HLA-DQA, -DQB AND -DRB ALLELE CONTRIBUTION TO NARCOLEPSY SUSCEPTIBILITY

The association of narcolepsy with HLA class I antigens and HLA class II alleles was studied in a series of Spanish narcoleptic patients. The haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 was found to be significantly associated with the disease, while the haplotype DRB1*0701-DRB4*01-DQA1*0201-DQB1*02 might confer a slight protective effect against narcolepsy. Gene dose–effect was not seen in any of the involved alleles, and linkage disequilibrium between the positively associated alleles was found to be stronger in patients than in controls. Statistical analysis applied to identify the HLA allele truly responsible for the association did not clearly discriminate between the contribution of DRB1*1501 and that of DQB1*0602, but it proved that the association with DQA1*0102 is secondary to that with DRB1*1501/DQB1*0602. Analysis of the diagnostic value of typing for the narcolepsy-associated alleles demonstrated a very high negative predictive value and revealed that this test can be convenient for exclusion of narcolepsy in cases when the diagnosis is not evident after clinical evaluation and the marker haplotype is absent. Finally, a family study indicated that narcolepsy is a multifactorial disorder that involves HLA genes under an incomplete penetrance model, with possible influences from environmental factors or other genes different to HLA genes.     

HLA CLASS II POLYMORPHISM AND IDDM SUSCEPTIBILITY IN THE GREEK POPULATION

The frequencies of HLA-DQA1, DQB1 and DRB1 alleles were compared between 50 Insulin-Dependent Diabetes Melitus (IDDM) patients and 49 healthy controls in the Greek population. Statistically significant difference in the frequencies of HLA-DQA1*0501-DQB1*0201 (P = 10^-4), DQA1*0301-DQB1*0201 (P= 0.01) and DQA P0301-DQB 1*0302 (P= 0.001) were observed. The DRB1*0405-DQA1*0301-DQB 1*0201 was the only DR, DQ combination significantly associated with the disease. The unexpected increase of DRB1*0405 observed in the Greek IDDM may suggest as reported in Chinese and Japanese IDDM a contribution of DRβ and DQα in susceptibility. Moreover, in contrast to the Asians, in the Greek, the DRβ, DQα are found with the usual DQβ 57-ve.     

FREQUENCY OF HLA-DPB1 ALLELES IN A SPANISH POPULATION: THEIR CONTRIBUTION TO RHEUMATOID ARTHRITIS SUSCEPTIBILITY

HLA-DPB1 allele frequencies in 181 unrelated control individuals and 70 rheumatoid factor-positive RA patients from Seville (Spain) were determined using oligonucleotide typing methods. All frequencies shown concern the percentage of individuals positive for a certain allele. HLA-DPB1*0401 was the most common DPB1 allele in the healthy individuals, possessed by 65.7% of them. In addition to HLA-DPB1 *0401, only the following alleles were found in normal subjects at frequencies greater than 10%: DPB1*0101 (15.5%), DPB1*0201 (12.2%), DPB1*0301 (16.6), and DPB1*0402 (29.3%). When HLA-DPB1 allelic frequencies were compared between seropositive RA patients and controls, a negative association for DPB1*0301 and DPB1*0401 was found in RA patients, although it failed to reach statistical significance after correction for the number of comparisons made. The other DPB1 alleles exhibited almost identical frequencies in both groups. However, when only DR4⁺ patients and controls were considered, the decrease in the frequency of the DPB1*0301 and DPB1*0401 alleles lacked statistical significance. On the other hand, when DR4^- RA patients and controls were compared, the frequency of DPB1*0301 was found decreased significantly again, even more than in the whole group of patients.     

原发性IgA肾炎与HLA-DQB1等位基因遗传多态性的研究

应用ＰＣＲ／ＳＳＯ方法对５１例经肾穿刺证实ＩｇＡ肾病虱和９６名健康对照人员进行了ＨＬＡ－ＤＱＢ１等位基因分型。结果显示ＩｇＡＮ患者组中ＤＱＢ１＾＊０３０２基因频率明显高于正常对照组；ＩｇＡＮ患者组中ＤＲ４，ＤＱＢ１＾０３０３均为阳性的表型频率也明显高于对照组，而ＤＲ４阳性，ＤＱＢ１＾０３０２阴性的表型频率在两组中无差异。     

THE HLA-DRB1*0101 ALLELE IS RESPONSIBLE FOR HLA SUSCEPTIBILITY TO LICHEN RUBER PLANUS

Serological studies have demonstrated that lichen ruber planus is associated with the HLA-DR1 antigen. This association was also confirmed by us in the Sardinian population. To establish which DRB1 molecular alleles are involved, we studied a selected group of 14 DR1 positive patients affected by cutaneous idiopathic lichen planus and a group of DR1 positive healthy controls using PCR with sequence-specific primers (PCR-SSP). Comparisons between the allele frequencies in patients and controls showed a positive association with cutaneous idiopathic lichen planus for the DRB 1*0101 allele (RR = 5.8, P= 0.0097). DRB1*0101 and DRB1*0102 are associated with the same DQA1 and DQB1 alleles and are different only for two amino acids in positions 85 and 86 of the DRB 1 gene. In our case report predisposition to cutaneous idiopathic lichen planus is correlated with a valine in position 85 and a glycine in position 86 at the second exon of the DRB 1 gene.     

