HLA-DQB1基因多态性与新疆汉族人群结核病易感性的研究

目的:探讨HLA-DQB1基因多态性与新疆汉族人群结核病发生发展的关联.方法:采用PCR-SSP技术对228例新疆塔城地区和石河子地区的肺结核患者及231例健康志愿者的HLA-DQB1的15个等位基因分型,比较各等住基因的频率(GF),并计算其优势比(OR).结果:肺结核病例组DQB1*0201位点的基因频率显著高于对照组(Pc<0.05)其GF和OR分别为10.27%和1.947.结论:HLA-OQB1*0201可能是新疆地区汉族人群结核病发病的易感基因.     

NRAMP1基因3′UTR多态性与新疆哈萨克族结核病易感性的研究

为了研究人类自然抵抗相关巨噬细胞蛋白NRAMP1基因3′UTR多态性与新疆哈萨克族结核病易感性的关系,研究选取新疆哈萨克族活动性结核病患者213例,新疆哈萨克族正常对照者211人,用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)分析的方法对NRAMP1基因3′UTR多态性进行基因分型,比较不同基因型及等位基因的频率,经统计学分析,探讨NRAMP1基因3′UTR多态性与新疆哈萨克族结核病易感性的关系.结果显示,在新疆哈萨克族活动性结核病患者组中NRAMP1基因3′UTR TGTG+/TGTG+基因型138例(64.8%),TGTG+/del基因型63例(29.6%),del/del基因型12例(5.6%);新疆哈萨克族正常对照组TGTG+/TGTG+基因型则为167例(79.1%),TGTG+/del基因型41例(19.5%),del/del基因型3例(1.4%).新疆哈萨克族结核病患者组TGTG+/del基因型和del/del基因型频率明显高于新疆哈萨克族正常对照组,差异有统计学意义(χ2=10.8,P0.01);在新疆哈萨克族结核病患者组的TGTG+等位基因频率为79.6%,del等位基因频率为20.4%,新疆哈萨克族正常对照组中TGTG+和del等位基因频率分别为88.9%和11.1%,del等位基因在新疆哈萨克族结核病患者组中的分布频率高,差异有统计学意义(χ2=13.7,P0.01).研究结果提示TGTG缺失等位基因可能是新疆哈萨克族结核病的易感基因,携带TGTG+/del和del/del基因型的新疆哈萨克族人群可能更易患结核病.     

甘肃裕固族HLA-DRB1基因多态性及其族源分析

目的:研究甘肃裕固族HLA-DRB1基因的多态性,探讨裕固族的起源、迁徙及其与其他民族的关系.方法:应用PCR-SSP基因分型技术,对54例裕固族个体进行了HLA-DRB1位点的基因分型并进行相应等位基因频率的比较.结果:甘肃裕固族HLA-DRB1位点共检出了14种等位基因,其中高频基因为DR5(0.2115),DR4(0.1346)和DR7(0.1250),低频的等位基因为DR14(0.0096)和DR13(0.0192);裕固族人HLA-DRB1座位等位基因总的分布格局与蒙古族最接近,与云南黎族则相差较远.结论:对裕固族和我国各地人群的HLA-DRB1频率进行了聚类分析,极为相似的HLA-DRB1背景提示裕固族和蒙古族之间密切的遗传关系.     

E 选择素基因多态性与新疆哈萨克族患者脑梗死的关系

目的:探讨E一选择素(E-selectin)基因多态性与新疆哈萨克族患者脑梗死(cebreral infarction,CI)的关系。方法:采用聚合酶链反应一限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)和DNA序列测定法检测103例CI及110例对照组E-selectin基因第4外显子A561C(S128R)、第10外显子C1839T(L554F)多态性。结果:E-se-lectin基因S128R基因型频率和等位基因频率在CI组和对照组比较差异有显著性(P<0.05),基因型频率的相对风险分析发现,SR基因型携带者患CI的风险是SS基因型的2.355倍(OR=2.355,95%CI:1.209～4.588);E-selectin L554F基因型在两组中的分布差异有显著性(X2=5.463,P<0.05),基因型频率的相对风险分析,LF基因型患CI的风险是LL基因型的2.315倍(OR=2.315,95%CI:1.132～4.737)。结论:E-selectin S128R和L554F多态性与脑梗死易感性有关;R等位基因和F等位基因可能是新疆哈萨克族CI发病的遗传易感基因。     

