Comprehensive meta-analysis reveals an association of the HLA-DRB1*1602 allele with autoimmune diseases mediated predominantly by autoantibodies

The human leukocytes antigen (HLA)-DRB1*16:02 allele has been suggested to be associated with many autoimmune diseases. However, a validation of the results of the different studies by a comprehensive analysis of the corresponding meta data is lacking. In this study, we performed a meta-analysis of the association between HLA-DRB1*16:02 allele with various autoimmune disorders. Our analysis shows that HLA-DRB1*16:02 allele was associated with systemic lupus erythematosus, anti-N-Methyl-d-Aspartate receptor (NMDAR) encephalitis, Graves' disease, myasthenia gravis, neuromyelitis optica and antibody-associated systemic vasculitis with microscopic polyangiitis (AASV-MPA). However, no such association was found for multiple sclerosis, autoimmune hepatitis type 1, rheumatoid arthritis, type 1 diabetes and Vogt-Koyanagi-Harada syndrome. Re-analysis of the studies after their categorization into autoantibody-dependent and T cell-dependent autoimmune diseases revealed that the HLA-DRB1*16:02 allele was strongly associated with disorder predominantly mediated by autoantibodies (OR = 1.93; 95% CI = 1.63–2.28, P = 1.95 × 10⁻¹⁴) but not with those predominantly mediated by T cells (OR = 1.08; 95% CI = 0.87–1.34, P = .474). In addition, amino acid sequence alignment of common HLA-DRB1 subtypes demonstrated that HLA-DRB1*16:02 carries a unique motif of amino acid residues at position 67–74 which encodes the third hypervariable region. Taken together, the distinct pattern of disease association and the unique amino acid sequence of the third hypervariable region of the HLA-DRB1 provide some hints on how HLA-DRB1*16:02 is involved in the pathogenesis of autoimmune diseases.     

HLA-DQB1 基因多态性与广西壮族女性HPV16 感染和宫颈癌易感性的关联研究

目的:探讨HLA-DQB1 等位基因多态性对广西壮族女性HPV16 感染和宫颈癌发生的影响,为寻找广西壮族女性宫颈癌的遗传易感基因或保护基因提供线索。方法:选取广西地区25 ~45 岁宫颈癌确诊的壮族患者、无癌健康壮族女性各171 例作为研究对象(按年龄依3 岁配对),采集研究对象样本并提取HPV 核酸和人基因组DNA,分别应用PCR-SSP 和分子导流杂交技术进行HLA-DQB1 基因型检测和HPV 基因分型检测,最后进行统计学分析。结果:(1)171 例宫颈癌患者中HPV总感染率为91.22%,其中高危型病毒占90.76%, HPV16 型为主要致病亚型(43.58%);(2)广西壮族女性宫颈癌患者组的HLA-DQB1*04 等位基因携带率高于无癌对照组,差异具有统计学意义(P<0.05);等位基因HLA-DQB1*06/09 在宫颈癌患者组中的携带率明显低于无癌组,差异具有统计学意义(P<0.05);而两组间的HLA-DQB1*02/05/07/08 等位基因携带率无显著性差异(P>0.05);(3)HLA-DQB1*04 基因在HPV16 阳性宫颈癌患者中出现的频率明显高于HPV16 阴性患者,差异具有统计学意义(P<0.05)。结论:HLA-DQB1*04 可能是广西壮族女性宫颈癌发生的易感基因,HLA-DQB1*06/09 可能是广西壮族女性宫颈癌的保护基因。而HLA-DQB1*02/05/07/08 等位基因可能与广西壮族女性宫颈癌遗传易感性无关。携带HLA-DQB1*04 等位基因的广西壮族妇女可能更容易感染HPV16 型病毒,从而增加了其患宫颈癌的危险性。     

Identification of a new HLA-DRB1 allele, HLA-DRB1*0436

Anovel allele, HLA-DRB1*0436, was identified in a Taiwan indigenous individual by sequence-based typing. DRB1*0436 was identical to DRB1*0403 in exon2 but differed at codons 67-74 with five nucleotide substitutions. This corresponded to three amino acid changes within the P4 peptide-binding pocket of the DR molecule. These substitutions constitute a motif that is also seen in other DRB1*11 alleles. It is possible that the new allele resulted from a gene conversion event.     

Identification of a novel HLA-DRB1 allele (HLA-DRB1*111902*)

In this paper, we report a new HLA-DRB1 allele identified in a male acute myeloid leukaemia Chinese patient. This sample was initially typed as DRB1*11XX using commercial polymerase chain reaction-sequence-specific primers kit. When it was typed using a chip-based sequence-specific oligonucleotide technique, a novel hybridization pattern that does not match any known alleles was observed. Through sequencing, we have identified this allele as a new HLA-DRB1 allele, which was later named HLA-DRB1*111902 by the WHO Nomenclature Committee. The sequence of this new allele differs from DRB1*111901 by one nucleotide (from G to C) at 203nt of exon 2 but does not cause any amino acid substitution.     

