Identification of HLA-DRB1 alleles associated with Graves' disease in Koreans by sequence-based typing

The human leukocyte antigen (HLA) region, particularly class II genes, plays a primary role in the susceptibility to development of GD. We investigated the allelic polymorphism of HLA class II DRB1 genes to examine its association with GD in Koreans. We performed the high resolution polymerase chain reaction-sequence based typing (PCR-SBT) of HLA-DRB1 in 133 patients with GD and 200 healthy controls. Compared to healthy controls, the patients with GD had increased frequencies of DRB1*030101 (4.9% vs.1.8%, p = 0.034), DRB1*080201 (5.3% vs. 2.3%, p = 0.050) and DRB1*140301 (3.4% vs. 1.0%, p = 0.043). In contrast, the frequencies of DRB1*070101 (3.0% vs. 7.3%, p = 0.024) and DRB1*130201 (4.1% vs. 9.0%, p = 0.010) were decreased in the patients with GD. However, the corrected p values were not significant in above all alleles. Patients with DRB1*040301 were significantly older than controls (45 years vs. 35 years, p = 0.017). DRB1*040301, DRB1*150201, DRB1*120101 and DRB1*120201 were associated with male predominance, strong familial associations, thyroid ophthalmopathy and radioactive iodine therapy, respectively. In conclusion, there were no significant HLA-DRB1 alleles associated with GD in Koreans, although some alleles were correlated with the clinical characteristics.     

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.     

Positive association of HLA-DRB1*15 with keloid disease in Caucasians

Keloid disease (KD) is a fibroproliferative dermal tumour of unknown aetiology. The increased familial clustering in KD, its increased prevalence in certain races and concordance in identical twins suggest a strong genetic predisposition to keloid formation. The most polymorphic genetic system in all vertebrates is the major histocompatibility complex (MHC) also known as the human leucocyte antigens (HLA) system. The MHC has been shown to be strongly associated with numerous conditions. Of particular interest is the association of DR2 with dermal fibrotic diseases such as sarcoidosis. To investigate the aetiology of KD, we compared the HLA-DRB1 phenotype frequencies of Caucasoid patients with keloid scars against those observed in a control population (n = 537). A total number of 67 keloid cases were evaluated in the study. HLA-DRB1 alleles were determined in all cases and controls using a commercially available semiautomated reverse hybridization polymerase chain reaction sequence-specific oligonucleotide probes typing system. HLA-DRB1*15 phenotype frequency was higher in KD-positive Caucasians (38.8%) when compared with controls (20.9%) (corrected P = 0.017). We conclude that in Caucasians of Northern European origin, HLA-DRB1*15 is associated with risk of developing KD following injury. We have demonstrated for the first time that a genetic association exists between HLA-DRB1*15 status and the risk of developing keloid scarring in Caucasians. Our data suggest the possible involvement of an immunogenic component to KD although the exact mechanisms involved in MHC-driven abnormal fibrosis will require further investigation.     

Positive association of HLA-DRB1*15 with Dupuytren's disease in Caucasians

Dupuytren's disease (DD) is a permanent nodular condition affecting the palms and digits of the hands, leading to progressive shortening and contractures of the digits often resulting in diminished function and severe deformity. DD is thought to be one of the most common hereditary connective tissue disorders in Caucasians. To elucidate further the aetiology of DD, we compared the HLA-DRB1 phenotype frequencies of DD patients (n=67) against the HLA-DRB1 phenotype frequencies observed in a control population (n=537). HLA-DRB1*15 phenotype frequency was higher in DD positive Caucasoids (37.3%) when compared with control data (20.9%) (corrected P=0.029): we conclude that in Caucasoids of European origin, HLA-DRB1*15 is associated with risk of developing DD.     

HLA-DRB1*03 is a susceptibility gene in patients with Graves' disease with and without ophthalmopathy

We sought an association between certain human leucocyte antigen (HLA) markers and Graves' disease (GD) with and without ophthalmopathy (OP). One hundred and thirty-one Turkish patients with GD (50 without OP, 81 with OP) and 250 local healthy controls were studied. HLA-DRB1 typing was performed by using polymerase chain reaction-sequence-specific primers (PCR-SSP) method. The frequencies of DRB1*03 was significantly increased in GD compared to controls (OR = 2.07; 95% CI = 1.24-3.44), whereas DRB1*13 (OR = 0.33; 95% CI = 0.18-0.61) and DRB1*07 (OR = 0.31; 95% CI = 0.13-0.70) were significantly increased in controls compared to patients. None of the three associations showed any specificity to the OP group.     