新疆维吾尔族人寻常型银屑病与HLA-Cw*0602等位基因的关联研究

目的:寻找新疆维吾尔族人银屑病与HLA-Cw*0602等位基因的相关性.方法:运用聚合酶链反应-序列特异性引物(PCR-SSP)法,检测新疆维吾尔族人200例寻常型银屑病患者和200例健康对照的HLA-Cw*0602等位基因频率,分析携带该基因的银屑病患者与其家族史的相互关系.结果:①病例组HLA-Cw*0602等位基因频率较对照组显著升高(73%vs24%,X2＝108.551,OR=10.171,95%可信区间6.410～16.140,P＝0.000),且无性别差异;②携带HLA-Cw*0602等位基因的银屑病患者发病年龄早于不具有该等位基因的患者(80.2%vs28.6%,X2=10.256,OR=0.950,95%可信区间0.920～0.981,P=0.001);③有银屑病家族史患者携带HLA-Cw*0602等位基因的频率与无银屑病家族史的患者无显著意义(X2=0.000,OR=0.986,95%可信区间0.252～3.860,P=1.000).结论:新疆维吾尔族银屑病患者与HLA-Cw*0602等位基因高度关联,且携带该等位基因的银屑病患者易发生早发型(发病年龄≤40岁)银屑病,但不能确定有家族倾向性.     

云南澜沧拉祜族HLA-DRB1基因多态性研究

采用我们改进的高分辨率基于内含子的PCR-SBT分型方法,首次检测云南拉祜族HLA-DRB1基因多态性。在55例拉祜族个体中共检出16种HLA-DRB1等位基因,最常见的DRB1等位基因是HLA-DRB1*12021、09012、15011,基因频率分别为30.909%、15.455%、13.636%,共占拉祜族可检出等位基因的60%,其中DRB1*0413、11081、1312、1418、1504首次在我国人群中检出,并且在世界各地人群中也比较罕见。对拉祜族和世界各地人群的HLA-DRB1频率进行了比较,分析了HLA-DRB1等位基因在各人种中的分布特点,并用Neighbor-joining法进行了聚类分析。比较分析的结果显示拉祜族明显属于中国南方族群,未显示出其族源来自北方的痕迹。对此遗传数据和民族学、历史学研究的矛盾,做了初步的分析。 Abstract:The HLA-DRB1 gene polymorphism in Lahu ethnic of Yunnan,China was the first time investigated using high resolution PCR-SBT method,which is based on sequences of HLA-DRB1 Intron 1 and Intron 2 and with our improvement.From 55 individuals of Lahu ethnic 16 DRB1 alleles were detected.The three most common alleles were HLA-DRB1*12021(30.909%),09012(15.455%),15011(13.636%),and they covered 60% of the total alleles detected from Lahu ethnic.HLA-DRB1*1413,*11081,*1312,*1418,*1504 were the first time detected in the Chinese,and were very rare in worldwide ethnic groups.With comparison of HLA-DRB1 gene frequencies between various ethnic groups we analysized the characteristics of HLA-DRB1 gene distribution in worldwide populations,and constructed the phylogenetic tree by Neighbor-joining method and Nei measure of genetic distance.The result showed Lahu ethnic obviously belong to the Chinese South ethnic groups and can't trace its origin from northern groups with the HLA-DRB1 genetic data.The preliminary explanations about the contradiction were given in this paper.     