HLA-DR4 SUBTYPE AND -B ALLELES IN DQB1*0302-POSITIVE HAPLOTYPES ASSOCIATED WITH IDDM

We determined the distribution of DR4 subtypes in 309 DQB1*0302-positive haplotypes found in insulin-dependent diabetes mellitus (IDDM) patients and 70 control haplotypes present only in healthy family members. An increased frequency of DRB1*0401 allele (74.4% vs. 55.7%, P = 0.003) and a decrease of DRB1*0404 allele (23.6% vs. 40.0%, P = 0.0064) was revealed. A further analysis of extended haplotypes demonstrated strong linkages between various B alleles and DRB1*04 subtypes. HLA-B39 was more frequent in DRB1*0404–DQB1*0302-positive IDDM haplotypes compared with control ones (37.0% vs. 14.3%, P = 0.049), suggesting an involvement of the region telomeric to HLA-DRB1 in the susceptibility to IDDM.     

北京地区中国人Apo（a）多态表型的分布及其与脂质及脂蛋白的关系

为探讨Ａｐｏ（ａ）基因在中国人群中的分布特点及其与脂质及脂蛋白的关系，应用Ｗｅｓｔｅｒｎ印迹法检测１０２名北京地区中国汉族健康人群（男５７名，女４５名，年龄２１～７４岁）的Ａｐｏ（ａ）多态表型，发现：（１）Ａｐｏ（ａ）表型的分布频率在不同性别之间无明显差异；低分子量表型（包括含有Ｂ、Ｓ１和Ｓ２的全部表型）占１５．７％，其中Ｓ２＞Ｓ２Ｓ３＞Ｂ和Ｓ２Ｓ４＞Ｓ１、ＢＳ４和Ｓ１Ｓ３；高分子量表型（包括只含有Ｓ３、Ｓ４和Ｓ３Ｓ４及Ｎｕｌｌ表型）占８４．３％，其中Ｓ４＞Ｎｕｌｌ＞Ｓ３Ｓ４＞Ｓ３１纯合型占５９．８％；杂合型占１６．７％，Ｎｕｌｌ型占２３．５％；（２）Ａｐｏ（ａ）分子量大小与Ｌｐ（ａ）血浆水平呈明显负相关；与其他脂质及脂蛋白相关不明显；（３）Ｌｐ（ａ）浓度的５６．４％取决于Ａｐｏ（ａ）多态表型的变化；而其他脂质及脂蛋白则不受Ａｐｏ（ａ）多态性的影响。为冠心病的研究积累了资料。     

HLA CLASS II AND SUSCEPTIBILITY AND RESISTANCE TO INSULIN-DEPENDENT DIABETES MELLITUS IN A POPULATION FROM THE NORTHWEST OF SPAIN

The role of HLA class II alleles in genetic predisposition to insulin-dependent diabetes mellitus(IDDM) was examined using Polymerase Chain Reaction/oligonucleotide probe typing (PCR/SSOs) of eight HLA class II loci in 58 IDDM patients and 50 healthy controls from the Northwest of Spain (Asturias). We compared the distribution of HLA class II alleles, haplotypes and genotypes between IDDM patients and controls, and tested three recently proposed HLA-IDDM susceptibility theories. By using the aetiologic fraction (δ) as an almost absolute measure of the strongest linkage of disequilibrium of a HLA marker to the putative Type I susceptibility locus, it has been found that the strength of association of the HLA markers may be quantified as follows: DQA1 *03-DQB1 *0302 or DQA1 *0501-DQB1 *0201 > DR3 or DR4; presence of more than one dimer DQαβ of the six proposed by Rønningen > non-Asp57 DQβ and Arg52 DQα > Arg52 DQα > non-Asp57 DQβ/non-Asp57 DQβ > DRB1*0301; DQA1*0501-DQB1*0201 > DQA1*03-DQB1*0302; DQB1*0302. The presence of at least one Asp57 DQβ allele was the best protection HLA marker to IDDM in our population. Therefore, the above data confirm that IDDM susceptibility to HLA locus is linked more to DQ than DR.     

