HLA-DQA1*0103-DQB1*0601 haplotype and Helicobacter pylori-positive gastric mucosa-associated lymphoid tissue lymphoma.

BACKGROUND & AIMS: Immune responses to Helicobacter pylori are important in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In this retrospective case study, we investigated whether certain alleles and haplotypes of major histocompatibility complex genes are associated with gastric MALT lymphoma and the efficacy of H pylori eradication therapy on the lymphoma. METHODS: Blood samples were obtained from 18 patients with H pylori-positive gastric MALT lymphoma (5 men and 13 women; age range, 51-80 years), 30 patients with H pylori-positive non-ulcer dyspepsia (17 men and 13 women; age range, 37-77 years), and 30 patients with H pylori-negative non-ulcer dyspepsia (12 men and 18 women; age range, 37-77 years). HLA-DQA1 and DQB1 allele typing was performed by use of a polymerase chain reaction sequence-specific oligonucleotide procedure. All patients with MALT lymphoma were treated with H pylori eradication therapy and followed up by repeated endoscopy and biopsy. RESULTS: We found a significant increase in alleles HLA-DQA1*0103 and HLA-DQB1*0601, and a haplotype DQA1*0103-DQB1*0601, in MALT lymphoma patients when compared with non-ulcer dyspepsia patients who were either H pylori-positive or not and with a healthy control population. After H pylori eradication, the lymphomas regressed completely in all 10 patients who possessed the DQA1*0103-DQB1*0601 haplotype but in only 4 of the 8 without this haplotype (P = .023). CONCLUSIONS: DQA1*0103-DQB1*0601 haplotype-positive gastric MALT lymphoma is likely to respond to therapy by eradication of H pylori.     

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 class II allele and haplotype frequencies in Iranian patients with leukemia

Previous studies demonstrated significant differences in a number of HLA allele frequencies in leukemia patients and normal subjects. In this study, we have analyzed HLA class II alleles and haplotypes in 110 leukemia patients (60 acute myelogenous leukemia "AML", 50 chronic myelogenous leukemia"CML") and 180 unrelated normal subjects. Blood samples were collected from all of the patients and control subjects. DNA was extracted by salting out method and HLA typing was performed using PCR-SSP method. Significant positive association with AML was obtained for HLA-DRB1*11allele (35% vs. 24.7%, P=0.033). Two alleles including HLA-DRB4 and -DQB1*0303 were significantly less frequent in AML patients than in controls. HLA-DQB1*0303 allele was never observed in CML patients compared with allele frequency in controls (4.2%). According to haplotype analysis, HLA-DRB1*0101/DQA1*0104/-DQB1*0501 frequencies were significantly higher and -DRB1*16/-DQA1*01021/-DQB1*0501 frequencies were significantly lower in CML patients than in controls. In conclusion it is suggested that HLA-DRB1*16 allele and HLA-DRB1*15/-DQA1*0103/-DQB1*06011 and -DRB1*16/-DQA1*01021/-DQB1*0501 haplotypes predispose individuals to AML and HLA-DRB4 allele predispose to CML. Future studies are needed to confirm these results and establish the role of these associations in AML and CML.     

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.     

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。     

HLA-DQ等位基因与哮喘相关性研究

目的探讨在中国汉族哮喘家系中,HLA-DQ基因与哮喘的相关性。方法对98例哮喘家系成员,用PCR-序列特异性引物(PCR-SSP)技术对HLA-DQA1和B1进行基因分型,并与正常对照进行比较。结果发现DQA1*0101和DQA1*0601等位基因频率在哮喘患者组(40.0%,45.0%)较正常对照组(16.4%,13.4%)显著升高(χ2=6.1860,P<0.05,RR=3.39;χ2=11.6090,P<0.01,RR=5.27);DQB1*0303和DQB1*0601等位基因频率在哮喘患者组(55.0%,47.5%)较正常对照组(13.7%,13.7%)显著升高(χ2=15.7400,P<0.01,RR=7.68;χ2=10.9300,P<0.01,RR=5.69)。同时发现HLA-DQB1*0201等位基因频率在对屋尘螨抗原特异性IgE反应哮喘家系成员(39.4%)较家系中非特应症者（12.0％）显著高频表达(t=2.3825,P<0.05)。结论HLA-DQA1*0101,*0601和DQB1*0303,*0601是哮喘遗传易感等位基因;HLA-DQB1*0201限定对屋尘螨抗原特异性IgE反应。     

Analysis of HLA-DRB1, DQA1, DQB1 haplotypes in Sardinian centenarians

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1 *15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1, DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1 *15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1 *01, DQB1 *05 and HLA-DQA1 *01,DQB1 *06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity.     

