HLA-DQA1基因与广西地区壮族、汉族2型糖尿病关联性研究

目的　研究HLA DQA1基因与广西地区壮族、汉族 2型糖尿病 (DM )的关联。方法　采用聚合酶链反应 序列特异性引物 (PCR SSP)技术 ,分别对广西 67例壮族和 72例汉族 2型DM及 69例壮族、65例汉族正常对照的HLA DQA1位点进行基因分型。结果　壮族 2型DM组DQA1 0 3 0 1、DQA1 0 40 1等位基因频率显著高于壮族对照组 (P <0 .0 0 1,RR =4.69和P <0 .0 0 1,RR =7.5 5 ) ,汉族 2型DM组DQA1 0 10 4等位基因频率明显高于正常汉族对照组 (P =0 .0 0 1,RR =6.5 1) ;DQA1 0 60 1在壮族 2型DM组明显低于对照组 (P <0 .0 0 1,RR =0 .14 ) ,DQA1 0 40 1等位基因频率在汉族 2型DM组明显低于汉族对照组 (P <0 .0 0 1,RR =0 .2 9)。结论　DQA1 0 40 1、DQA1 0 3 0 1可能是广西壮族 2型DM的易感基因 ,而DQA1 0 10 4可能为汉族 2型DM的易感基因 ;DQA1 0 60 1可能是壮族 2型DM的保护基因 ,DQA1 0 40 1则可能是汉族 2型DM的保护基因     

山东沿海地区自身免疫性甲状腺病与HLA等位基因DQA1*0501、DQA1*0201的相关性研究

目的　探讨山东沿海地区自身免疫性甲状腺疾病 (AITD)与HLA DQA1 0 5 0 1、DQA1 0 2 0 1的相关性。方法　采用多聚酶链反应序列特异引物分析 (PCR SSP)技术 ,扩增DQA1 0 5 0 1、DQA1 0 2 0 1的目的基因片段 ,选取 15 6例AITD患者和 74例健康对照 ,分析比较两对等位基因在两组人群中分布频率的差异。结果　Graves病 (GD)和桥本甲状腺炎 (HT)患者HLA DQA1 0 5 0 1的频率均显著高于对照组 (P <0 .0 5 ) ;而HLA DQA1 0 2 0 1在GD和HT两组患者中分布频率明显低于正常对照组 (P <0 .0 1,P <0 .0 5 )。按性别分层分析后 ,仅发现DQA1 0 2 0 1的频率在两组女性患者中显著降低。结论　HLA DQA1 0 5 0 1与山东沿海地区GD和HT的发病易感性相关 ,而DQA1 0 2 0 1与该地区GD和HT ,尤其女性患者的保护性相关。     

广西汉族妊娠期糖尿病与HLA-DQA1基因相关性研究

目的探讨广西地区汉族妊娠期糖尿病（GDM）与HIA-DQA1等位基因的相关性。方法采用聚合酶链反应-序列特异性引物法检测50例GDM孕妇和50例正常孕妇的HLA．DQAI基因型。结果GDM孕妇与正常孕妇相比较,HLA-DQA1＊0501基因频率明显升高,差异有显著性（P=0．006）。HLA—DQA1＊0101、0104、0201、0601等位基因频率在GDM孕妇中有增高趋势,但差异没有显著性（P均〉0．05）。GDM孕妇中HLA—DQA1＊0102、0103、0301、0302和0401基因频率有降低趋势,差异亦无著性（P均〉0．05）。结论广西地区汉族GDM与HLA—DQA1基因相关,HLA—DQA1％0501基因可能为广西地区汉族GDM的易感基因,未发现与HIA—DQA1相关的GDM保护基因。     