HLA-DRB1等位基因和抗HLA-DRB1抗体在尿毒症患者中的分布特征

为了研究华南地区尿毒症患者的HLA-DRB1等位基因频率分布及抗HLA-DRB1抗体类型,收集尿毒症患者和健康对照者的外周血,通过聚合酶链反应-序列特异性寡核苷酸探针(PCR-SSO)方法对HLA-DRB1等位基因进行基因分型。经Luminex系统检测因尿毒症进行肾移植的患者中抗HLA-DRB1抗体的类型和频率,用HLAMatchmaker数据库比较和分析HLA-DRB1的表位及其氨基酸序列,通过统计软件分析患者中HLA等位基因和抗HLA抗体的类型和频率。结果发现:与健康对照者相比,尿毒症患者HLA-DRB1*13等位基因的频率显著低于健康对照者(4.33%vs. 13.37%,P0.001);HLA-DRB1*14等位基因的频率显著高于健康对照者(12.01%vs.4.12%,P0.001)。在所有类型的抗HLA-DRB1抗体中,抗HLA-DRB1*01/*13/*14抗体的频率显著低于其他抗HLA-DRB1抗体的频率(P0.05)。经HLAMatchmaker数据库分析发现,HLA-DRB1*01/*13/*14等位基因中的常见表位为77T。这表明:在基因频率上,HLA-DRB1*13与尿毒症患病率呈负相关,可能对个体具有保护作用;HLADRB1*14与尿毒症患病率呈正相关,可能是尿毒症的易感因素。尿毒症患者中抗HLA-DRB1*01/*13/*14抗体的水平显著低于其他抗HLA-DRB1抗体,这可能是由存在的共同表位77T所致。研究结果将为深入了解HLA-DRB1基因与尿毒症的关系奠定基础,对阐明HLA-DRB1基因在尿毒症及肾移植中的作用提供试验依据。     

组织相容性抗Ⅱ类HLA-DRB71等位基因与原发性胆汁性肝硬化患者人群的相关性研究

目的:探讨组织相容性抗Ⅱ类HLA-DRB71等位基因与原发性胆汁性肝硬化患者人群的相关性。方法:资料选自2011年3月-2013年3月在我院就诊的原发性胆汁性肝硬化患者95例,健康人群203例,分为原发性胆汁性肝硬化组与健康人群组,皆予以序列特异性引物PCR分析,对两组的等位基因进行分析研究。结果:原发性胆汁性肝硬化组DRB71*07基因频率为36.84%,高于健康人群组13.79%,差异具有统计学意义(P0.05);原发性胆汁性肝硬化组其他基因低于健康人群组,差异无统计学意义(P0.05);DRB71*07 OR值是2.67,表明原发性胆汁性肝硬化组DRB71*07阳性率与健康人群组相比较,是其2.67倍,比值差异具有统计学意义(P0.05);原发性胆汁性肝硬化患者易感性与DRB71*0701高度相关。结论:中国原发性胆汁性肝硬化患者可能同DRB71*0701较易感染有密切关系,为其临床的治疗提供线索。     

新疆哈萨克族脑梗塞与ICAM-1 基因G241R 多态性的关系

目的:探讨新疆哈萨克族脑梗死与细胞黏附分子1(ICAM-1)G241R基因多态性的关系。方法:采用多聚酶链式反应法及限制性内切酶片段长度多态性技术,对新疆哈萨克族100例脑梗死患者及110例健康者(对照组)进行ICAM-1基因G241R多态性检测,比较不同基因型与哈萨克族脑梗塞发病风险的关系。结果:脑梗塞患者ICAM-1基因G41R多态性的基因型频率和等位基因频率与健康对照组相比无明显差异。结论:ICAM-1基因G214R多态性可能不是新疆哈萨克族脑梗塞发病的遗传学危险因素。     