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     

Autoantibodies to islet antigen-2 are associated with HLA-DRB1*07 and DRB1*09 haplotypes as well as DRB1*04 at onset of type 1 diabetes: the possible role of HLA-DQA in autoimmunity to IA-2

AIMS/HYPOTHESIS: To further our understanding of antigen presentation by HLA class II molecules, we have examined the influence of HLA class II genotype on expression of autoantibodies to islet antigen-2 (IA-2A). METHODS: HLA class II genotype and IA-2A were determined within 3 months of diagnosis in 618 patients with type 1 diabetes (median age 11 years [range 0.7-20.9]). Antibodies to the juxtamembrane region of IA-2 were measured by a radiobinding assay in 481 of 484 IA-2A-positive patients. RESULTS: IA-2A prevalence was highest in patients carrying at least one HLA-DRB1*04-DQA1*0301 (385 of 450; 86%), DRB1*07-DQA1*(0201 or 0301) (58 of 64; 91%) or DRB1*09-DQA1*0301 haplotype (18 of 19; 95%). Multiple regression showed that IA-2A were strongly associated with the number of these haplotypes carried; only 69 of 132 (52%) patients carrying none of these haplotypes had IA-2A, compared with 322 of 391 (82%) patients with one and 93 of 95 (98%) with two of these haplotypes (p < 0.001). IA-2 juxtamembrane antibodies were less frequent in IA-2A-positive patients with one (35%) or two (36%) DRB1*03-DQB1*02 or DRB1*07-DQB1*02 haplotypes than in those negative for these haplotypes (52%) (p = 0.002), but showed an independent positive association with IA-2A level (p < 0.001). CONCLUSIONS/INTERPRETATION: HLA class II alleles strongly influence the prevalence of IA-2A. The high IA-2A prevalence in patients carrying DRB1*04, DRB1*07 and DRB1*09 alleles in linkage disequilibrium with DQA1*0301 or the closely related DQA1*0201 suggests the humoral response to IA-2 may be driven by HLA-DQA1 genes.     

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.     

Curative effects of interferon-α and HLA-DRB1 -DQA1 and -DQB1 alleles in chronic viral hepatitis B

AIM: To investigate the association between curative effects of interferon-α and partial human leucocyte antigen (HLA)Ⅱ alleles in chronic viral hepatitis B.METHODS: Sixty patients with chronic viral hepatitis B in Shanghai were treated with a standard course of treatment with interferon-α for 6 mo. HLA-DRB1, -DQA1, and -DQB1 alleles were detected by polymerase chain reaction-sequence specific primer (PCR-SSP) method. RESULTS: Frequencies of HLA-DRB1*04(P＜0.025) and HLA-DQA1*0303 (P＜0.01) in non-responders were significantly higher than those in partial and complete responders. Frequencies of HLA-DQAI*0505(P＜0.025) and HLA-DQB1*0301(P＜0.005) in partial and complete responders were significantly higher than those in non-responders.CONCLUSION: Non-response to interferon-α therapy is positively correlated with HLA-DRB1*04 and HLA-DQA1*0303, and negatively correlated with HLA-DQA1*0505 and -DQB1*0301 in patient with chronic viral hepatitis B.HLA Ⅱ genes of the identification alleles provide a method for evaluating outcome of interferon-α treatment.     

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.     

HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis

OBJECTIVES: To elucidate the contribution of HLA-DR-DQ haplotypes and their genotypic combinations to susceptibility to rheumatoid arthritis, and to evaluate the various models for HLA associated risk for the disease in a series of Finnish patients. METHODS: 322 Finnish patients with rheumatoid arthritis were typed for common north European HLA-DR-DQ haplotypes and compared with a series of 1244 artificial family based control haplotypes. RESULTS: The association of the so called shared epitope (SE) haplotypes (DRB1*0401, *0404, *0408, and *01) with rheumatoid arthritis was confirmed. The DRB1*0401 haplotypes carried a far stronger risk for the disease than the (DRB1*01/10)-(DQA1*01)-DQB1*0501 haplotypes. Seven protective HLA haplotypes--(DRB1*15)-(DQA1*01)-DQB1*0602; (DRB1*08)-(DQA1*04)-DQB1*04; (DRB1*11/12)-DQA1*05-DQB1*0301; (DRB1*1301)-(DQA1*01)-DQB1*0603; (DRB1*1302)-(DQA1*01)-DQB1*0604; (DRB1*07)-DQA1*0201-DQB1*0303; and (DRB1*16)- (DQA1*01)-DQB1*0502--were identified. In accordance with the reshaped shared epitope hypothesis, all the protective DRB1 alleles in these haplotypes share either isoleucine at position 67 or aspartic acid at position 70 in their third hypervariable region motif. However, differences in the disease risk of haplotypes carrying the same DR but different DQ alleles were also found: (DRB1*07)-DQA1*0201-DQB1*0303 was protective, while (DRB1*07)-DQA1*0201-DQB1*02 was neutral. The same haplotypes carried different risks for rheumatoid arthritis depending on their combination in genotypes. CONCLUSIONS: When assessing the influence of HLA genes on the susceptibility to rheumatoid arthritis, not only should the HLA-DR or -DQ alleles or haplotypes be unravelled but also the genotype. The effect of HLA class II region genes is more complicated than any of the existing hypotheses can explain.     