DIFFERENCES IN THE SUSCEPTIBILITY OF MHC AND NON-MHC MIXED LYMPHOCYTE REACTIONS TO SUPPRESSION BY MURINE AMNIONIC FLUID AND ITS COMPONENTS

The ability of mouse amniotic fluid (MAF), alpha-foetoprotein (AFP) and MAF depleted of AFP (MAF - AFP) to suppress primary one-way MLR's was investigated. It was found that MAF, AFP and MAF - AFP were all suppressive of MLR's specific for MHC, K, D or I + S determinants. Suppression was observed when either lymph node or spleen cells were used as the responder cells. Nylon wool column passage of these cells did not significantly affect the immunosuppressive action of these substances. In contrast, MLR's specific for non-MHC/M-locus determinants demonstrated either diminished suppression or augmentation of the response, compared with the MHC stimulated MLR's. Our results show a differential effect of whole MAF and its fractions on the proliferative responses induced by various allogeneic stimuli and suggest that suppression is not due to a non-specific effect on proliferation regardless of the stimulus or cell type involved.     

HLA IN POPULATIONS: AN APPROACH FOR GENETICAL SUSCEPTIBILITY TO CANCER

The geographical correlations between the incidence of various cancers and the HLA and ABO antigen frequencies are studied. There is, for example, a positive correlation between breast and colorectal carcinoma and AI, B8 and B12 antigens, and a negative one between prostate carcinoma and B12. The role of the HLA system itself or other genes involved in these associations is discussed. This study gives some evidence of a possible genetic background of susceptibility or resistance to cancer.     

HLA-DRB1*0401 IS ASSOCIATED WITH SUSCEPTIBILITY TO INSULIN-DEPENDENT DIABETES MELLITUS INDEPENDENTLY OF THE DQB1 LOCUS

The distribution of DRB1*04 alleles and DRB1/DQB1 haplotypes was analysed in 57 DR4⁺ caucasoid subjects with insulin-dependent diabetes mellitus (IDDM) and 96 DR4⁺ healthy controls selected on the basis of DR serology, and the findings were analysed in relation to age at diagnosis of IDDM. DNA samples were amplified using specific DR and DQ primers and hybridized with sequence-specific oligonucleotide probes. A significantly increased combined frequency of DRB 1*0401 and 0402 was observed in IDDM subjects aged ≤12 years at diagnosis (allele frequency 88.4% compared with 62.0% in controls, P < 0.025). There was a non-significant increase in DRB 1*0401 and 0402 in IDDM subjects ≤12 years when compared with IDDM subjects >12 years (P < 0.1). DRB 1 *0404 was decreased in the total IDDM subject group compared with controls (4.8% vs. 19.0%, P < 0.025) but did not reach statistical significance in the individual age at diagnosis groups. In contrast, the frequency of DQB1 *0302 was increased uniformly across both ages at diagnosis groups. In controls DRB 1*0401 occurred in haplotype association with DQB 1*0301 in a significantly greater frequency than with DQB 1*0302. However, 95.0% of DRB 1*0401 IDDM subjects were DQB 1*0302. DRB 1*0404, which was decreased in frequency in IDDM subjects, occurred in association significantly more frequently with DQB 1 *0302 in controls. These results imply that DRB 1 and DQB 1 have independent roles as HLA susceptibility genes in IDDM. DQB1 may have a permissive role whereas DRB1 could influence the rate at which underlying disease progresses to clinical IDDM.     

HLA DPB1 ALLELES AND SUSCEPTIBILITY TO RHEUMATOID ARTHRITIS

HLA-DPB1 genotypic and phenotypic frequencies were investigated in a series of 35 adult rheumatoid arthritis (RA) patients and 42 controls. No significant associations between DPB1 alleles and susceptibility to RA were demonstrated, although some non-significant differences in DPB1*0301 and 0401 allele frequencies between patients and controls were observed.     

ISOLATION OF AN ISOANTIGEN ASSOCIATED WITH LEUKOSIS-SARCOMA VIRUS SUSCEPTIBILITY IN CHICKENS AND ITS RELATION TO HUMAN BLOOD-GROUP MN SUBSTANCES

The R₁ antigen of chicken red cells, which is associated with susceptibility to a subgroup B leukosis-sarcoma virus, has been isolated. This antigen is cross-related to structures on the human blood-group MN antigens and, as in the latter, sialic acid is apparently part of its immunodominant grouping. R₁ antigen inhibited influenza viruses and to a lesser extent Vicia graminea anti-N reagent. Plant proteases inactivated the antigen.     