MICB基因多态性与乳腺癌的易感关联性研究

目的:研究海南汉族人群MICB等位基因的多态性与乳腺癌易感性之间的关联性。方法:采用PCRSSP(PCR sequence-specific primers)和PCR-SBT(PCR sequence-based typing)方法对样本MICB等位基因的多态性进行检测。结果:乳腺癌患者中检出14种MICB等位基因;和对照组相比较,MICB*002和MICB*014等位基因在乳腺癌患者组分布频率较少,MICB*002和MICB*014等位基因可能对乳腺癌不易感(MICB*002:OR=0.31,95%CI:0.19-0.51,Pc0.05;MICB*014:OR=0.32,95%CI:0.17-0.60,Pc0.05)。MICB*016和MICB*003等位基因在乳腺癌患者组分布较多;MICB*016和MICB*003等位基因可能对乳腺癌易感(MICB*016:OR=10.68,95%CI:2.52-45.28,Pc0.05;MICB*003:OR=3.57,95%CI:1.34-9.49,Pc0.05);MICB*002/002和MICB*014/014基因型可能对乳腺癌不易感(MICB*002/002:OR=0.12,95%CI:0.04-0.36,Pc0.05;MICB*014/014:OR=0.30,95%CI:0.10-0.89,Pc0.05)。结论:MICB等位基因的多态性与乳腺癌的易感性之间存在关联性。     

Association of HLA-DRB alleles and pulmonary tuberculosis in North Chinese patients

Human leukocyte antigen (HLA) plays a central role in the regulation of the immune response. HLA class II molecules are essential for T cell-mediated adaptive immunity and present peptide antigens to CD4(+) T cells. Because of its important role in the immune response and its high degree of polymorphism, the HLA system is associated with many diseases. We examined the polymorphisms of HLA-DRB alleles and the sequences of the HLA-DRB promoter region in 97 unrelated patients with pulmonary tuberculosis and in 62 unrelated normal controls of the Han nationality from North China, using PCR with sequence-specific primers and PCR direct sequencing. We found that the frequency of HLA-DRB1*15 was significantly higher in the pulmonary tuberculosis group than in the healthy control group. The P value was 0.001, and the odds ratio was 3.793. The pulmonary tuberculosis group had the same HLA-DRB1 promoter region sequences as the control group. We concluded that the HLA-DRB1*15 allele is associated with pulmonary tuberculosis in the Han nationality from North China. The HLA-DRB1 promoter region sequences had no association with the development of pulmonary tuberculosis.     

Two critical genes (HLA-DRB1 and ABCF1)in the HLA region are associated with the susceptibility to autoimmune pancreatitis

We have previously reported that autoimmune pancreatitis (AIP) is a bioclinical entity characterized by high serum immunoglobulin G4 concentrations and association with the HLA-DRB1*0405-DQB1*0401 haplotype. However, the precise identity of gene(s) within this haplotype directly responsible for AIP pathogenesis is yet to be established. To dissect the genetic contribution of the incriminated haplotype, we have now performed an association analysis within the human leukocyte antigen (HLA) region using various types of polymorphic markers. Genomic DNAs from 43 AIP patients and 213 unrelated Japanese controls were used in this analysis. In each DNA sample, we established the genotype of 25 microsatellite markers distributed throughout the HLA region, that of single nucleotide polymorphism within the 5'-flanking regions of the TNFA and IkBLI (also known as NFKBIL1) as well as HLA class I and II genes. The HLA-linked susceptibility regions for AIP were localized to two segments: HLA-DRB1 (*0405; OR = 3.20, P = 0.00063, Pc = 0.0016) -DQB1 (*0401; OR = 3.29, P = 0.00046, Pc = 0.0069) in the HLA class II and C3-2-11 microsatellite (allele 219; OR = 2.96, P = 0.0076, Pc = 0.099) in the HLA class I regions. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium within the major histocompatibility complex, it was established that each segment contributed to disease pathogenesis. The two critical HLA regions for susceptibility to AIP are limited to the HLA-DRB1*0405-DQB1*0401 in the class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions.     