Implication of the HLA-DRB3 gene in Graves' disease: predominance of allele Dw24

Using RFLP, the present study sets off to determine the MHC class II gene polymorphism in Graves' disease, in order to define the HLA-related genetic susceptibility. Considering the preferential link between Graves' disease and the HLA-DR3 antigen, 42 HLA-DR3 Graves' disease patients were studied and compared with 42 HLA-DR-matched controls. Hybridization with a DQ alpha probe of DNAs digested by Taq I revealed a polymorphism of the DR3 haplotype with an overrepresentation of a 2.1 kb(U) fragment in patients, but this was merely a sign of the linkage disequilibrium between U and B8DR3. Hybridization with the DR beta probe of DNAs digested by Taq I yielded more facts. It revealed the overrepresentation of the Dw24 specificity (Taq I:9.8 kb) in DR3 Graves' disease patients. This study thus enabled us to determine precisely the susceptibility linked to the DR3 haplotype, implicating the DRB3 gene and its Dw24 allele, which appear to be the most reliable markers of the disease, providing a higher relative risk than B8DR3.     

A novel HLA-DRB1 allele, HLA-DRB1*0465, was identified in a Hodgkin's lymphoma cell line

The new human leucocyte antigen-DRB1*0465 allele was identified in the Hodgkin's lymphoma cell line KM-H2. This novel allele differs from the DRB1*0406 allele by a single nucleotide exchange at position 288 (211) (A→T), which results in an arginine to tryptophan amino acid replacement at codon 90 in the new allele.     

Identification of HLA-DRB1 Alleles Associated with Graves' Disease in Koreans by Sequence-Based Typing

The human leukocyte antigen (HLA) region, particularly class II genes, plays a primary role in the susceptibility to development of GD. We investigated the allelic polymorphism of HLA class II DRB1 genes to examine its association with GD in Koreans. We performed the high resolution polymerase chain reaction-sequence based typing (PCR-SBT) of HLA-DRB1 in 133 patients with GD and 200 healthy controls. Compared to healthy controls, the patients with GD had increased frequencies of DRB1*030101 (4.9% vs.1.8%, p = 0.034), DRB1*080201 (5.3% vs. 2.3%, p = 0.050) and DRB1*140301 (3.4% vs. 1.0%, p = 0.043). In contrast, the frequencies of DRB1*070101 (3.0% vs. 7.3%, p = 0.024) and DRB1*130201 (4.1% vs. 9.0%, p = 0.010) were decreased in the patients with GD. However, the corrected p values were not significant in above all alleles. Patients with DRB1*040301 were significantly older than controls (45 years vs. 35 years, p = 0.017). DRB1*040301, DRB1*150201, DRB1*120101 and DRB1*120201 were associated with male predominance, strong familial associations, thyroid ophthalmopathy and radioactive iodine therapy, respectively. In conclusion, there were no significant HLA-DRB1 alleles associated with GD in Koreans, although some alleles were correlated with the clinical characteristics.     

Identification of a novel HLA-DRB1 allele, HLA-DRB1*1217, in a Korean individual

We report a new DRB1 allele, DRB1*1217, identified by direct sequencing of a bacterial artificial chromosome (BAC) clone originated from genomic DNA of a Korean donor. DRB1*1217 differs from previously reported DRB1*120201 by a single nucleotide substitution, which results in an amino acid change at codon 67 [TTC→ATC (F>I)].     

A novel HLA-DRB1*120204 allele found in a Chinese individual

The HLA-DRB1*120204 allele differs by a single synonymous nucleotide change from the DRB1*120201 allele at position 203 in exon 2 from C to G.     

A novel HLA-DRB1*09 allele, HLA-DRB1*090103*, isolated from the Han population of Guangdong, China

A novel HLA-DRB1*09 allele, HLA-DRB1*090103, has been identified in a Guangdong Han person. Its sequence was confirmed by sequencing polymerase chain reaction products and clones. This allele differed by one nucleotide from HLA-DRB1*090102 at position 50(G-->C), which represents a silent mutation.     

