中国汉族人群类风湿性关节炎与HLA-DQ基因多态性和HLA-DR-DQ连锁性的关系

目的 评价中国汉族人群类风湿性关节炎(RA)与HLA-DQ基因多态性和HLA-DR-DQ连锁性的关联情况.方法 以RA组和对照组(正常人)各HLA-DQ、HLA-DR-DQ等位基因频数分布的OR值为统计量.全面检索已发表的有关中国汉族人群RA和HLA-DQ的文献,应用Me-ta分析对基因分型研究结果进行汇总分析.结果 四项研究共入选348例RA患者和162名正常者进行对照,经Meta分析中国汉族人群RA的易感基因有HLA-DQA1*0301(OR=1.820,P=0.01)、DQB1*0401(OR=4.807,P＜0.01).DR4.DQA1*0301(OR=8.437,P=0.024)、DR4-DQB1*0401(OR=3.215,P＜0.01)在中国汉族人群RA中有连锁性并且是RA的危险基因型.HLA.DOA1*0102(OR=0.352,P=0.040)、DQB1*0602(OR=0.404,P=0.01)、DQB1*0604(OR=0,P＜0.05)是中国汉族人群RA的保护基因.结论 DQA1*0301、DQB1*0401是中国汉族人群RA的易感基因,其中DR4-DQA1*0301和DQB1*0401与DR4相连锁是RA的危险基因型,DQA1*0102、DQB1*0602和DQB1*0604是中国汉族人群RA的保护基因.     

儿童期1型糖尿病与HLA—DQB1等位基因的关联研究

目的 研究哈尔滨市儿童期1型糖尿病与HLA－DQB1等位基因的关联关系。方法 选取49例0－14岁发病的1型糖尿病患者和75名健康儿童对照,运用PCR－SSOP技术对部分HLA－DQB1等位基因进行了分型。结果 发现在HLA－DQB1位点上,病例组的DQB1＊0201、＊0303、＊0401频率显著高于对照组,而DQB1＊0301、DQB1＊0501和＊0601频率是显著下降的。结论 研究提示：HLA－DQB1位点的＊0201、＊0303和＊0401对儿童期1型糖尿病具有强易感性,而DQB1＊0301、＊0501和＊0601具有保护性。但未证实DQB1＊0602具有保护作用。     

Ⅱ类人白细胞抗原等位基因与晚期肝脾型日本血吸虫病的相关性研究

目的　探讨Ⅱ类人白细胞抗原 (HLA-Ⅱ)基因多态性与晚期肝脾型日本血吸虫病的相关性。　方法　用聚合酶链反应-序列特异性引物 (PCR-SSP)技术对 46例晚期肝脾型日本血吸虫病患者 (实验组 )和 43例慢性日本血吸虫病患者 (对照组 )HLA-DRB1、DPA1、DQA1和DQB14个基因位点的等位基因进行分型。对两组间等位基因频率的差异进行 χ² 检验。　结果　实验组HLA-DRB1*04、DPA1*0103、DQA1*0601和DQB1*020 1等位基因频率明显高于对照组 ,而HLA-DQA1*0501和DQB1*0601等位基因频率明显低于对照组。　结论　HLA-DRB1*04、DPA1*0103、DQA1*0601和DQB1*0201等位基因 ,因其与晚期肝脾型日本血吸虫病呈显著的正相关 (P <0.0 5 )而可能是该病的遗传易感基因 ,而HLA-DQA1*0501和DQB1*0601等位基因与对该病存在抵抗性有关。     

