原发性胆汁性肝硬化患者HLA-Ⅰ类基因的高分辨多态性及单体型分析

目的 分析原发性胆汁性肝硬化(PBC)患者人类白细胞抗原(HLA)Ⅰ类等位基因的高分辨多态性及单体型特征. 方法 采用基于序列测定的聚合酶链反应技术(SBT-PCR)对146例PBC患者和500例健康对照者进行HLA-Ⅰ类基因高分辨分型,比较Ⅰ类基因及单体型在PBC患者和健康对照者间的差异.对PBC患者与健康对照者的基因频率进行x2检验或Fisher精确检验. 结果 PBC患者HLA-A、B、C座位分别检出26、51和21个等位基因,其分布频率在PBC患者和健康对照者间,差异无统计学意义(Pc＞0.05);PBC患者A*11:01-B*40:06和A *02:01-B*15:01单体型频率明显高于健康对照者(7.53％对比1.40％,P＜0.01,OR=5.38;6.85％对比2.00％,P=0.003,OR=3.425). 结论 PBC患者有独特的HLA-A*-B*单体型,可能与疾病遗传易感性相关.     

山东地区汉族骨髓捐献者HLA-DRB1基因分型及多态性分析

目的观察山东地区汉族人群人白细胞抗原(HLA)-DRB1基因多态性及其分布特点。方法采用聚合酶链反应—测序为基础的分型方法(PCR-SBT)对随机抽取的909例中华骨髓库山东分库内山东汉族骨髓供者血样进行HLA-DRB1基因分型和多态性分析。结果共检测出42种HLA-DRB1等位基因,其中HLA-DRB1*0901等位基因频率最高(16.28%),其次为HLA-DRB1*1501(15.13%)和HLA-DRB1*0701(14.04%),基因频率最低的是DRB1*0408、DRB1*0809、DRB1*1103、DRB1*1303、DRB1*1412、DRB1*1425、DRB1*1601,各占0.06%。山东汉族骨髓供者HLA-DRB1等位基因的分布与江苏、湖北、新疆、广东、韩国、日本和德国人群存在明显差异(P均<0.05)。结论掌握了山东地区汉族人群HLA-DRB1基因多态性及其分布特征。     

人类白细胞抗原DRB1基因与肺结核的相关性研究

目的探讨HLA-DRB1基因多态性与肺结核(PTB)的遗传关联性及其与临床表现的关系。方法采用聚合酶链反应-序列特异性引物(PCR-SSP)方法,对74例PTB患者及90名正常人的HLA-DRB1等位基因进行分型。结果与对照组相比,PTB病例组的DRB1*15等位基因频率显著增高(34.3%比17.0%,Pc<0.05,RR=2.91),HLA-DRB1*12基因频率高(15.4%比7.5%),但统计学上无显著性差异(Pc>0.05);而DRB1*11基因频率显著低于对照组(1.4%比9.9%,Pc<0.05,RR=0.12)。HLA-DRB1*15阳性患者中复治病例数和耐药病例数均显著高于HLA-DRB1*15阴性组(P<0.05)。结论HLA-DRB1*15可能是PTB的易感基因,DRB1*11可能为保护基因,HLA-DRB1*15基因与PTB临床特征有一定相关性。     

HLA-DRB1、-DQB1基因多态性与食管鳞癌遗传关联性

目的　从基因水平探讨食管鳞癌HLA DRB1 , DQB1等位基因的遗传易感性 ,以阐述其免疫遗传学特征。方法　运用序列特异性引物聚合酶链反应技术 ,检测无亲缘关系湖北汉族健康人 1 36例、食管鳞癌患者 42例的HLA DRB1 , DQB1等位基因。结果　湖北汉族人食管鳞癌患者与正常人比较 ,HLA DRB1 0 90 1等位基因分布频率显著增高 (0 .2 50 0比 0 .1 397,P =0 .0 2 8,OR =2 .0 53 ,病因分数 =0 .1 2 82 ) ,HLA DQB1 0 30 1基因分布频率显著增高 (0 .2 976比 0 .1 875 ,P =0 .0 4 6 ,OR =1 .835 ,病因分数 =0 .1 35 4)。两者间其余HLA DRB1、 DQB1等位基因分布频率差异均无显著性。结论　HLA DRB1 0 90 1及 DQB1 0 30 1等位基因均与食管鳞癌正关联 ,为其易感基因。该两等位基因测序结果与其基因库第 2外显子序列吻合。     