慢性乙型肝炎干扰素疗效与人类白细胞抗原-等位基因的关系

目的　探讨慢性乙型病毒性肝炎干扰素 α治疗 6个月疗效与人类白细胞抗原 (HLA)部分等位基因的关系。方法　应用聚合酶链反应 序列特异性引物 (PCR SSP)技术对 6 0例上海地区接受干扰素 α正规治疗 6个月的慢性乙型肝炎患者的HLA Ⅱ类分子DRB1、DQA1、DQB1进行等位基因多态性分析。结果　无应答组的HLA DRB1 0 4携带率高于有应答组 (P <0 .0 2 5 ) ,有应答组的HLA DQA1 0 5 0 5 (P <0 .0 2 5 )、DQB1 0 30 1(P <0 .0 0 5 )的携带率高于无应答组。结论　干扰素 α治疗无应答与HLA DRB1 0 4 (P <0 .0 2 5 )呈正相关 ,与HLA DQA1 0 5 0 5、HLA DQB1 0 30 1呈负相关     

扩张型心肌病心力衰竭患者HLA-DQA1及-DQB1基因多态性研究

目的研究人类白细胞抗原(HLA)-DQA1,-DQB1基因多态性对扩张型心肌病(IDC)心力衰竭患者心功能的影响.探讨IDC发病的免疫学机制及遗传易感性.方法采用PCR-SSP方法对68例无血缘关系、长期居住在中国北方地区的汉族IDC患者和4个IDC家系成员及100名健康者进行HLA-DQA1,-DQB1基因分型;IDC组所有研究对象均接受超声心动图检测心脏射血分数(EF值)并据此进行分层EF值35%～50%者为亚组1,EF值15%～35%者为亚组2,＜15%者为亚组3.结果HLA-DQA1*0501基因和HLA-DQB1*0303基因频率在IDC组(分别为0.3889和0.1806)明显高于正常对照组(分别为0.0900和0.0364),OR值分别为5.20(95%CI3.60-8.50)和4.85(95%CI2.56-9.39).且该趋势随射血分数降低而愈趋明显,表现为HLA-DQA1*0501及HLA-DQB1*0303基因型在EF值＜15%的IDC患者中分布高于EF值≥15%者.相反,IDC组HLA-DQAl*0201基因(0.2000比0.0139)和HLA-DQB1*0502(0.0727比0.0139)、*0504(0.1091比0.0417)基因明显低于正常对照组(P＜0.05).IDC组中HLA-DQAI*0501基因型患者与IDC组中其他基因患者相比,临床心力衰竭症状较重,EF值明显降低(P＜0.01).HLA-DQB1各基因型间EF值未见统计学差异.HLA-DQA1,-DQB1基因与IDC家系连锁分析LOD值＜1.结论HLA-DQA1*0501和HLA-DQB1*0303与我国北方汉族IDC患者遗传易感性相关;而HLA-DQA1*0201和-DQB*0502、*0504则是IDC的保护基因.DQB1基因外显子第57位的丝氨酸对IDC具有保护性,其缺失或取代有可能造成IDC易患倾向.HLA-DQ基因多态性可作为IDC的遗传标记.     

内蒙古籍汉族儿童过敏性紫癜关节胃肠道肾脏受轻与HLA—DQA1的相关性

目的 探讨内蒙古籍汉族儿童过敏性紫癜（AP）关节、胃肠道、肾脏受累与HLA－DQA1等位基因的相关性。方法 采用聚合酶链反应－序列特异性引物（PCR－SSP）技术,在内蒙古汉族无血缘关系及其他风湿性疾病史或家族史的人群中,收集儿童AP累及关节45例、胃肠道39例和肾脏32例分别与90名健康儿童HLA－DQA1等位基因作型别分析。结果 AP累及关节、胃肠道和肾脏DQA1＊0301等位基因频率分别为28．5％、24．9％和25％,均明显高于对照组10．6％,差异有非常显著性（χ^2分别为12．008、7．639和6．882,P值分别为0．001、0．006和0．009,均＜0．01,RR分别为3．83、3．09和3．11,EF分别为0．36、295和0．297）;而DQA1＊0302等位基因频率分别为5．7％、3．9％和6．5％,明显低于对照组19％,差异有非常显著性（χ^2分别为8．352、10．633和5．557,P值分别为0．004、0．002和0．018,前二者P＜0．01,后者P＜0．05,RR分别为0．24、0．159和0．272,PF分别为1．09、1．80和0．92）。结论 HLA－DQA1＊0301等位基因可能是内蒙籍汉族儿童AP累及关节、胃肠道和肾脏发病单体型中一个遗传易感基因,而DQA1＊0302等位基因可能为其遗传保护基因。     