Association between the frequency of class II HLA antigens and the susceptibility to intrauterine infection of hepatitis B virus

Multiple factors determine the susceptibility to intrauterine hepatitis B virus (HBV) infection. These factors include the HBV structure, HBV mutation, HBV DNA level, placental barrier, the immune status of the mother, and the genetic make-ups of the newborn infants. Since HLA system is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are the key determinants of intrauterine HBV infection. In this study, we selected newborn infants of HBsAg-positive mothers, and divided the infants into 2 groups: intrauterine infection group and non-intrauterine infection group according to the status whether or not they were infected at birth. Each infected infant was compared with 2 controls from the same birth cohort. HLA-DR allele typing was performed using a PCR-sequence specific primer (PCR-SSP) for 24 subjects with intrauterine infection and 48 controls without infection. We found that, among the fifteen (15) HLA-DR alleles assessed, HLA-DRB1*07 was the one, and the only one, significantly in excess (OR = 6.66, P = 0.004) in the intrauterine infection group compared to the non-intrauterine infection group. Our findings thus suggest that high frequency of HLA class II molecules, e.g. HLA-DRB1*07, is associated with the susceptibility of the infants to intrauterine HBV infection.     

A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001) and were highly significant in the combined dataset (P ≤ 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.     

新疆哈萨克族,维吾尔族和蒙古族头面部观察特征比较

对新疆伊犁的哈萨克族５５１人,维吾尔族５２７人和蒙古族５３３人的头面部３０项指标进行了活体观察和比较。他们既有许多相似之处又有各自不同的特点,哈萨克族与蒙古族在许多方面较为相似,哈萨克族与维吾尔族,蒙古族与维吾尔族也有相似的特征。     

新疆维吾尔族、哈萨克族人群HLA-DQA1、-DQB1两基因座多态性的研究及与25个种族或民族的比较分析

应用ＰＣＲ－ＲＦＬＰ基因分型技术,首次对我国新疆地区维吾尔族和哈萨克族２个少数民族群体的ＨＬＡ－ＤＱＡ１、－ＤＱＢ１两个基因座的多态性进行了研究。结果显示,在ＤＱＡ１８个等位基因中,维族和哈族均表现为ＤＱＡ１＊０３０１最常见。最少见的ＤＱＡ１等位基因,在维族中为ＤＱＡ１＊０４０１和＊０６０１,而在哈族中为ＤＱＡ１＊０６０１;在ＤＱＢ１１６个等位基因中,ＤＱＢ１＊０２０１和＊０３０１在维族和哈族中均表现为最常见。在维族中未观察到ＤＱＢ１＊０５０２、＊０５０３２和＊０５０４,在哈族中未观察到ＤＱＢ１＊０５０３２、＊０５０４和＊０６０５等位基因。统计分析表明,维族和哈族ＤＱＡ１、ＤＱＢ１各等位基因的分布无显著性差异,说明维、哈族间具有较密切的亲缘关系。在以２７个种族或民族的ＨＬＡ－ＤＱＡ１、－ＤＱＢ１两基因座基因频率构建的分子系统树上,维族和哈族独立于其他群体而聚类,独处一支。维族和哈族接近蒙古人种,而离高加索人种较远。     

Tumour necrosis factor-alpha polymorphism as one of the complex inherited factors in pemphigus

The aim of our study was to analyse a significance of tumour necrosis factor (TNF)-alpha promoter gene polymorphisms in relation to the HLA-DR locus in genetic predisposition to pemphigus. TNF-alpha gene polymorphisms in position -238 and -308 were identified using a modified polymerase chain reaction-restriction fragment length polymorphism method in 53 patients with pemphigus (38 with pemphigus vulgaris, 15 with pemphigus foliaceus) and 87 healthy controls. The HLA-DRB1 locus was typed using the polymerase chain reaction SSO method in all the patients and 152 population controls. Carriers of the TNF-alpha polymorphic -308 A allele were found to be more frequent in the pemphigus foliaceus group in comparison with the control group (odds ratio (OR) = 8.12; p = 0.0005). A significant association between HLA-DRB1*04 (OR = 3.86; pcor = 0.0001) and DRB1*14 (OR = 8.4; pcor = 0.0001) and pemphigus vulgaris was found. In this group of patients a decreased frequency of HLA-DRB1*07 (OR = 0.08; pcor = 0.006) was also identified. We have shown for the first time a positive association of TNF-alpha polymorphism in position -308 with pemphigus foliaceus.     