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     

成人隐匿性自身免疫性糖尿病与HLA-DQ、DR基因的关联性

探讨成人隐匿性自身免疫性糖尿病（LADA）与HLA-DQ、DR基因的关联性. 方法用聚合酶链反应序列特异性引物（PCR-SSP）检测60例正常人、41例1型糖尿病人（TlDM）和39例LADA患者的HLA-DR、DQ基因频率. 结果HLA-DR3、DR4、HLA-DQA1＊0301、HLA-DQB1＊0201与TlDM的易感性相关;HLA-DR15、HLA-DQB1＊0601与T1DM的保护性相关.HLA-DR4、HLA-DQA1＊0301、HLA-DQB1＊0201与LADA的易感性相关,HLA-DQB1＊0601的基因频率在LADA组中显著高于TlDM组（P＜0.05）. 结论不同的遗传背景可能是影响LADA和TlDM起病方式及病情进展的重要因素之一.     

Curative effects of interferon-α and HLA-DRB1 -DQA1 and -DQB1 alleles in chronic viral hepatitis B

AIM: To investigate the association between curative effects of interferon-α and partial human leucocyte antigen (HLA) Ⅱ alleles in chronic viral hepatitis B.METHODS: Sixty patients with chronic viral hepatitis B in Shanghai were treated with a standard course of treatment with interferon-α for 6 mo. HLA-DRB1, -DQA1, and -DQB1 alleles were detected by polymerase chain reaction-sequence specific primer (PCR-SSP) method.RESULTS: Frequencies of HLA-DRB1*04 (P＜0.025) and HLA-DQA1*0303 (P＜0.01) in non-responders were significantly higher than those in partial and complete responders. Frequencies of HLA-DQA1*0505 (P＜0.025) and HLA-DQB1*0301 (P＜0.005) in partial and complete responders were significantly higher than those in nonresponders.CONCLUSION: Non-response to interferon-α therapy is positively correlated with HLA-DRB1*04 and HLADQA1*0303, and negatively correlated with HLA-DQA1*0505 and -DQB1*0301 in patient with chronic viral hepatitis B.HLA Ⅱ genes of the identification alleles provide a method for evaluating outcome of interferon-α treatment.     

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.     

Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility

Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101–HLA-DRB1*1501–HLA-DQA1*0102–HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.     

DR- and DQ-associated protection from type 1A diabetes: comparison of DRB1*1401 and DQA1*0102-DQB1*0602*

The transmission disequilibrium test was used to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type 1 diabetes repository (n = 1371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (n = 2441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P < 0.001, vs. the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P < 0.0001). Rare DQA1*0102-DQB1*0602 haplotypes without DRB1*1501 were never transmitted to affected offspring (n = 6). The DQA1*0101-DQB1*0503 haplotype was transmitted to 2 of 42 (4.8%) affected offspring (P < 0.001, vs. 50% expected transmission). Although DRB1*1401 is in linkage disequilibrium with DQB1*0503, neither of the two affected children who carried DQA1*0101-DQB1*0503 had DRB1*1401. However, all 13 nonaffected children who inherited DQA1*0101-DQB1*0503 had DRB1*1401. In a case-control comparison of patients from the Barbara Davis Center, DQA1*0101-DQB1*0503 was found in 5 of 110 (4.5%) controls compared with 3 of 728 (0.4%) patients (P < 0.005). Of the three patients with DQB1*0503, only one had DRB1*1401. Our data suggest that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type 1A diabetes.     

HLA-DRB1、DQB1基因与汉族哮喘的相关性研究

探讨 HL A- DRB1、DQB1位点基因在中国汉族哮喘家系中与哮喘的相关性。用序列特异性引物 -聚合酶链反应 (PCR- SSP)方法 ,对 10 1例哮喘家系成员和 6 0例正常对照者进行了 HL A- DRB1、DQB1等位基因的分型 ,并分析了 DRB1、DQB1基因在两组中的分布。结果示 ,与正常对照组比较 ,哮喘患者组 DRB1* 15等位基因频率 (2 0 .93% )较正常对照组 (6 .6 7% )明显增高 (χ2 =10 .95 ,P<0 .0 5 ) ;DQB1* 0 6 0 1等位基因频率在哮喘患者组(31.4 0 % )较正常对照组 (7.5 % )明显增高 (χ2 =2 3.0 8,Pc<0 .0 1)。同时发现 HL A- DRB1* 0 7等位基因频率在对屋尘螨抗原皮试阳性家系成员中 (2 7.4 2 % )较家系中皮试阴性者 (5 .36 % )显著增高 (χ2 =10 .83,Pc<0 .0 5 )。HL A- DRB1* 15和 DQB1* 0 6 0 1可能是汉族哮喘的遗传等位易感基因 ,HL A- DRB1* 0 7在限定对屋尘螨抗原特异性 Ig E反应过程中起重要作用