广州地区汉族人群和白血病患者Rb基因P68RS2.0区的遗传多态性

为了解Ｒｂ基因在正常人群和白血病患者中的遗传多态性，作者采用３２Ｐ－标记的Ｒｂ基因Ｐ６８ＲＳ２．０探针分别与４种限制性内切酶消化的广州地区汉族人群和白血病患者ＤＮＡ进行了分子杂交，发现一个新的多态位点：正常人ＥｃｏＲ１３．２ｋｂ和３．４ｋｂ，等位基因频率分别为０．７４和０．２６，杂合子频率为０．３７；白血病患者ＥｃｏＲⅠ３．２ｋｂ和３．４ｋｂ，等位基因频率分别为０．８４和０．１６，杂合子频率为０．２４．为白血病的病因学研究提供了资料。     

Gm AND Inv MARKERS IN WHOLE MYELOMA SERA IN AN IRISH POPULATION

A survey has been carried out on sera from 136 myeloma patients for distribution of Gm markers 1, 2, 4 and 12 and Inv 1. It was found that with Gm (1), Gm(2) and Gm (12) the distribution was normal. However, Gm (4) was found to be present in 41 % of the sera compared with an expected value of 90%.     

江浙沪地区汉人HLA－DQA1基因对重症肌无力的遗传易感性研究

采用一种新的多聚酶链反应－限制性片段长度多态性（ＰＣＲ－ＲＦＬＰ）基因分型法，研究了江浙沪地区中国汉人重症肌无力（ｍｙａｓｔｈｅｎｉａｇｒａｖｉｓ，ＭＧ）４５例和对照组９８例的ＨＬＡ－ＤＱＡ１等位基因。发现ＭＧ的胸腺瘤型和非胸腺瘤型ＤＱＡ１基因遗传背景有所不同，ＨＬＡ－ＤＱＡ１＊０３０１基因参与非胸腺瘤型ＭＧ（尤其是男性组）的遗传易感作用（ＲＲ＝３．６３，Ｐ＜０．０５），家系分析支持群体研究结果。推测了中国汉人ＭＧ可能的ＨＬＡ易感单体型：ＤＱＡ１＊０３０１ＤＱＢ１＊０３０３－ＤＲＢ１＊０９０１和ＤＱＡ１＊０３０１－ＤＱＢ１＊０３０３－ＤＲＢ１＊０４０６．结果从基因分型的角度统一了关于华人ＭＧ与ＨＬＡ相关抗原提法不一致的报道，并揭示了ＭＧ的其它ＨＬＡⅡ系统易感基因ＤＱＢ１＊０３０１、ＤＲＢ１＊０９０１及ＤＲＢ１＊０４０６或ＤＢＲ＊０４０５存在的极大可能性。为进一步分析ＭＧ的遗传易感机理提供了重要依据。     

西双版纳傣族及上海汉族群体HLA－DR2相关的DR／DQ单倍型分析

对４４名西双版纳傣族和９名上海地区汉族ＤＫ２阳性个体进行了与其相关的ＤＲ／ＤＱ单倍型组合的分析。傣族群体中ＤＲＢＩ－ＤＲ２亚型分布以＊１６０２与＊１５０２为最常见，其等位基因频率分别为４３．６％与，４０．０％和汉族群体中以＊１５０１为主明显不同。傣族群体中共检出１０种与ＤＲ２相关联的ＤＲ／ＤＱ单倍型；最常见的是ＤＲＢ１＊１６０２、ＤＲＢ５＊０１０１、ＤＱＡ１＊０１０２、ＤＱＢ１＊０５０２（３４．５％）与汉族及其他群体明显不同，本研究表明傣族不仅具有高频率的ＤＲ２，而且与ＤＲ２相关联的ＤＲＢ１、ＤＲＢ５、ＤＱＡ１、ＤＱＢ１单倍型组合有其独特性。     

HLA A*, B*-BF* AND C4 A*, ALLELE ASSOCIATIONS,WITH SPECIAL REFERENCE TO BF*S07, IN THE TUNISIAN POPULATION

The HLA A*2, Bw*50-BF*S07-C4 A*2, B*l linkage group was transmitted unambiguously in four unrelated Tunisian families. In one of these, another allele association, also carrying BF*S07, HLA A*9, Bw*50-BF* S07-C4 A*1, B*1, was encountered. The previously reported linkage disequilibrium between BF*S07 and HLA Bw*50, a subtypic speficity of HLA Bw*21, is confirmed in our study. The C4 A*2, B*1, haplotype, rare in the other populations until now studied, seems more frequent in Tunisia since it has been also found linked to HLA A* 11, B*27 and BF*S in one of these familie. Other allele associations were unambiguously demonstrated with predominantly the C4 A*3, B*1 haplotype, particularly a rare HLA A*3, B*18-BF* F1-C4 A*3, B*1 linkage group. A silent gene at the C4 A locus was found linked to HLA B*.