新疆地区维吾尔族和汉族人群CaSR基因多态性与草酸钙肾结石关系的研究

目的:探讨新疆地区维吾尔族和汉族草酸钙结石与钙敏感受体(calcium sensitive receptor,Ca SR)基因多态性之间的关系。方法:选择398例临床确诊泌尿系草酸钙结石患者(200例维吾尔族,198例汉族)和399例正常对照者(200例维吾尔族,199例汉族),应用Sna Pshot方法对Ca SR基因两位点(rs1042636,rs1801726)的基因型及等位基因频率进行检测,并分析其与草酸钙结石发病的相关性以及对血钙、24 h尿钙水平的影响。结果:各组2个位点的基因型分布均符合Hardy-Weinberg平衡。汉族结石组与汉族对照组及维吾尔族结石族与维吾尔族对照组rs1042636、rs1801726位点基因型分布及基因频率差异均无统计学意义(P0.05)。维吾尔和汉族rs1042636基因型及等位基因频率比较差异有统计学意义(P0.05),且维吾尔族人群携带rs1042636等位基因A的风险高于汉族人群(病例组中OR值=2.145,%95CI=[1.602~2.866],P0.01;对照组中OR值=1.773,%95CI=[1.332~2.359],P0.01),其中维/汉病例组中等位基因频率分别为A=278(69.5%)/204(51.5%),G=122(30.5%)/192(48.5%);维/汉对照组中等位基因频率分别为A=264(66.0%)/208(52.3%),G=136(34.0%)/190(47.7%)。而病例组和对照组rs1801726基因型频率差异无统计学意义(P0.05);汉族病例组、对照组发现GG+AG基因型较AA基因型有较高的尿钙水平(病例组:P=0.007和对照组:P=0.006),维吾尔族人群该位点与两项指标无相关性。结论:Ca SR基因2个基因位点rs1042636、rs1801726可能不是新疆地区维吾尔族和汉族草酸钙结石发病的危险因子,两族rs1042636基因多态性分布存在差异,rs1042636位点基因多态性能影响汉族人群尿钙排泄,可能汉族调节钙排泄的遗传因素之一。     

HLA class II haplotypic association and DQCAR microsatellite polymorphisms in Croatian patients with psoriasis

The purpose of the present study was to investigate polymorphism of HLA class II haplotypic associations (HLA-DRB1, -DQA1, -DQB1) and DQCAR alleles in 78 Croatian patients with psoriasis. Patients were divided into two groups according to a family history of disease and age of onset: type I (positive family history and early onset) and type II (negative family history and late onset). The difference in frequency of HLA class II haplotypic associations between type I patients and controls was observed for the following combinations: HLA-DRB1*0701, -DQA1*0201, -DQB1*02 (23.6% vs. 7.2%; p < 0.001), HLA-DRB1*0701, -DQA1*0201, -DQB1*0303 (8.5% vs. 1.3%; p = 0.0018) and HLA-DRB1*1601, -DQA1*0102, -DQB1*0502 (2.8% vs. 9.3%; p = 0.06). The difference between type II psoriasis and controls for association: HLA-DRB1*1501, -DQA1*0102, -DQB1*0602 is not significant (20.0% vs. 8.9%; p = 0.06). The significantly higher frequency of DQCAR 113bp and 119bp alleles in patients with type Ipsoriasis is a result of linkage disequlibrium of these alleles with both HLA-DRB1*0701 haplotypic associations. Analysis ofDQCAR alleles in the HLA-DRB1*0701 haplotypic associations in patients with psoriasis vulgaris and matched controls did not reveal any difference in polymorphism of DQCAR alleles. These data suggest that HLA-DRB*0701 haplotypic combinations are associated with type I but not for type II psoriasis in the Croatian population. DQCAR polymorphism is not useful genetic marker to distinguish susceptible HLA class II haplotypic association.