Naming HLA diversity: A review of HLA nomenclature

The development of a standardized HLA nomenclature has been critical in our understanding of the HLA system and in facilitating the clinical applications of HLA. The Nomenclature Committee for Factors of the HLA System, established in 1968, has overseen the development and usage of nomenclature based on serologic specificities, cellular responses, and DNA sequences. Their decisions have been guided by community consensus reached through 17 international workshops beginning in 1964 and continuing today. Two websites provide a curated database of the sequences of over 26,000 HLA alleles and a reference site for the current nomenclature. This review covers the major steps in the development of the HLA nomenclature as well as the efforts of other groups to extend its usefulness for research and clinical applications.     

Human leukocyte antigen-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects

Human leukocyte antigens (HLA) play a key role in antigen presentation. HLA genes, especially HLA-A, -B, and -DRB1, which are highly polymorphic, have been thought to be candidate loci for the etiology of sarcoidosis. This study aimed to assess the association between the polymorphism of HLA-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects. Genomic DNA was extracted from 131 patients with sarcoidosis and 122 healthy controls. The polymorphisms of the HLA-A, -B, and -DRB1 alleles were determined using a polymerase chain reaction sequence-specific primer method. The frequency of allele HLA-DRB1*11 in sarcoidosis patients was significantly higher than that in controls (24.43% vs 4.92%, p/p_c = 0.0001/0.002), whereas the frequencies of allele HLA-B*13 and HLA-DRB1*07 were markedly lower in sarcoidosis patients than in controls (12.21% vs 27.87%, p/p_c = 0.002/0.045; 7.63% vs 22.95%, p/p_c =0.001/0.009). HLA-B*51 was overrepresented in patients with erythema nodosum and Löfgren's syndrome (p < 0.001 [p_c = 0.015], p < 0.0001 [p_c < 0.001], respectively). These results support the hypothesis that HLA-A, -B, and -DRB1 polymorphisms may play a role in susceptibility and manifestation of sarcoidosis.     

广东籍家系HLA基因重组3例报告

目的 探讨广东籍家系人类白细胞抗原等位基因的重组及规律.方法 采用PCR-序列特异性引物(sequence specific primer,SSP)和基因序列测定(sequence-based test,SBT)两种方法对2010年1月至2012年5月间进行骨髓移植配型的3个基因重组广东籍家系进行HLA-A、Cw、B、DRB1、DQB1高分辨分型,并通过短片段串联重复序列(short tandem repeat,STR)法对各家系的亲子关系进行鉴定.结果 3个家系中2例为母源性的A/Cw位点之间的基因重组,1例为父源性的B/DRB1位点之间的基因重组.重组后均产生了新的单倍型.结论 A/C、B/DRB1间的基因重组较为多见,母源性基因重组多于父源性基因重组.此次研究发现了1例B/DRB1间的父源性基因重组.     

Description of a new HLA-B allele: HLA-B*4077

HLA-B*4077 differs from B*400101, B*4036, and B*401401 in five, four, and three nucleotides, respectively. However, amino acid alignment would indicate a closer relationship with B*4036 allele, showing a single amino acid replacement at codon 131 (R>S).     

HLA-A、HLA-B、DRB1等位基因多态性与中国北方汉族肺癌患者遗传易感相关性的研究

目的探讨中国北方汉族人中HLA-A、B、DRB1等位基因与肺癌遗传易感性间的关系。方法采用测序分型技术(sequence-based typing,SBT)技术,对无血缘关系的籍贯为中国北方的140名肺癌患者及483名健康志愿者的HLA-A、B、DRB1基因进行检测。arlequin软件(ver2.000)及SPSS软件进行统计分析。结果 A*2601、B*1518、B*3802、DRB1*0401、DRB1*0402、DRB1*1201在肺癌病人中频率显著性高于正常对照,P值分别为0.021、0.001、0.015、0.021、0.010和0.046,OR值分别为3.513、3.842、2.715、3.512、13.986、1.828;HLA-DRB1*1001、DRB1*1302在肺癌病人中频率显著性低于正常对照,P值分别为0.017和0.014,OR值分别为0.135和0.122。单倍型HLA-A*0207-B*4601-DRB1*0901、HLA-A*0206-B*5101在肺癌病人中频率显著性高于正常对照,P值分别为0.034和0.006,OR值分别为2.348和3.969;单倍型HLA-A*110...     