壮族人2型糖尿病HLA—DQA1基因遗传易感性的研究

目的：探讨壮族2型糖尿病患者（DM）及其并发症与人类白细胞抗源（HLA）的相关性。方法：采用聚合酶链反应－序列特异性引物（PCR－SSP）法,对40例壮族2型DM患者和82名壮族正常人HLA－DQA1位点进行基因分型研究。结果：壮族人2型DM组DQA1＊0104等位基因频率明显低于对照组（P＜0．001）,DQA1＊0401等位基因频率明显高于对照组（P＜0．001）。结论：壮族2型DM与HLA有关联,壮族和汉族2型DMA与HLA有不同的关联格局。     

云南汉族原发性高血压左室重构与HLA-DQA1等位基因的相关研究

目的探讨云南汉族原发性高血压（EH）左室重构包括左室肥厚（LVH）及左室扩大（LVD）与HLA—DQA1等位基因的相关性。方法对超声心动图诊断的云南汉族中43例高血压合并LVH患者（EH—LVH＋组）与48例高血压非LVH患者（EH—LVH-组）、对16例高血压伴左室扩大患者（EH—LVD＋组）与75例高血压不伴左室扩大患者（EH—LVD-组）分别进行病例-对照研究，采用PCR—SSP技术对其进行HLA—DQA1等位基因分型。结果（1）EH—LVH＋组中DQA1＊0302频率明显高于EH-LVH-组（18．8％vs5．8％，χ^2=6．876，P〈0．01；RR=3．73）；EH-LVH＋组中DQA1＊0201频率明显低于EH—LVH-组（5．2％vs24．4％，χ^2=13．671，P〈0．01；RR=0．17）；（2）HLA—DQA1等位基因频率在EH-LVD＋组与EH—LVD-组的比较无统计学意义（P〉0．05）；（3）原发性高血压伴左室肥厚的易患因素是：病程、收缩压、DQA1＊0302。结论云南汉族HIA—DQA1等位基因可能与高血压病左室重构中的心肌肥厚有关而与心腔扩大无明显相关。DQA1＊0302可能是云南汉族EH-LVH的易感基因；DQA1＊0201可能是EH—LVH的保护基因。病程长、收缩压高是原发性高血压伴左室肥厚的易患因素。     

抗原肽运载体基因多态性与Graves病关联性的初步探讨

目的　探讨抗原肽运载体 (TAP)基因在华南地区一组汉族人中的分布及其与Graves病的关联性。方法　采用扩增阻滞突变体系 (ARMS)检测TAP1及TAP2基因各多态性位点在 67例Graves病患者及 69例正常对照组中的分布。结果　TAP基因各多态性位点在本组华南地区健康汉族人中的分布与国内外其他组资料基本一致 ,但存在一定程度的差异 ,提示TAP1及TAP2基因可能有民族、地区分布的差异。TAP1基因的单倍体型TAP1D在正常人群中的分布频率显著高于Graves病组(RR =0 1 7,P <0 0 1 ) ,TAP1C在正常人群中的分布频率显著低于Graves病组 (RR =2 0 5 ,P <0 0 5) ;而TAP2基因的单倍体型TAP2A在正常人群中的分布频率显著高于Graves病组 (RR =0 46 ,P <0 0 5) ,TAP2F在正常人群中的分布频率显著低于Graves病组 (RR =9 95 ,P <0 0 5)。结论　TAP1D及TAP2A与Graves病的保护性相关 ,可能是Graves病的保护基因 ;TAP1C及TAP2F与Graves病的易感性相关 ,可能是Graves病的易感基因     

