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。     

成人晚发自身免疫性糖尿病的特点及诊断要点探讨

为加强临床医师对成人晚发自身免疫性糖尿病（ＬＡＤＡ）的认识，本研究比较了ＬＡＤＡ２５例、胰岛素依赖型糖尿病５７例（儿童发病２１例、成人酮症发病３６例）、非胰岛素依赖型糖尿病３８例（轻至中度３０例、重度８例）及正常人４２例的临床、空腹血糖、血浆Ｃ肽水平及ＨＬＡ－ＤＱＡ１、－ＤＱＢ１链基因频率，提出ＬＡＤＡ的特点及诊断要点为：（１）２０～４８岁发病，发病时多饮、多尿、多食症状明显，体重下降快，体重指数（ＢＭＩ）≤２５，空腹血糖≥１６．５ｍｍｏｌ／Ｌ；（２）空腹血浆Ｃ肽≤０．４ｎｍｏｌ／Ｌ，早晨空腹１００ｇ馒头餐后１小时或（和）２小时Ｃ肽≤０．８ｎｍｏｌ／Ｌ；（３）谷氨酸脱羧酶抗体阳性；（４）ＨＬＡ－ＤＱＢ１链第５７位点为非天门冬氨酸纯合子基因（易感基因）。第（１）点是基本临床特点，加上第（２）、（３）、（４）点中任何一点就考虑诊断ＬＡＤＡ，尽早采用饮食、运动及胰岛素治疗，使空腹及三餐后血糖、糖化血红蛋白（ＨｂＡ１ｃ）控制到正常水平，以保护受自身免疫破坏的胰岛Ｂ细胞功能，有利于防止糖尿病眼、肾、神经并发症。     

Gastric parietal cell antibodies are associated with glutamic acid decarboxylase-65 antibodies and the HLA DQA1*0501-DQB1*0301 haplotype in Type 1 diabetes mellitus. Belgian Diabetes Registry.

AIMS: To assess the prevalence of thyrogastric autoimmunity in relation to age, sex, beta-cell antibody status and HLA DQ haplotypes in Type 1 diabetes mellitus. METHODS: One hundred and seventy-one patients with Type 1 diabetes mellitus were studied (male/female 86/85; mean age 19 +/- 11 years; duration of diabetes 5 +/- 4 years). Islet cell antibodies (ICA) and parietal cell antibodies (PCA) were measured using indirect immunofluorescence; glutamic acid decarboxylase-65 antibodies (GADA) by radiobinding assay and thyroid peroxidase antibodies (TPO) with an immunoradiometric assay (IRMA). RESULTS: The majority of subjects (81.3%) showed one or more autoantibodies. The prevalence rates were: GADA 64.9%, ICA 46.2%, PCA 19.9% and TPO 19.3%. Patients with ICA+ > or = 3 years after diagnosis had a higher prevalence of GADA (P = 0.03, odds ratio (OR) 2.66) and thyrogastric antibodies (P = 0.05, OR 2.23) than subjects ICA- after 3 years. PCA+ patients were older (P = 0.04), had a higher prevalence of GADA (P = 0.005, OR 3.89) and TPO (P = 0.05, OR 2.50) than PCA- subjects. Logistic regression analysis showed that PCA status was determined by the HLA DQA1*0501-DQB1*0301 haplotype (beta = 2.94, P = 0.04) and GADA status (beta = 2.44, P = 0.041). CONCLUSIONS: Thyrogastric antibodies are highly prevalent in Type 1 diabetes mellitus, especially in patients with persisting ICA. Screening for gastric autoimmunity is particularly advised in patients who are positive for GADA and for the HLA DQA1*0501-DQB1*0301 haplotype.     

家族性肥厚型心肌病易感基因的定位分析

目的对肥厚型心肌病可能的致病基因或易感基因在染色体上的位置进行定位分析。方法应用ＰＣＲ／ＳＳＯ方法，分析４个家族性肥厚型心肌病家系的亲代和子１代ＨＬＡＤＱＡ１ＤＱＢ１单倍型，以Ｌｏｄｓ法分析未知的易感基因或致病基因与ＨＬＡＤＱ基因的连锁情况。结果发现家族性肥厚型心肌病的致病基因或易感基因与ＨＬＡＤＱＡ１与ＤＱＢ１单体型之间存在连锁，其图距为零分摩，提示易感基因与ＨＬＡＤＱＡ１与ＤＱＢ１之间距离很近。结论根据家系分析结果，初步认为家族性肥厚型心肌病的致病基因除βＭＨＣ突变之外，可能还存在一个易感基因，它位于ＨＬＡＤＱＡ１与ＤＱＢ１之间。     

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。     

抗SSA和SSB抗体与HLA-Ⅱ基因的相关性分析

目的：探讨云南汉族系统性红斑狼疮（SLE）患者抗SSA和SSB抗体与HLA－DRB1、DQA1、DQB1等位基因及单体型的相关性。方法：采用多聚酶链反应－序列特异性引物（PCR－SSP）技术对63例云南汉族SLE患者和54名同民族健康对照进行DRB1、DQA1、DQB1基因分型。结果：云南汉族SLE患者中DR15（P＜0．01）、DR16（P＜0．05）、DQA1＊0102（P＜0．05）、DQA1＊0103（P＜0．01）、DQB1＊0601（P＜0．05）等位基因频率明显增高；抗SSA和SSB抗性阳性的SLE病人中DQA1＊0103频率均显著增高（P＝0．042，P＝0．006）；抗SSB抗体阳性的SLE患者中的DQA1＊0501 频率均显著增高（P＝0．009）。结论：云南汉族SLE 抗SSA和SSB抗体的产生与DQA1＊0103等位基因相关；抗SSB抗体的产生还与DQA1＊0501相关。     