Identification of a new allele, HLA-DRB1*1366*

High-resolution polymerase chain reaction sequence-specific primer typing of the human leucocyte antigen (HLA)-DRB1 gene of an Italian patient candidate for bone marrow transplantation revealed a new allelic variant of HLA-DRB1*13. The sequence was named DRB1*1366, and comparison with previously described DRB1 alleles demonstrated the two closely related sequences were HLA-DRB1*1330 and HLA-DRB1*130302.     

A novel HLA-DRB1 allele,DRB1*0707

We report herein the identification of a new HLA-DRB1 allele, DRB1*0707. This new allele was seen in a volunteer bone marrow donor (ID#118069) belonging to the German bone marrow donor registry (DKMS). HLA-DRB1*0707 was detected while performing HLA-DRB1 high resolution typing by sequence based typing. This novel allele differs from DRB1*070101 by a single nucleotide substitution at position 163 (C-->T) in exon 2.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

Objective To identify a novel human leukocyte antigen (HLA) allele by cloning and sequence-based typing in Chinese population, and analyzing the sequence of the introns 1 and 2. Methods The routine HLA-A, -B, -DRB1 low resolution genotyping for stem cell donor from Guangdong province was performed with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). An unknown HLA-DRB1 allele was initially detected by HLA typing. Genomic DNA of the proband was amplified by using HLA-DRB1 locus group-specific primer, the amplified product was cloned, sequenced, and compared to the closest DRB1 * 120201 allele and the closest intron sequence of the DRB1 * 030101 allele. Results The sequencing results showed that a normal DRB1 * 080302 and a novel DRB1 * 1218 variant allele were identified. The sequence of the novel allele has been submitted to GenBank (FJ481086). The novel allele had 1 nucleotide substitution of the closest matching allele HLA-DRB1 * 120201 at nt262(G →C) in exon 2, resulting in an amino acid change from GIu(GAG)→Gln (CAG) at codon 59. The intron 2 sequence is identical between the novel HLA-DRB1 * 1218 and DRB1 * 030101, but there are 12 nucleotides substitution in intron 1. Conclusion A novel HLA allele was confirmed by cloning and sequence-based typing in Chinese. It was officially designated as HLA-DRB1 * 1218 by WHO Nomenclature Committee.     

人类白细胞抗原新等位基因DRB1*1219的确认及其序列分析

目的 鉴定分析1个白血病患者家庭HLA-DRB1位点1个新等位基因.方法 应用PCR-序列特异性引物及Luminex DNA杂交流式分型技术进行HLA分型,发现1个与HLA-DRB1*120201相关的未知基因.应用DNA测序技术进行鉴定分析并与已知序列比对分析.结果 先证者DRB1位点有1个等位基因的核苷酸序列与所有已知基因序列均不相同,与同源性最高的DRB1*120201相比,第2外显子第341位核苷酸碱基发生了C→T,结果导致相应85位密码子编码的丙氨酸变为缬氨酸.结论 测序表明被测样本含有1个HLA-DRB1新等位基因,被世界卫生组织HLA因子命名委员会正式命名为HLA-DRB1*1219(序列号EJ374889).

Abstract：

Objective To identify a novel HLA DRB1 allele in a Chinese leukemia family. Methods A new HLA-DRB1 allele was initially detected by polymerase chain reaction-sequence specific primer and unusual reaction pattern by Luminex RSSO, then DNA sequencing was performed to identify the sequence of the novel allele. Results The DNA sequencing revealed the presence of the new allele which differs from the closest macthing HLA- DRB1 * 120201 by a single nucleotide substitution at position (341 C→T in exon 2),resulting in an amino acid change from Ala to Val at coden 85. Conclusion A novel allele was confirmed by DNA sequencing and has been designated HLA-DRB1 * 1219 by the WHO Nomenclature Committee.     

HLA-DRB1*1218新等位基因克隆测序鉴定及内含子序列分析

目的 鉴定中国人群人类白细胞抗原(human leukocyte antigen,HLA)DRB1基因,分析新等位基因第1和2内含子序列信息.方法 采用聚合酶链反应-序列特异寡核苷酸探针反向杂交法(polymerase chain reaction-sequence specific oligonucleotide probes,PCR-SSOP)对广东地区随机正常人群进行HLA常规基因分型,发现1个与HLA-DRB1*120201相近的未知基因,对先证者DNA应用组特异性引物扩增HLA-DRB1位点第2外显子,PCR产物经克隆到质粒载体中以获得单链,对克隆所得产物进行HLA-DRB1基因的第2外显子及第1和第2内含子双向测序分析.并与DRB1*120201基因序列的第2外显子和DRB1*03010101等位基因内含子相比较.结果 发现该个体的一个HLA-DRB1*080302基因被确认,而另一个HLA-DRB1基因为新等位基因,其序列被GenBank接受(编号为FJ481086).新等位基因与最相近的DRB1*120201相比,在第2外显子上有1个核苷酸的不同,即第262位G→C(密码子59 GAG→CAG,氨基酸59 Glu→Gln).DRB1*1218与DRB1*03010101等位基因第2内含子序列完全相同,而与DRB1*03010101等位基因第1内含子序列相比较有12个碱基不同.结论 发现并鉴定一个新的HLA等位基因,经世界卫生组织HLA因子命名委员会正式命名为HLA-DRB1*1218.