HLA-DR基因与中国南方汉族部分人群肺结核易感基因的研究

目的　探讨人类白细胞抗原 (HLA) DR基因与中国南方汉族部分人群肺结核发病的关联性 ,并寻找与肺结核发病可能相关的HLA易感基因。方法　采用病例 对照的研究方法 ,应用聚合酶链反应 序列特异性引物 (PCR SSP)技术对 110例中国南方汉族肺结核患者 (肺结核病例组 )和 10 1例中国南方汉族健康对照者 (健康对照组 )的 2 3个HLA DR等位基因进行分型 ,比较其等位基因频率(GF)并计算其比值比 (OR)。结果　HLA DR基因PCR SSP分型显示 :(1)肺结核病例组中的DR16等位基因的基因频率显著高于健康对照组 ,两组的GF值分别为 12 6 2 %、5 6 0 % ,两者之间差异具有显著性 (χ2 =5 915 ,PC<0 0 5 ,OR值为 2 5 3)。 (2 )肺结核病例组中的DR1、DR13 3等位基因的基因频率分别为 8 0 8%、2 3 5 7% ,显著低于健康对照组的 2 9 2 9%、5 0 2 4 % ,两组比较 ,差异具有显著性 (χ2值分别为 17 84 7和 14 2 5 8,PC 值均 <0 0 1;OR值分别为 0 2 6、0 33)。结论　 (1)DR16等位基因与南方汉族部分人群的肺结核发病可能密切相关 ,或与真正起作用的易感基因连锁。 (2 )中国南方汉族部分人群DR1、DR13 3等位基因的表达对结核分枝杆菌感染者的发病可能具有拮抗作用。     

HLA-DQ haplotypes in Spanish and German families with Graves' disease: contribution to DQA1*0501-DQB1*0301 mediated genetic susceptibility from fathers.

Genetic and environmental factors are involved in the pathogenesis of Graves' disease. The human leukocyte antigen (HLA) locus is considered to be one risk factor for Graves' disease but parent of origin effects have not been studied. Therefore, we investigated the transmission of HLA risk haplotypes DQA1*0501, DQA1*0501-DQB1*0201 (DQ2), and DQA1*0501-DQB1*0301 (DQ7) in two Graves' disease family-cohorts from Spain and Germany. Altogether 208 trio-families (109 from Spain and 99 from Germany; n = 624 individuals) with Graves' disease were genotyped for HLA-DQ alleles DQA1*0501 and the haplotypes DQA1*0501-DQB1*0201 (DQ2) and DQA1*0501-DQB1*0301 (DQ7). Since both family groups-German and Spanish-showed the same pattern of HLA transmission and nontransmission, they were analyzed together. HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) were significantly overtransmitted from the parents to the affected offspring (204 vs. 131, p = 0.0057, pc = 0.0228 and 109 vs. 55, p = 0.0036, pc = 0.0144, respectively). These haplotypes were preferentially transmitted from fathers and DQA1*0501-DQB1*0301 (DQ7) was also more prevalent in fathers (24.0% vs. 17.1%, p = 0.0162, pc = 0.0648). We conclude, that HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) are strongly associated with Graves' disease in both populations. A parent of origin effect of risk haplotypes can not be excluded at present, warranting further family studies.     

The association between the genetic polymorphism of HLA-DQA1, DQB1, and DRB1 and serum alanine aminotransferase levels in chronic hepatitis C in the Chinese population

Background and Aim:  To investigate a possible association between HLA genes with serum alanine aminotransferase (ALT) levels and evaluate whether the HLA-DQA1, DQB1, and DRB1 genes could influence the development of liver damage in chronic hepatitis C.
Methods:  A total of 145 patients with chronic hepatitis C virus (HCV) infection (36 patients with persistently normal ALT values; 109 patients with elevated ALT levels) and 160 uninfected healthy controls were examined for HLA-DQA1, DQB1, and DRB1 molecules by using polymerase chain reaction–sequencing based typing (PCR-SBT).
Results:  Among the patients chronically infected with HCV, the frequencies of DQA1*0501, DQB1*0301, and DRB1*0401 alleles were significantly increased in the normal ALT group compared with those with abnormal ALT levels, whereas that of DQB1*0201 was significantly lower. As compared to uninfected healthy controls, DQA1*0501, DQB1*0301, and DRB1*0401 allele frequencies were also statistically higher in the normal ALT group, whereas that of DQB1*0201 was the inverse. The haplotype frequencies of DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 were found to be significantly higher in the normal ALT group. Multivariate logistic regression indicated that female sex, and the DQB1*0301 allele and DRB1*0401 allele were independently associated with normal ALT values, whereas DQB1*0201 allele was the inverse.
Conclusions:  These results suggest that particular HLA alleles may have an influence on the serum ALT level of chronic HCV infection as a host genetic factor in the Chinese population. The DQA1*0501, DQB1*0301, and DRB1*0401 alleles, and the DQA1*0301-DQB1*0301, DQA1*0501-DQB1*0301, and DRB1*1101-DQB1*0301 haplotypes seem to be associated with low hepatitis activity; whereas DQB1*0201 allele is closely correlated with the progression of liver injury in chronic HCV infection.     