HLA-DR4-DQw8, but not DR4-DQw7 haplotypes occur in Indian patients with rheumatoid arthritis

Summary The distribution of HLA class II antigens in the Asian Indian patients with rheumatoid arthritis (RA) was studied in the present investigation. The results demonstrated that DR4 was significantly increased in both northern (²=36.9, P<0.00001) as well as southern Indian (²=17.3, P<0.0001) patients. HLA haplotype analysis revealed the presence of B17-DR4 among southern Indians. Amongst northern Indians, four DR4 haplotypes occurred significantly: A1,B17,DR4; A19,B7, DR4; A30,B13,DR4; and A33,B44,DR4. An analysis of TA10 and DQ'Wa' specificities revealed that all the DR4-DQw3 positive northern Indian RA patients were DQw8 positive association observed between DR4-DQw7 and RA in some western Caucasian populations was not present in this series. A group of three DR4 positive RA patients were found to be DQw3 negative and DQ'Wa' or DQw4 positive. These results indicated that susceptibility to RA may be controlled by genes in the DR locus independent of any DQ associations.     

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.     

扩张型心肌病HLA-DQA1等位基因多态性研究

目的　探讨扩张型心肌病 (IDC)的遗传背景及免疫学发病机制。方法　采用聚合酶链反应 序列特异性引物 (PCR SSP)技术对 38例IDC患者、5 0例病因明确的心力衰竭 (HF)患者及 10 0例正常对照进行HLA DQA1等位基因分型 ,研究其多态性。结果　IDC组HLA DQA1 0 5 0 1基因频率(2 8次 )显著高于HF组 (14次 )及正常对照组 (2 2次 ) (P <0 0 5 ) ,该趋势随射血分数降低而愈趋明显 ;HF组HLA DQA1 0 30 1也有较其他两组增高趋势 (P >0 0 5 ) ;而对照组HLA 0 2 0 1及 0 10 3基因频率分别高于IDC及HF组 (P <0 0 5 )。结论　HLA DQA1 0 5 0 1是IDC相关基因 ,HLA DQA1 0 30 1与充血性心力衰竭的发生相关 ;HLA DQA1 0 10 3和HLA DQA1 0 2 0 1与IDC及HF组分别呈负相关 ,表明IDC与其他病因所致心力衰竭可能存在不同的免疫遗传学发病机制。     

类风湿关节炎HLA-DQβ1易感基因研究

目的 探讨HLA-DQβl基因多态性在中国汉族类风湿关节炎(RA)发病中的作用及与患者临床指标的关系。方法 选取类风湿关节炎患者及健康对照各42例，以序列特异性引物PCR(PCR—SP)技术对HLA-DQβl的42种亚型进行检测，并分析患者病情、免疫学指标及关节破坏程度与各亚型之间的关系。结果 在RA患者组中HLA-DQβl*0401和*0501等位基因的频率(分别为11．9％、7．1％)显著高于对照组(分别为3．6％、1．2％)(X^2＝4．085，RR＝4．06；X^2＝4．725，RR＝6．83;P＜0．05)，而HAL-DQβ1*0602的频率则明显低于对照组(7．1％vs19．0％)(x^2＝5．23 ;P＜0．05)。HLA-DQβ*l0401／0301或*0401/0303及HLA-DQβl*0501/0301基因型在RA患者中的阳性率(分别为19．05％、9．52％)显著高于对照组(分别为2．38％、0％＞(X^2＝6．098，P＝0．014；X^2＝4．200，P＝0．040)，差异具有显著性。HLA-DQβl*03阳性的RA患者与阴性患者相比发病年龄早，关节破坏严重，关节外表现明显增多，并与部分实验室指标异常呈正相关，其中HLA-DQβ1*03纯合子(HLA-DQβl*03/03)患者的上述异常更为显著。结论 HLA-DQβl*0401及*0501亚型、HLA-DQβl*0401／03及HLA-DQβ1l*0501用301基因型可能与中国汉族RA的易感性有关，而HLA-DQβl*0602可能为抗RA基因;HLA-DQβl*03则与RA的严重程度相关。     

Celiac Disease in African-Americans

Celiac disease is generally under diagnosed in the United States and it is unclear whether the disease is encountered in ethnic minorities. Our purpose is to describe a case series of African-American patients with celiac disease. Nine (1.3%) African-American patients with celiac disease were identified from a prospectively generated database of 700 patients with biopsy proven celiac disease and seen between 1981 and 2004. Females predominated, with seven, compared to two males. Diarrhea was the presentation in only two patients, while three presented with iron deficiency anemia. One third had at least one autoimmune disease. Compliance with a gluten-free diet, the only medical therapy of this disease, was poor. Only four patients adhered strictly to the diet. Celiac disease occurs in African-Americans and may well be underdiagnosed. Special attention needs to be given to methods that encourage adherence to the diet in minority groups.     

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.     

Prognostic irrelevance of HLA-G in B-cell chronic lymphocytic leukemia

In the last few years, it has been suggested that the involvement of human leukocyte antigen-G (HLA-G) in several tumoral processes and its likely participation as a factor of immune tolerance in malignant cells. Recently, positive HLA-G surface expression has been associated with a poor prognosis in a small group of patients with B-cell chronic lymphocytic leukemia (B-CLL), a lymphoproliferative disorder characterized by a heterogeneous clinical course. In the present work, 169 patients suffering from B-CLL were analyzed for the expression of HLA-G by flow cytometry in order to verify its prognostic value in a larger cohort. We observed a low expression of this molecule on leukemic B cells and no significant relation to clinical data or progression-free survival time, indicating that this molecule is not as good immunologic prognostic marker for B-CLL as suggested.