支气管哮喘发病与HLA-DRB1等位基因关系的研究

目的　探讨山东汉族支气管哮喘 (简称哮喘 )人群中人类白细胞抗原 (HL A) - DRB1基因型的分布 ,明确与哮喘有关的 HL A- DRB1易感基因。方法　选取急性发作期哮喘患者 (哮喘组 ) 5 0例 ,健康献血员 (对照组 )6 0例。应用序列特异性引物聚合酶链反应 (PCR- SSP)方法检测其 HL A- DRB1等位基因。结果　哮喘组 HL A-DRB1* 130 1- 130 2基因频率显著高于对照组 (P<0 .0 1) ,相对危险度 (RR)为 4 .13;其他等位基因频率两组无显著性差异 (P>0 .0 5 )。结论　 HL A- DRB1* 130 1- 130 2基因与哮喘发病相关 ,是山东汉族哮喘人群的易感基因。     

泌尿生殖道沙眼衣原体慢性持续感染患者人类白细胞抗原DQB1等位基因多态性研究

目的探讨人类白细胞抗原(HLA)-DQB1等位基因多态性与泌尿生殖道沙眼衣原体慢性持续感染的遗传易感相关性。方法应用聚合酶链反应-序列特异性引物(PCR-SSP),分别对泌尿生殖道沙眼衣原体慢性持续感染患者、一般感染患者和正常人各80例,进行HLA-DQB1等位基因分型,分析HLA-DQB1等位基因与泌尿生殖道沙眼衣原体慢性持续感染的相关性。结果泌尿生殖道沙眼衣原体慢性持续感染患者中HLA-DQB1*0602等位基因频率为45%,一般感染组为15%,健康对照组为22.5%,差异有统计学意义(χ2=14.08,P<0.01)。结论 HLA-DQB1*0602可能是沙眼衣原体泌尿生殖道慢性持续感染的易感基因或与致病基因相连锁;PCR-SSP可用于快速检测HLA-DQB1等位基因型。     

应用基因芯片分析HLA-DRB与晚期肝脾型日本血吸虫病的相关性

目的 探讨人类白细胞抗原Ⅱ类(HLA-Ⅱ）基因多态性与晚期肝脾型日本血吸虫病的遗传关联性。 方法 应用基因芯片分析技术对武汉市蔡甸45例晚期肝脾型日本血吸虫病患者（实验组）和44例慢性日本血吸虫病患者（对照组）的HLA-Ⅱ基因DRB位点等位基因进行基因分型，并比较两组各等位基因频率以及与晚期肝脾型日本血吸虫病的相关性。 结果 实验组HLA-DRB1*04x等位基因频率明显高于对照组（P＜0.01， RR=3.928），而对照组HLA-DRB1*15x等位基因频率明显高于实验组（P＜0.01， RR=0.050）。等位基因DRB1*15x总与DRB5*010x/020x连锁，对照组DRB1*15x-DRB5*010x/020x连锁体频率明显高于实验组（P＜0.01）。 结论 HLA-DRB1*04x与晚期肝脾型日本血吸虫病呈正相关，而HLA-DRB1*15x与晚期血吸虫病呈负相关。     

系统性红斑狼疮与人类白细胞抗原-Cw基因相关性的研究

目的 探讨系统性红斑狼疮(SLE)与人类白细胞抗原(HLA)-Cw等位基因的相关性.方法 应用聚合酶链反应-序列特异性引物(PCR-SSP)的方法对108例SLE患者和102名健康人HLA-Cw01-08等位基因进行检测,比较两组间各等位基因的基因表型频率分布差异.结果 SLE患者组中HLA-Cw07的基因表型频率高于对照组,差异有统计学意义.结论 HLA-Cw07可能是SLE的易感基因或易感连锁基因.     