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians

OBJECTIVE: To define the relative importance (RI) of class II major histocompatibility complex (MHC) alleles and peptide binding motifs as risk or protective factors for juvenile dermatomyositis (DM), and to compare these with HLA associations in adult DM. METHODS: DRB1 and DQA1 typing was performed in 142 Caucasian patients with juvenile DM, and the results were compared with HLA typing data from 193 patients with adult DM and 797 race-matched controls. Random Forests classification and multiple logistic regression were used to assess the RI of the HLA associations. RESULTS: The HLA-DRB1*0301 allele was a primary risk factor (odds ratio [OR] 3.9), while DQA1*0301 (OR 2.8), DQA1*0501 (OR 2.1), and homozygosity for DQA1*0501 (OR 3.2) were additional risk factors for juvenile DM. These risk factors were not present in patients with adult DM without defined autoantibodies. DQA1 alleles *0201 (OR 0.37), *0101 (OR 0.38), and *0102 (OR 0.51) were identified as novel protective factors for juvenile DM, the latter 2 also being protective factors in adult DM. The peptide binding motif DRB1 (9)EYSTS(13) was a risk factor, and DQA1 motifs F(25), S(26), and (45)(V/A)W(R/K)(47) were protective. Random Forests classification analysis revealed that among the identified risk factors for juvenile DM, DRB1*0301 had a higher RI (100%) than DQA1*0301 (RI 57%), DQA1*0501 (RI 42%), or the peptide binding motifs. In a logistic regression model, DRB1*0301 and DQA1*0201 were the strongest risk and protective factors, respectively, for juvenile DM. CONCLUSION: DRB1*0301 is ranked higher in RI than DQA1*0501 as a risk factor for juvenile DM. DQA1*0301 is a newly identified HLA risk factor for juvenile DM, while 3 of the DQA1 alleles studied are newly identified protective factors for juvenile DM.     

中国人群1型糖尿病HLA-DQ基因多态性的Meta分析

目的　综合评价中国人群HLA DQ基因多态性与 1型糖尿病 (DM)的关联性。方法　以 1型DM组和健康对照组的各HLA DQ等位基因频数(基因型频数、单倍型频数 )分布的OR值为统计量,全面检索相关文献;应用Meta分析软件包REVMAN4. 2,在基因分型水平上,对各研究的结果进行一致性检验和数据合并,并评估发表偏倚。结果　等位基因DQA1* 0301、DQA1* 0501、DQB1* 0201、DQB1* 0303、DQB1* 0401和DQB1* 0604是中国人群 1型DM的危险基因 (均P<0. 05), 他们的合并OR值分别为2. 83、2. 90、4. 17、1. 65、2. 00和 3. 00;基因型 (或单倍型 )DQA1* 0301 /DQB1* 0201、DQA1* 0301 /DQB1*0302、DQA1* 0501 /DQB1* 0201、DQA1* 0301 /DQB1* 0201 /DRB1* 0301和DQB1* 0302 /DRB1* 0405是中国人群 1型DM的危险基因型(或单倍型,均P<0. 05),他们的合并OR值分别为 8. 95、3. 09、6. 01、6. 57和 14. 85。而等位基因DQA1* 0101、DQA1* 0102、DQA1* 0103、DQA1* 0104、DQA1* 0201、DQA1* 0401、DQA1* 0601、DQB1* 0301、DQB1* 0501、DQB1* 0503、DQB1* 0601和DQB1* 0602是中国人群 1型DM的保护等位基因(均P<0. 05),他们的合并OR值分别为 0. 47、0. 38、0. 21、0. 07、0. 44、0. 39、0. 44、0. 19、0. 33、0. 32、0. 42和 0. 28; 基因型     