蒙族和汉族人群HLA-DQA1基因多态性与支气管哮喘的关系

目的 研究蒙族和汉族人群HLA-DQA1基因多态性与支气管哮喘的关系.方法 采用引物序列特异性聚合酶链反应（PCR-SSP）方法对祖籍三代居住在内蒙古地区无血缘关系、异族通婚史,无高血压、糖尿病、免疫系统疾病、炎性肠病等与HLA相关病史及家族史的汉族哮喘患者32例、蒙古族哮喘患者34例进行HLA-DQA1等位基因频率的检测,并分别与符合以上标准、长期居住在内蒙古地区的33例健康汉族和30例健康蒙古族对照者进行比较分析.结果 汉族哮喘组DQA1 ＊ 0501、0301、0302、0201等位基因频率分别为35.93%、46.88%、43.75%和40.63%,较汉族健康组（19.70%、36.37%、6.06%和6.06%）明显增高（P〈0.05）;蒙古族哮喘患者DQA1 ＊ 0501、0302、0104等位基因频率分别为22.06%、36.77%和16.18%,较健康蒙古族（5.00%,5.00%和5.00%）明显增高（P〈0.05）;健康汉族人群DQA1 ＊ 0501等位基因频率高于健康蒙古族人群（P〈0.05）;DQA1 ＊ 0201和0301等位基因却在汉族哮喘患者中明显增高,在健康蒙古族与蒙古族患者之间分布无差异.结论 DQA1 ＊ 0501、0302是汉族和蒙古族哮喘患者共同的易感基因;DQA1＊ 0201、0301等位基因是汉族哮喘患者发病特有的易感基因;DQA1 ＊ 0501等位基因是蒙古族人群中的一个少见基因;DQA1 ＊ 0104等位基因是蒙古族哮喘患者发病的易感基因;该研究进一步证明HLA-DQ基因的种族差异性和在哮喘发病方面的多态性.     

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。     

1型糖尿病一级亲属胰岛自身抗体与HLA-DQ基因型的关系

目的探讨1型糖尿病一级亲属谷氨酸脱羧酶抗体（GADA）、蛋白酪氨酸磷酸酶抗体（IA-2A）、胰岛素自身抗体（IAA）与HLA—DQ基因型之间的关系。方法横断面、病例对照研究。采用放射配体法检测351例糖耐量正常的1型糖尿病一级亲属与376名正常对照者GADA、IA-2A与IAA。其中156例自身免疫1型糖尿病一级亲属与278名正常对照采用PCR-直接测序法明确HLA-DQ基因型。结果（1）与正常对照比较，1型糖尿病一级亲属DQA1＊03、DQB1＊0303、＊0401等位基因与DQA1＊03-DQBl＊0303、DQA1＊05-DQB1＊0201、DQA1＊03-DQB1＊0401单体型频率增高（均P〈0．05或P〈0．01），而DQA1＊0601、＊0201和DQB1＊0301、＊0602等位基因与DQA1＊0102-DQB1＊0602单体型频率减少（均P〈0．05或P〈0．01）。（2）与1型糖尿病患者比较，1型糖尿病一级亲属DQA1＊03等位基因频率减少（45．8％vs54．5％，P〈0．05）。（3）携带DQA1＊03-DQB1＊0303单体型者，GADA、IA-2A与IAA任一自身抗体阳性率高于不携带此单体型者（23．0％们8．6％，P〈0．05）。结论携带DQA1＊03-DQB1＊0303单体型的一级亲属，GADA、IA-2A与IAA任一自身抗体检出率最高。     

1型糖尿病与HLA-DQB1基因及自身抗体相关性研究

采用基因分型技术,确定32例1型糖尿病患者及23例正常对照的HLA-DQB1等位基因.用酶联免疫吸附法测定血清中谷氨酸脱羧酶抗体(GADA)、胰岛细胞抗体(ICA)及胰岛素自身抗体(IAA).结果在1型患者中,DQB1*0201、*0303、*0604等位基因频率显著高于对照(P＜0.05),DQB1*0301则低于对照(P＜0.05),其余DQB1等无显著性差异.等位基因为DQB1*0201的患者中GADA阳性率显著高于阴性率.结论在中国汉族人群中,DQB1*0201、*0303、*0604是1型糖尿病易感性等位基因,DQB1*0301是1型糖尿病保护性等位基因.DQB1*0201可能对GADA的产生起允许作用.     

1型糖尿病与HLA—DQB1基因及自身抗体相关性研究

采用基因分型技术,确定32例1型糖尿病患及23例正常对照的HLA-DQB1等位基因。用酶联免疫吸附法测定血清中谷氨酸脱羧酶抗体（GADA）、胰岛细胞抗体（ICA）及胰岛自身抗体（IAA）。结果在1型患中,DQB1*0201、*0303、*0604等位基因频率显高于对照（P＜0.05),DQB1*0301则低于对照（P＜0.05),其余DQB1等无显性差异。等位基因为DQB1*0201的患中GADA阳性率显高于阴性率。结论：在中国汉族人群中,DQB1*0201、*0303、*0604是1型糖尿病易感性等位基因,DQB1*0301是1型糖尿病保护性等位基因。DQB1*0201可能对GADA的产生起允许作用。     