Detection of four novel alleles: DRB1*1130, DRB1*13072, DRB1*1315 and DRB1*1331

Four new DR52-associated DRB1 alleles are described. One allele, DRB1*1130, is a hybrid between a DRB3*02 allele and a DRB1*11011 allele. The other alleles, DRB1*13072, DRB1*1315, and DRB1*1331, are simple reshufflings of known polymorphic motifs.     

人类白细胞抗原新等位基因B*55:35的鉴定及家系调查

目的 鉴定人类白细胞抗原(human leukocyte antigen,HLA)基因B位点的1个新等位基因并调查其遗传情况.方法 应用聚合酶链反应-序列特异性寡核苷酸探针(polymerase chain reactionsequence specific oligonucleotide probe,PCR-SSOP) HLA分型技术发现1个疑似的新HLA等位基因,通过DNA测序鉴定其序列,并与同源性最高的HLA基因进行核苷酸序列比对,对携带者家系进行调查.结果应用PCR-SSOP进行HLA基因分型时,该样本HLA-B位点反应格局异常.DNA序列分析证实其为1个新HLA-B等位基因.与同源性最高的等位基因B*55:02比较,在第2外显子区域中有7个碱基发生改变,导致6个密码子发生了变化,造成2个氨基酸改变,即第69位的氨基酸由谷氨酸(Glu)变为甲硫氨酸(Met)、第70位的氨基酸由谷氨酸(Glu)变为丙氨酸(Ala).结论 发现并鉴定了HLA-B位点的1个新等位基因,GenBank注册号为FJ898284,被世界卫生组织HLA因子命名委员会正式命名为HLA-B* 55:35.     

Common and well-documented (CWD) alleles of human leukocyte antigen-A, -B, -C, -DRB1, and -DQB1 loci for the Chinese Han population do not quite correlate with the ASHI CWD alleles

Human leukocyte antigen (HLA), which is extremely polymorphic, plays an important role in stem cell transplantation. The Chinese Han comprise a large population of approximately 1.3 billion with diverse HLA alleles that need to be characterized. Data from 3,296 independent, unrelated Chinese Han individuals (1,457 recipients and 1,839 donors) were provided by the China Marrow Donor Program (CMDP) for donor-recipient confirmatory typing. Sequence-based typing, sequence-specific oligonucleotide probe (SSOP)/High Definition-SSOP, and sequence-specific primer methods were used to obtain 4-digit alleles. A total of 49, 86, 50, 63, and 24 HLA-A, -B, -C, -DRB1, and -DQB1 alleles were observed. Following American Society for Histocompatibility and Immunogenetics (ASHI) common and well-documented (CWD) criteria, CWD alleles for Chinese Han in our laboratory test and other laboratory reports do not quite correlate with the ASHI CWD alleles: A*11:53, A*02:34, A*02:53N, B*27:24, B*46:02, B*55:12, C*01:06, C*03:17, C*06:06, C*07:66, C*07:67, C*08:22, DRB1*12:10, DQB1*03:13, and DQB1*06:05 are CWD, but are not included in the ASHI CWD list. A series of alleles are well-documented alleles and are listed in the ASHI CWD list. Conversely, A*26:03, B*51:03, C*12:05, C*15:09, C*15:11, C*17:03, DRB1*11:07, DRB1*11:11, DRB1*13:05, DRB1*13:13, DRB1*14:06, DRB1*14:12, DRB1*14:22, DRB1*14:25, and DQB1*06:11 are rare alleles, but are included in the ASHI CWD list. HLA ethnic diversity is the main reason for the differences in HLA alleles worldwide. The ASHI HLA CWD alleles help reduce the workload and expenses in high-resolution donor registries and the HLA allele frequencies provide a basis from which to predict the chances of finding HLA matching donors. Our data will be meaningful for the CMDP, for other worldwide donor registries, and for an updated ASHI CWD allele list.     