HLA DQA1*0501 and DRB1*0301 antigens do not independently convey susceptibility to Graves' disease

Genes of, or closely associated to, the HLA complex are assumed to contribute to the genetic predisposition of Graves' disease. The aim of this study was to investigate the presence of the HLA DQA1*0501 and DRB1*0301 antigens in Greek patients with Graves' disease. In addition, we tried to establish if there is any association between these antigens and any of the clinical manifestations of the disease. We examined 117 patients with Graves' disease and 104 healthy controls. DNA was extracted from peripheral lymphocytes and the HLA DQA1*0501 and DRB1*0301 genomic regions were amplified by PCR and characterized by hybridization with sequence specific oligonucleotides (SSO). Two of the patients had a positive family history for Graves' disease and 46 had clinical thyroid eye disease (TED). The frequencies of both DQA1*0501 and DRB1*0301 antigens were significantly increased in patients compared to controls (relative risk [RR] 4.2 and 4.5 for each antigen respectively). Neither of these two antigens was an independent risk factor for Graves' disease. However, the combination of both these HLA antigens resulted in a striking increase in the RR for development of Graves' disease especially in females (RR/F=27, RR/M=8.4). No association was found between these antigens and positive family history or the presence of TED. These data suggest that HLA DQA1*0501 and DRB1*0301 antigens are not independent risk factors for the development of Graves' disease. On the contrary, the presence of both these alleles results in a significant increase in the RR for the development of Graves' disease in the Greek population, particularly in females.     

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—DQA1位点寡核苷酸探针检测上海地区汉族IDDM易感性

应用聚合酶链反应(PCR)和寡核苷酸探针点杂交技术分析了中国上海地区汉族42例胰岛素依赖型糖尿病(IDDM)患者和40例正常对照的DQA_1基因。结果发现IDDM组DQA_1*0301和DQA_1*0501等位基因频率显著高于正常对照组,而IDDM组DQA_1*0103和DQA_1*0201等位基因频率显著低于正常对照组。这些表明在中国上海地区汉族人群中,DQA_1*0301和DQA_1*0501与ID-DM易感性相关联,而DQA_1*0103和DQA_1*0201则增强对IDDM的抵抗性。对DQA_1链52位氨基酸多态性分析,提示:DQA_1链52位编码精氨酸可能与IDDM易感性有关,52位非精氨酸与IDDM无     

HLA-DQ screening for risk assessment of insulin dependent diabetes in northern Italy

Genetic markers may be used to improve the prediction of insulin-dependent diabetes mellitus (type 1) in individuals with islet autoantibodies. In order to develop a risk assessment strategy for the Lombardy region of northern Italy based on genetic and immunological markers, we analyzed HLA DQA1 and DQB1 alleles in 60 type 1 probands and their first-degree relatives and 65 unrelated control subjects from the same area using polymerase chain reaction (PCR) and oligonucleotide probes. The major risk haplotypes were DQA1 *0501-DQB1 *0201 (39.1% of diabetic vs 8.9% of non-diabetic haplotypes) and DQA1 *0301-DQB1 *0302 (20% of diabetic vs 7.1% of non-diabetic haplotypes). Stratified analysis showed DQA1 *0102-DQB1 *0502 also to be associated with type 1 susceptibility when found together with DQA1 *0501-DQB1 *0201 or DQA1 *0301-DQB1 *0302. One type 1 patient had the type 1-protective DQA1 *0102-DQB1 *0602 haplotype. Overall, 88% of patients and 20% of unrelated control subjects had either DQA1 *0501-DQB1 *0201 or DQA1 *0301-DQB1 *0302 in the absence of DQA1 *0102-DQB1 *0602. These data suggest that typing for markers identifying these three haplotypes in the Lombardy population will achieve a sensitivity of almost 90% and exclude 80% of children from subsequent islet autoantibody testing.     

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.     

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