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。     

人类白细胞抗原DQBl＊0201／0302基因型与2型糖尿病患者β细胞功能的关系

目的 探讨人类白细胞抗原(Human leucocyte antigen HLA)-DQBl*0201／0302基因型与中国人群2型糖尿病(T2DM)β细胞功能的关系。方法 用多聚酶链式反应(PCR)对184例T2DM患者进行HLA—DQBl*0201、*0302基因检测，并同时测定c肽等临床指标。结果 HLA—DQBl*0201／0302组较HLA—DQBl*X／X组(X为非*0201、*0302等位基因)餐后2hC肽明显减低(P=0．005)，用Loglstic回归分析，校正了影响C肽的其他因素后，HLA—DQBl*0201／0302基因型对胰岛功能的0R值为2．88(P=0．024，95％CI为1．15～7．21)。结论 HLA—DQBl*0201／0302基因型可能是中国人群中加速T2DM患者β细胞功能破坏的独立危险因素。     

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.     

Specific human leukocyte antigen DQ influence on expression of antiislet autoantibodies and progression to type 1 diabetes

CONTEXT: Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with type 1 diabetes (T1DM) risk. OBJECTIVE: The objective of the study was to analyze whether HLA DQ alleles influence the development of antiislet autoantibodies, the progression to T1DM among autoantibody-positive relatives, or both. DESIGN: The Diabetes Prevention Trial-1 screened more than 90,000 nondiabetic relatives of patients for cytoplasmic islet-cell autoantibody (ICA) expression between 1994 and 2002. SETTING: The study was conducted in the general community. PARTICIPANTS: The Diabetes Prevention Trial-1 found 2817 ICA-positive relatives who were tested for biochemical autoantibodies (GAD65, ICA512, and insulin) and HLA-DQ haplotypes, and 2796 of them were followed up for progression to diabetes for up to 8 yr (median, 3.6 yr). MAIN OUTCOME MEASURE: Progression to T1DM was measured. RESULTS: High-risk DQ haplotypes and genotypes were associated with a higher percentage of relatives expressing multiple biochemical autoantibodies and higher T1DM risk (e.g., respectively, 59 and 36% at 5 yr for carriers of the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype). The number of autoantibodies expressed significantly increased T1DM risk and across different DQ genotypes, autoantibody positivity directly correlated with diabetes risk. However, multivariate analyses indicated that the influence of most genotypes on T1DM risk was not independent from autoantibody expression, with the possible exception of DQA1*0102-DQB1*0602. Specific genotypic combinations conferred 5-yr diabetes risks significantly lower (e.g. 7%-DQA1*0201-DQB1*0201/DQA1*0501-DQB1*0201 and 14%-DQA1*0301-DQB1*0301/DQA1*0501-DQB1*0201) than when those haplotypes were found in other combinations. CONCLUSION: HLA DQ alleles determine autoantibody expression, which is correlated with diabetes progression. Among autoantibody-positive relatives, most HLA DQ genotypes did not further influence T1DM risk.     

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.     

HLA-patterns in patients with multiple sclerosis and type I diabetes mellitus: evidence for possible mutual exclusion of both diseases

BACKGROUND: Type I diabetes mellitus (T1DM) and multiple sclerosis (MS), both immune-mediated diseases, rarely co-exist in the same individual or co-segregate in families. HLA susceptibility genes for T1DM (DRB1*0401, DRB1*0404, DQB1*0302, DRB1*0301, DQB1*0201) rarely occur in MS patients. HLA genes known to confer "resistance" to T1DM (DRB1*1501, DQB1*0602-DQA1*0102) predispose to MS. To test the hypothesis of mutually exclusive HLA patterns, patients affected by T1DM plus MS were compared to those of patients affected by either of the diseases alone in a case-control study. METHODS: Blood was sampled for analysis of HLA class I and class II alleles from 66 patients of German ancestry, of whom 33 had T1DM plus MS, and 33 had MS-only. For comparison to patients with T1 DM-only we referred to published data. HLA typing was performed using conventional serology (immuno-magnetic beads) and genotyping (SSP-PCR Dynal(R) SSP low/high resolution kits). RESULTS: Individuals with co-existing MS plus T1DM displayed the expected T1DM associated HLA-pattern (75.8% carried DRB1*04, 69.7% carried DQB1*0302, 42% were DR4, DR3 heterozygous), but failed to display the expected MS associated HLA-pattern (0% carried DQB1*0602, 3.1% carried DQA1*0102).The expected MS associated HLA-pattern of Caucasoid patients, however, was found in the MS-only patients (42% carried DRB1*1501-DQB1*0602, 58% carried DQA1*0102), while the prevalence of T1DM susceptibility and 'resistance' alleles was not different from the general population. The allele frequency of DRB1*1501 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQB1*0602 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQA1*0102 was 18/66, 27.3%, in the 33 MS-only patients, and 1/66 1.5% in the 33 MS plus T1DM patients. CONCLUSION: These data confirm the hypothesis of mutually exclusive HLA-patterns of T1DM and MS, and are consistent with a low rate of co-morbidity of both diseases.     

HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM

Summary Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB1^*0301, DQA1*0501 and DQB1^*0201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 (p > 0.05) and DQB1^*0201/0302 (p < 0.01). The findings of the present study suggest that DQB1^*0201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB1^*0301-DQA1*0501-DQB1^*0201/DRB1*0401 -DQA1^*03-DQB1*0302) are at greater risk of developing severe retinopathy. [Diabetologia (1996) 39: 1313–1317] Received: 15 February 1996 and in revised form: 24 April 1996     

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.     

Clinical,serologic, and immunogenetic studies in childhood-onset systemic lupus erythematosus

Objective. To determine the frequency of systemic lupus erythematosus (SLE)—associated clinical manifestations, autoantibodies, and HLA class II alleles in a large cohort of patients with childhood-onset SLE. Methods. Eighty children with SLE onset before age 18 (27 before age 11) were studied for the frequency of renal, neuropsychiatric, and hematologic complications as well as for anti—native DNA, Ro, La, Sm, and U1 RNP autoantibodies. HLA—DR, DQ, and DP alleles were determined by oligotyping. The results were compared with findings in 213 adults with SLE onset at or after age 18 years. Results. Renal involvement was more frequent in those with childhood-onset SLE, especially those with onset before age 11 (82%, compared with 53% in adults). Anti—U1 RNP was more common in American blacks with SLE onset before age 18. HLA—DRB1*0301, DQA1*0501, DQB1*0201 was more common in Caucasians and DRB1*1503, DRB5*0101, DQA1*0102, DQB1*0602 in American blacks, regardless of age at SLE onset. Anti-Sm autoantibodies were most highly associated with HLA—DQA1*0102 and DQB1*0602. Conclusion. While childhood-onset SLE shares many immunogenetic and serologic similarities to adultonset disease, important clinical differences nevertheless exist in children with this disease.     

Relationship between HLA-DQ and -DR genotypes and clinical characteristics in a French population of Type 1 diabetic patients.

AIMS: The present study was designed to look for a heterogeneity in the association between Type 1 diabetes mellitus (DM) and class II alleles of major histocompatibility complex (MHC) according to clinical presentation and C-peptide secretion during the first year of the disease, in a population living in south of France. METHODS: HLA DRB1 and DQB1 genotypes were determined in 129 Caucasoid patients with Type 1 DM and compared to a control group (n = 88). In a subgroup of 46 young adult diabetic patients, basal and postglucagon C-peptide secretion was followed during the first year of the disease (at 0, 1, 3, 6, 9 and 12 months). RESULTS: The two main haplotypes associated with Type 1 DM were DRB1*04DQB1*0302 and DRB1*03DQB1*02. The genotypes DRB1* 04DQB1 *0302/DRB1*04DQB1*0302 and DRB1 *03DQB1*02/DRB1*04DQB1* 0302 were associated with an early onset of diabetes, while homozygosity for DRB1*03DQB1*02 was characterized by later onset. Levels of residual insulin secretion in patients genotyped DRB1*03DQA1*0501DQB1* 02/DRB1* 04DQA1*0301DQB1*0302 were higher than in patients genotyped DRB1* 3DQA1*0501DQB1*02/DRB1*XDQA1*XDQB1*X or DRB1* XDQA1* XDQB1*X/DRB1*XDQA1*XDQB1*X. CONCLUSIONS: This study confirms some clinical heterogeneity of Type 1 DM linked to HLA DR and DQ genotypes, and leads to a paradoxical finding: DQB1*02/ DQB1*0302 combination predisposes to an early onset in the whole population but residual secretion of insulin disappears more slowly in a subgroup of young adults with recently diagnosed diabetes. These data suggest that interrelations between MHC genotype and diabetogenic process could be different at various ages of life.     

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.     

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.