山东地区汉族人群中HLA-A、-B、-DRB1等位基因与原因不明卵巢早衰相关性研究

目的探讨HLA-A,-B和-DRB1位点等位基因多态性与原因不明卵巢早衰(premature ovarian failure,POF)的相关性。方法利用毛细管电泳测序技术(Capillary Electrophoresis),对36例汉族原因不明POF患者进行HLA-A,-B,-DRB1基因分型,并以865例山东健康汉族个体造血干细胞分型资料作为对照,分析HLA等位基因频率在两组中的分布差异。结果 POF组中HLA-A*33、HLA-B*07、HLA-B*52和HLA-B*55等位基因频率显著高于对照组(P<0.05)。HLA-A*33的等位基因频率POF组为19.44%,而正常对照组为10.17%,RR=2.18;HLA-B*07的等位基因频率POF组为12.50%,而正常对照组为5.32%,RR=2.65;HLA-B*52的等位基因频率POF组为11.11%,而正常对照组为4.10%,RR=3.06;HLA-B*55的等位基因频率POF组为5.56%,而正常对照组为1.50%,RR=4.23。结论山东汉族人群中HLA-A*33、HLA-B*07、HLA-B*52和HLA-B*55等位基因可能是POF的易感基因。     

Thirty-six novel HLA alleles: 7 HLA-A, 11 HLA-B, 15 HLA-C and 3 HLA-DRB1

Thirty-six novel human leukocyte antigen (HLA) alleles are described in this article: A*9225N, A*9234, A*030106, A*0337, A*2317, A*2480, A*3023; B*070206, B*0759, B*0761, B*0765, B*150106, B*1827, B*352002, B*3585, B*3943, B*4082, B*5151; Cw*0342, Cw*0343, Cw*0344, Cw*0428, Cw*0430, Cw*0433, Cw*050104, Cw*0519, Cw*060203, Cw*070109, Cw*070202, Cw*0750, Cw*0815, Cw*120306, Cw*1409; DRB1*0336, DRB1*0473 and DRB1*1382.     

Two DR2-associated novel alleles arose from the silent mutation of codon 72: DRB1*16012, DRB5*01012

Two DRB1*02-associated alleles, DRB1*16012 and DRB5*01012, are described. Both alleles carry the same silent substitution at codon 72.     

Two new HLA-DQB alleles routinely identified by sequence-based typing: DQB1*030103 and DQB1*0505

Here, we report the identification of two novel human leukocyte antigen-DQB1 alleles, DQB1*030103 and DQB1*0505, found by routine typing using commercial kits.     

青光眼睫状体炎综合征与杀伤细胞免疫球蛋白样受体-人类白细胞抗原受配体复合物遗传多态性的相关性研究

目的 研究和分析南方汉族人群青光眼睫状体炎综合征（PSS）与杀伤细胞免疫球蛋白样受体（KIR）及其人类白细胞抗原（HLA）配体基因多态性的相关性.方法 随机选择100例无关健康个体作为对照组,收集97例临床诊断为PSS的患者血样,采用KIR PCR-SSP方法检测KIR框架基因的有无,PCR-SBT法进行HLA-A、B、C基因的测序分型;统计分析健康对照组与患者的KIR框架基因频率、KIR基因单倍体组合型的频率、HLA配体的频率、单个KIR-HLA配体复合物的频率之间的差异.结果 与正常人群相比,PSS患者KIR框架基因频率及单倍体组合型频率差异无统计学意义（P均＞0.05）;HLA配体中的HLA-Bw4-80T在PSS患者及正常人群中的比例分别为22.1％和41.0％,差异有统计学意义（P＜0.01）;KIR-HLA配体组合中的3DL1＋ HLA-Bw4-80T在PSS患者及正常人群中的比例分别为22.1％和40.0％,差异有统计学意义（P＜0.05）,患者组与正常人群组相比都显著降低.结论 PSS与KIR框架基因及单倍型频率无关,但可能与HLA配体或KIR-HLA配体组合相关,这对研究PSS的发病机制及治疗方法具有重要意义.     