人类白细胞抗原—DRB1和DQB1基因与肺结核合并糖尿病的相关性分析

目的 探讨人类白细胞抗原（HLA）－DRB1手DQB1基因与肺结核合并2型糖尿病的关联性;寻找与肺结核合并2型糖尿病可能相关的HLA基因。方法 采用病例对照和聚合酶链反应－特异性序列引物（PCR－SSP)方法,对我国北方汉族123例肺结核合并2型糖尿病患者和与其无因缘关系的46名健康对照以及45全单纯2型糖尿病患者分别进行HLA－DRB1和DQB1闰点的等位基因分型。结果 肺结核合并2型糖尿病患者组中DRB1＊09基因频率明显高于健康人组,分别为25．10％和14．03％,RR为2．22,肺结核合并2型糖尿病患者组中DRB1＊09基因频率明显高于单纯2型糖尿病患者组,分别为25．10％和9．32％,RR为3．16,统计学上差异均有显著性;在肺结核合并Ⅱ型糖尿病患者组中DQB1＊05基因频率明显低于单纯2型糖尿病患者组,分别为7．17％和21．12％,RR为0．26,统计学差异有非常显著性。结论 研究提示DRB1＊09基因可能是肺结核合并2型糖尿病的易感基因;DQB1＊05基因可能是肺结核合并2型糖尿病的保护基因;可以推测DRB1＊09和DQB1＊05基因在肺结核合并2型糖尿病的发病中起一定作用,或是真正起作用的基因与它们连锁,有待于进一步研究。     

广东地区汉族人HLA-DQB1基因对胃溃疡患者的遗传易感性研究

目的 探讨广东地区汉族人人类白细胞抗原-DQB1(HLA-DQB1)基因与胃溃疡(GU)的遗传关联.方法 应用HLA基因的聚合酶链反应-序列特异性引物(PCR-SSP)核苷酸分型技术,对135例GU患者和105例正常人的HLA-DQB1等位基因进行分析.结果 GU患者HLA-OQB1*0602等位基因频率与正常对照组比较明显增高,差异有显著性(P=0.001,RR=0.115,Pc=0.014),而GU患者HLA-DQB1* 0604等位基因频率与正常对照组比较明显降低,差异有显著性(P=0.001,RR=17.290,Pc=0.014).结论 HLA-DQB1*0602基因对GU患者有遗传易感作用,而HLA-DQB1 * 0604基因对GU患者有遗传抵抗作用,GU患者与正常人之间存在着免疫遗传异质性的差异.     

Analysis of HLA alleles polymorphism in Chinese patients with primary biliary cirrhosis

BACKGROUND: A familial dustering of patients with primary biliary cirrhosis (PBC) and the presence of immunological abnormalities in family members suggest a genetic component involved in the pathogenesis of PBC. The aims of this study are to investigate the frequencies of human leukocyte antigen HLA-A, -B, and -DRB1 alleles in Chinese patients with PBC by polymerase chain reaction (PCR)-based techniques, and to assess the correlation of the above-mentioned HLA with some clinical and laboratory features. METHODS: Genotyping of HLA alleles were performed in 65 well-characterized PBC patients and 431 healthy controls with sequence-specifc primers PCR amplification. RESULTS: HLA-DRB1~*07 allele detected in 19 of the 65 (29.2%) PBC patients was subtyped as DRB1~*0701, as well as in 13.9% of controls (P_C<0.05, OR=2.55, 95% CI: 1.4-4.6). An increased frequency of DRB1~*03 (18.4% vs. 7.2% in healthy controls) and a decreased frequency of DRB1~*12 (16.9% vs. 28.8%) in PBC patients were statistically significant. There was no association with HLADRB1~*08 reported. The frequencies for HLA-A, B and the other DRB1 alleles were similar between patients and healthy controls. CONCLUSIONS: The susceptibility to PBC in Chinese individuals is associated with DRB1~*0701 allele. This association differs from that in North Americans, South Americans, North Europeans and even Japanese, but it is not restricted to any particular subgroup of patients.     

Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis

Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA) DRB1*08:03 allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the DRB1*08:03-DQB1*06:01 (13% versus 6%; P = 0.000025; odds ratio [OR] = 2.22) and DRB1*04:05-DQB1*04:01 haplotypes (17% versus 13%; P = 0.044; OR = 1.38). Conversely, there were significant protective associations with the DRB1*13:02-DQB1*06:04 (2% versus 5%; P = 0.00093; OR = 0.27) and DRB1*11:01-DQB1*03:01 haplotypes (1% versus 4%; P = 0.03; OR = 0.37). The frequency of the DRB1*09:01-DQB1*03:03 haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%; P = 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (P = 0.0000015; OR = 1.83) of the DRβchain differed the most in patients with PBC, compared with healthy subjects. CONCLUSION: This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC.     

Human leukocyte antigen Class II associations in serum antimitochondrial antibodies (AMA)-positive and AMA-negative primary biliary cirrhosis.

BACKGROUND/AIMS: An association of Class II HLA-DR8 antigen is reported in patients with serum antimitochondrial antibodies (AMA)-positive primary biliary cirrhosis (PBC); no information exists as to an association with AMA-negative PBC. We compared the frequency of HLA Class II genes in AMA-positive and AMA-negative PBC patients and healthy controls. METHODS: Genomic DNA was extracted from the blood of 154 AMA-positive and 26 AMA-negative Caucasian PBC patients and from 216 healthy Caucasian controls and tested for the alleles at two HLA Class II loci, DRbeta1 and DQbeta1. RESULTS: Higher allele frequencies of HLA-DRbeta1*08 and DQbeta1*04 were found in the AMA-positive PBC patients versus controls (14.9% vs. 6.5%, odds ratio (OR)=3.3, global P=0.03 and 14.4% vs. 6.5%, OR=2.6, global P=0.002). All patients positive for DRbeta1*0801 were positive for the DQbeta1*0402 allele, delta score=22 for AMA-positive patients, 11 for controls. In AMA-negative PBC, the frequency of DRbeta1*08 and DQbeta1*04 was 0%, significantly different from the AMA-positive patients (P=0.05, P=0.05). CONCLUSIONS: AMA response may identify a group of PBC patients with a distinctive expression of the disease with the response associated with a gene(s) in the class II region of the major histocompatibility complex on the short arm of chromosome 6.     

Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease of unknown etiology with a highly variable progression rate and prevalence among different geographical areas. Data concerning human leukocyte antigen (HLA) polymorphisms in PBC come from a limited number of geographical areas, from which the association with the HLA-DRB1*08 allele has been consistently reported. METHODS: To investigate whether HLA polymorphisms contribute toward disease susceptibility, we compared 186 well-defined Italian PBC patients with 558 healthy subjects matched by age, gender and geographical area (Northern, Central and Southern Italy). Patients and controls were HLA typed at low resolution by PCR-sequence specific oligonucleotides for the loci A and B; HLA-DRB1 alleles were typed by reverse line blot assay of PCR-amplified DNA. RESULTS: HLA-DRB1*11 was associated with a markedly reduced risk of developing PBC (OR: 0.3; 95% CI: 0.2-0.5). No association was found with HLA-DRB1*08. The B*15 (2.5; 1.3-4.6), B*41 (12.0; 2.7-72.1), B*55 (2.9; 1.1-7.5) and B*58 alleles (6.8; 1.1-46.3) were more frequent in PBC. The frequency of HLA polymorphisms was similar in PBC patients with progressive or non-progressive disease, and in those with or without anti-mitochondrial antibodies. CONCLUSIONS: Our data on a large series of Italian patients suggest that PBC may have a peculiar genetic background in the Mediterranean area.     

