assessment. METHODS: Patients with T1D (n=488), control subjects (n=846), and offspring of parents with T1D (n=1122) were IDDM1 and IDDM2 genotyped. Offspring were followed for islet autoantibodies and T1D from birth until the age of 2 to 12 years. RESULTS: Compared to the I/I INS VNTR genotype, the I/III and III/III genotypes reduced T1D risk conferred by IDDM1/HLA in all HLA genotype categories of the case-control cohort by 1.6-fold to three-fold. The highest T1D risk was associated with INS VNTR class I/I plus HLA DR3/DR4-DQ8 (20.4% in patients, 0.6% in control subjects) or HLA DR4-DQ8/DR4-DQ8 (6.3% in patients, 0.2% in control subjects). In the offspring, HLA DR3/DR4-DQ8 and DR4-DQ8/DR4-DQ8 conferred increased risk for early development of islet autoantibodies (14.6% and 12.9% by age 2 years). Offspring with these high risk IDDM1 genotypes plus the INS VNTR class I/I genotype (n=71; 6.3%) had the highest risk of developing islet autoantibodies (21.8% by age 2 years vs 8.9% in offspring with high risk IDDM1 plus INS VNTR class I/III or III/III genotypes, p<0.05) and T1D (8.5% by age 6 years vs 4.3%). Offspring who developed autoantibodies to multiple antigens had increased frequencies of both high risk IDDM1 and IDDM2 genotypes (p<0.0001), whereas offspring who developed autoantibodies to GAD only had increased frequencies of high risk IDDM1 and protective IDDM2 genotypes, suggesting that IDDM2 influences the autoimmune target specificity. CONCLUSION/INTERPRETATION: Combining IDDM1 and IDDM2 genotyping identifies a minority of children with an increased T1D risk.     

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.     

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.     

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.     

HLA-DRB1*15021 is the predominant allele in Japanese patients with juvenile dermatomyositis

OBJECTIVE: To investigate HLA molecules and genes in Japanese patients with juvenile dermatomyositis (JDM). METHODS: Twelve patients (8 girls and 4 boys) with ages of onset between 3 and 15 years were included. HLA class I antigen phenotypes were serologically typed by the Terasaki-NIH standard method. DNA was extracted from peripheral blood leukocytes using the phenol-chloroform extraction procedure, and stored at -70 degrees C until use. Genomic DNA for HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles in JDM patients and controls was determined by the direct sequence method. RESULTS: HLA-A24 and B52 were each detected in 7 cases (OR = 0.86, 5.02, p = 0.930, 0.006, respectively). HLA-DRB1*15021 was observed in 7 patients. This was significantly more frequent than occurred in the controls (OR = 5.72, p = 0.002). Seven patients out of 12 (58%) had the combination HLA-B52, DRB1*15021, DQA1*0103, and DQB1*0601. CONCLUSION: Our results suggest that the susceptibility gene for JDM either is HLA-DRB1*15021 or is present near the HLA-DRB1 locus. This differs from previous reports that describe the association with HLA-DQA1*0501 in Caucasian patients with JDM. The combination HLA-B52, DRB1*15021, DQA1*0103, and DQB1*0601 may contribute to the pathogenesis of JDM in Japanese patients.     

DRB1, DQA1, DQB1 genes in Turkish children with rheumatic fever

OBJECTIVES: Several studies have suggested that genetic susceptibility to rheumatic fever (RF) may be linked to HLA Class II alleles. The purpose of this study was to examine the association between HLA Class II genes and RF in Turkish children. METHODS: DNA typing HLA Class II genes (DRB1, DQA1, DQB1) were performed in 55 children with RF and 50 healthy unrelated controls using sequence specific primers (SSP). RESULTS: The frequency of the HLA DQA1*03 (OR: 0.462, p < 0.05) allele was significantly decreased in the patient group. Also, the frequency of the combination of DRB1*04 and DQA1*03 allele (OR: 0.42, p < 0.01) was more significantly decreased in the patient group. Differences in frequencies of the DRB1 and DQB1 alleles between groups were not significant. CONCLUSIONS: Our data indicate that the HLA DQA1*03 allele may be a protecting factor in Turkish children with RF. Our results also suggest that the combination of the DRB1*04 and DQA1*03 alleles may be a stronger protective factor than the DQA1*03 allele alone.     

Frequency analysis of HLA-DQA1 and HLA-DQB1 gene alleles and susceptibility to type 1 diabetes mellitus in Russian patients

The HLA-DQA1 and DQB1 genes have recently been recognized to be strong genetic markers of susceptibility to type 1 (insulin-dependent) diatetes mellitus. The Arg52 DQA1 and non-Asp57 DQB1 alleles of these genes correlate with the disease predisposition and the Asp57 DQB1 and non-Arg52 DQA1 alleles with disease protection. We investigated 113 patients with type 1 diabetes and 121 healthy subjects from the Russian population of Moscow using DNA amplification and dot-blot hybridization with sequence-specific oligonucleotides (SSO). Using conventional statistical methods we confirmed previous observations indicating the important role of the abovementioned amino acid residues in susceptibility and resistance to type 1 diabetes. Relative risk values for all alleles and absolute risk for carriers of most predisposing allele combinations were calculated. The absolute risk for carriers of DQA1 and DQB1 gene alleles allowing for the formation of four possible diabetogenic heterodimers on the surface of immunocompetent cells, regardless of the type of coding (cis ortrans), was 2.54%, which is 13 times greater than the background risk for the Russian population –0.2% up to 30 years of age.     

Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles.

OBJECTIVE: To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes. METHODS: We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories. RESULTS: Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect. CONCLUSION: These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.