Identification and characterization of novel HLA alleles: Utility of next-generation sequencing methods

The HLA genes are the most polymorphic of the human genome, and novel HLA alleles are continuously identified, often by clinical Sanger sequencing-based typing (SBT) assays. Introduction of next-generation sequencing (NGS) technologies for clinical HLA typing may significantly improve this process. Here we compare four cases of novel HLA alleles identified and characterized by both SBT and NGS. The tested NGS system sequenced broader regions of the HLA loci, and identified novel polymorphisms undetected by SBT. Subsequent characterization of the novel alleles in isolation of coencoded alleles by SBT required custom-designed primers, while the NGS system was able to sequence both alleles in phase. However, the tested assay was unable to amplify buccal cell DNA for subsequent NGS sequencing, presumably due to the lower quality of these samples. While NGS assays will undoubtedly increase novel allele identification, more stringent DNA sample requirements may be necessary for this new technology.     

云南汉族2型糖尿病与HLA-DQA1基因的关联研究

目的　探讨云南汉族 2型糖尿病及 2型糖尿病肾病与 HL A- DQA1基因的关联性。方法　采用聚合酶链反应 -序列特异性引物技术对云南汉族 10 8例 2型糖尿病患者及 5 6名同地区同民族健康对照人群进行 DQA1基因分型。结果　云南汉族 2型糖尿病患者与正常对照组比较 ,DQA1* 0 30 1( RR=3.0 92 ,P<0 .0 1) ,DQA1* 0 5 0 1( RR=3.2 5 7,P<0 .0 5 )等位基因频率明显增高 ,DQA1* 0 4 0 1( RR=0 .371,P<0 .0 1)等位基因频率显著下降。糖尿病合并肾病组与正常对照组及不合并肾病的 2型糖尿病组比较 ,糖尿病合并肾病患者 HL A- DQA1* 0 30 2等位基因频率显著升高 ( RR=3.35 6 ,P<0 .0 1) ,各期糖尿病肾病比较中 DQA1* 0 30 2频率差异无显著性 ( P>0 .0 5 )。结论　 HL A- DQA1* 0 30 1,DQA1* 0 5 0 1是云南汉族 2型糖尿病的易感基因 ,HL A- DQA1* 0 4 0 1是云南汉族 2型糖尿病的抵抗基因 ;HL A- DQA1*0 30 2是 2型糖尿病合并肾病的易感基因     

中国东北地区汉族人寻常型天疱疮与HLA相关的研究

目的 探讨中国人寻常型天疱疮（pemphigus vulgaris,PV)相关的HLA抗原及等位基因。方法 应用标准微量淋巴细胞毒试验方法及聚合酶链反应－序列特异性引物（PCR－SSP）技术对27例PV患者HLAI类分子及Ⅱ类分子DR、DQ等位基因检测，并和健康对照组比较。结果 PV组中HLA－A3、A26（10）、B13和B60（40）抗原频率明显增高，校正P值后，HLA－A3、A26（10）、B60（40）与对照组差异仍有显著意义。HLA－DRB1＊140x(1401、1404、1405、1407、1408）、DRB1＊120x和DQB1＊0503等位基因出现频率明显高于对照组，校正P值后两组差异仍有显著意义。结论 中国汉族PV患者中，PV的发生与HLA显著相关。     