HLA DPB Polymorphism in primary sclerosing cholangitis and primary biliary cirrhosis

In recent years there has been an increasing interest in the link between susceptibility to autoimmune liver disease and genes of the HLA system, although the role of the DPB1 locus in British patients has only been investigated in autoimmune hepatitis. The aim of the current study was to determine the distribution of DPB1 alleles in a large series of British patients with the two other autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, and compare the allele frequencies obtained with those of a geographically matched control group. Polymerase chain reaction sequence-specific oligonucleotide probing was used to assign 18 DPB1 alleles in 82 patients with primary biliary cirrhosis (PBC), 71 patients with primary sclerosing cholangitis (PSC), and 103 controls. The frequencies of the DPB1 alleles were not significantly different comparing patients and controls. However, two important observations were made. Firstly, in primary sclerosing cholangitis, the previously reported association with the haplotype A1-B8-DR3-DQ2 does not extend to the DPB1 locus, suggesting that the genetic determinants of susceptibility for this disease lie closer to the DRB loci. Secondly, in primary biliary cirrhosis there is evidence that the reported association with DR8-DQB110402 includes the DPB110301 allele. The weak HLA association reported here is in contrast with recent data from Japan, where susceptibility is strongly linked to a particular amino acid residue encoded by the DPB110501 allele. These data clearly demonstrate that the alleles of the DPB1 locus are not associated with susceptibility to or protection from either primary biliary cirrhosis or primary sclerosing cholangitis in British patients.     

山东地区慢乙肝的预后与HLA-DRB1等位基因相关性研究

探讨山东地区慢乙肝的各种预后与HLA-DRB1等位基因之间的相关性。采用聚合酶链反应/序列特异性引物技术进行HLA-DRB1等位基因的检测,结果发现在慢乙肝组中,HLA-DRB1*0701/*1001出现的频率明显高于正常对照;其乙肝肝硬化组,后者出现的频率与正常对照比较具有统计学上的意义。在乙肝病毒携带组,HLA-DRB1*0701出现的频率明显高于正常对照。     

HLA class II genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in Poland

AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.     

Susceptibility to primary biliary cirrhosis is associated with human leukocyte antigen DRB1*0803 in Japanese patients

An association of primary biliary cirrhosis (PBC) with human leukocyte antigen (HLA) class II has been reported in previous studies based on the results of serological HLA typing. To evaluate the association between PBC and HLA class II more precisely, we performed HLA-DRB1 and DPB1 genotyping in 53 Japanese patients with PBC using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In DRB1 genotyping, the frequency of the^*0803 allele was significantly higher in patients with PBC than that in control subjects. Twenty out of 53 patients were^*0803 positive (37.7%), whereas only five out of 60 controls (8.3%) had the allele (relative risk = 6.67;P < 0.001; correctedP < 0.05). In DPB1 genotyping, there was no significant difference in the frequency of the DPB1 alleles between patients with PBC and controls. Amino acid analysis of the DRβ chain revealed that the frequency of leucine at position 74 was significantly higher in patients with PBC than that in controls. These results suggest that HLA-DRB1^*0803 allele and a subsequent amino acid substitution encoded by the polymorphic regions of the allele may play an important role in the pathogenesis of PBC.     

Human leukocyte antigen in primary biliary cirrhosis: an old story now reviving

Primary biliary cirrhosis (PBC) is an autoimmune biliary disease characterized by injury of small and medium size bile ducts, eventually leading to liver cirrhosis and death. Although the causes remain enigmatic, recent evidence has strengthened the importance of genetic factors in determining the susceptibility to the disease. Besides the strong heritability suggested by familial occurrence and monozygotic twins concordance, for decades there has not been a clear association with specific genes, with the only exception of a low risk conferred by a class II human leukocyte antigen (HLA) variant, the DRB1*08 allele, at least in some populations. The picture has become more complete when strong protective associations between PBC and the HLA DRB1*11 and DRB1*13 alleles were found in Italian and UK series. However, HLA genes have begun again to attract interest thanks to recent genome-wide association studies (GWAS), which clearly demonstrated that the major components of the genetic architecture of PBC are within the HLA region. As expected in a genetically complex disease, GWAS also identified several novel non-HLA variants, but it is worth noting that all of them are in immuno-related genes. In this review, the paradigmatic tale of what, and how, we learned about HLA genes in PBC will be retraced with particular focus on how GWAS are enabling a rewriting the story of PBC pathogenesis. These recent discoveries will not only drive functional studies but will also hold the promise of developing novel disease-specific treatments.