山东省烟台和威海地区汉族HLA-A、B和DRB1等位基因多态性及遗传距离分析

目的 分析山东省烟台和威海地区汉族人群人类白细胞抗原(human leukocyte antigen,HLA)-A、B、DRB1等位基因的多态性分布特征,并探讨该人群与其他人群的亲缘关系.方法 应用聚合酶链反应-序列特异性寡核苷酸探针方法(polymerase chain reaction-sequence specific olignucleotide probe,PCR-SSOP)对山东省烟台和威海地区4062名无亲缘关系的汉族健康个体进行HLA-A、B、DRB1基因分型.采用Arlequin3.5软件计算HLA等位基因频率、单倍型频率和连锁不平衡参数,按内氏公式计算出不同人群之间的遗传距离,并利用Mega5.0软件构建系统发生树.结果 该人群HLA-A、B、DRB1等位基因分布均符合Hardy-Weinberg平衡(P＞0.1).3个基因座分别检出18、33和13个等位基因,其中等位基因频率分布最高的分别是A* 02 (0.2935)、B* 15 (0.1485)和DRB1* 15 (0.1621);最常见的单倍型为A* 30-B* 13-DRB1* 07(0.0649),A* 33-B* 58、A*66-DRB1* 13、B*08-DRB1* 03呈现最强的连锁不平衡;山东省烟台和威海汉族人群与吉林省汉族人群遗传距离最小,为0.0034.结论 山东省烟台和威海地区汉族人群HLA-A、B、DRB1等位基因和单倍型具有较高的遗传多态性,该人群与吉林汉族人群亲缘关系最近.     

HLA-A*3101、B*4001、B*5801、DRB1*1602等位基因与遵义地区汉族肾综合征出血热发病的相关性研究

目的 探讨HLA-A*31、B*40、B*58、DRB1*16位点基因多态性与遵义地区汉族肾综合征出血热(HFRS)的关联性.方法 采用群体研究方法,应用聚合酶链反应-序列特异性引物(PCR-SSP)技术对100例HFRS患者(患者组)和100例健康对照者(健康对照组)进行HLA-A*31、B*40、B*58、DRB1*16基因亚型分型,比较基因频率(GF),并计算其相对危险度(RR).结果 HFRS患者组HLA-A*3101、B*5801、DRB1*1602的基因频率均较对照组明显增高(RR=13.825,x2=4.296,P=0.038;RR=2.614,x2=6.133,P=0.013;RR=8.523,x2=8.865,P=0.003),差异有统计学意义(P均＜0.05);患者组HLA-B*4001的基因频率较对照组明显降低(RR=0.414,x2=6.640,P=0.010),差异有统计学意义(P＜0.05).结论 遵义地区汉族人群中,HLA-A*3101、B*5801、DRB1*1602等位基因与HFRS呈正相关,HLA-B*4001等位基因与HFRS呈负相关.     

DRB3 alleles with variations in the annealing sites of commonly used amplification primers

New HLA alleles are often identified initially from observing uncommon patterns found in low-resolution typing performed via polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP). Recently, the HLA-DR oligotyping analysis of two Caucasian, one Caucasian/American Indian and two African American individuals resulted in the identification of three novel DRB3 alleles. Using DRB-specific primer sets commonly employed in amplification-based typing, all four individuals were originally characterized as DRB3 negative. Direct sequencing identified DRB3*0104 (variation at codon 8, TCG instead of TTG), and DRB3*0101202 (variation at intron (-13), G instead of C). One individual appeared to carry a DR52-associated DRB1 allele without an associated DRB3 allele. Lack of conservation at the junction of intron 1 and exon 2 of the DRB3 gene suggests that commonly used DRB-specific primer sets may need to be modified.     

河南地区汉族人群复发性流产患者HLA-DRB1、DQB1等位基因多态性的研究

目的探讨复发性流产易感性与人类白细胞抗原(HLA)DR、DQ区域基因多态性的关系。方法采用序列特异性引物聚合酶链反应(PCR-SSP),分析200例复发性流产患者(患者组)和200例无不良妊娠史正常妇女(对照组)的DRB1和DQB1基因型。结果患者组中的DQB1*03(39.25%)等位基因频率显著高于对照组(32.5%)(P=0.047<0.05,RR=1.208),DQB1*05(14%)等位基因频率较对照组显著降低(22.75%)(P=0.001<0.05,RR=0.615);患者组中DRB1*09(14%)等位基因频率显著高于对照组(9.25%)(P=0.036<0.05,RR=1.514),DRB1*12(8.5%)等位基因频率较对照组显著降低(14%)(P=0.014<0.05,RR=0.607)。结论河南地区汉族人群中DQB1*03、DRB1*09可能是复发性流产的易感基因,而DQB1*05、DRB1*12可能对复发性流产的发生有保护作用。