HLA-DRB1基因多态性与克山病及其核心家系的关系研究

目的探讨HLA-DRB1基因多态性在我国北方克山病地区的分布特征及其与克山病核心家系的关联和连锁。方法采用聚合酶链反应-序列特异性寡核苷酸探针(polymerase chain reaction-sequence specific oligonucleotide probing,PCR-SSOP)技术,对118例克山病(Keshan disease,KD)患者HLA-DRB1基因进行分型,其中潜在型KD63例,慢型KD55例,65名正常人为对照;采用单倍型相对风险(haplotype based haplotype relative risk,HHRR)和传递不平衡检验(transmission disequilibrium test,TDT)方法对该基因在18个KD核心家系中的分布进行关联和连锁分析。结果(1)在KD患者和对照人群中,HLA-DRB1位点共检出13种等位基因;(2)DR7等位基因在KD组中的分布频率显著低于对照组(P<0.01,OR=0.1695);(3)DR7等位基因在慢型KD中的分布频率显著低于对照组(P<0.01,OR=0.091),而在潜在型KD中的分布频率与对照组比较差异无统计学意义;(4)DR15等位基因与KD显著关联(χ2=9.32,P<0.01),并与KD易感位点连锁(χ2=7.40,P<0.01)。结论KD可能存在遗传易感性,HLA-DRB1的DR7等位基因可能是KD保护性基因,携带DR7等位基因的KD患者可能不易发展为慢型KD,DR15等位基因可能与KD易感基因连锁。     

HLA-DRB1 and MHC class 1 chain-related A haplotypes in Basque families with celiac disease

The contribution of HLA genes to the genetic risk for celiac disease (CD) has been known for a long time. Recent publications have pointed to the possibility that a second, independent susceptibility locus could be located in the same genomic region, and a triplet repeat polymorphism in exon 5 of the gene MHC class I chain-related protein A (MICA; located between TNFA and HLA-B) has been associated with several autoimmune disorders, including type 1 diabetes mellitus (DM1) and Addison's disease. On the other hand, a single amino acid change in exon 3 of MICA (M129V) has been shown to strongly reduce MICA binding to NKG2D, an activating natural killer receptor expressed also on T cells, and this could have significant effects on autoimmune reactions. In this study, we have analyzed the contribution of these polymorphisms to CD in 37 Basque families, and have constructed MICA-HLA-DRB1 haplotypes to determine whether MICA has an effect independent from the HLA class II conferred risk. In our population, HLA-DRB1*0301 was associated with an increased risk for CD, while HLA-DRB1*1501 conferred protection from the disease (OR: 7.38 and 0.06, respectively). On the other hand, MICA allele A4 was positively associated with the disease (OR: 4.69) whereas allele A9 showed a trend towards protection (OR: 0.18), although significance did not hold after correction. No association of the exon 3 biallelic polymorphism was observed. A positive allelic association was found for haplotypes A5.1-DRB1*0301 (associated with risk for disease), A4-DRB1*0301 and A6-DRB1*07. In view of our results, both HLA-DRB1 and MICA are associated with CD, but stratification analysis did not show any independent contribution of the MICA polymorphisms analyzed to CD risk. Besides, MICA allele A4 (also A5.1 was associated with risk for CD and other diseases) is in strong linkage disequilibrium with HLA-DRB1*0301. Finally, the major histocompatibility complex region's conferred susceptibility to CD, at least in Basque, is very similar to that observed for DM1, with shared risk and protective haplotypes.     

Identification of a novel DRB1 allele through intergenic recombination between HLA-DRB1 and HLA-DRB302 in a Chinese family

In this study, a novel DRB1 allele was revealed by routine HLA-SBT typing noted for its extensive mismatches to any known DRB1 alleles within the exon 2. Sequences containing the exons 2, 3 of HLA-DRB1, their surrounding introns, and the full-length cDNA of DRB1 were analyzed to determine a possible recombination event. Interestingly, the sequences of entire exon 2 were characterized as DRB3^∗02:02:01:01/02; while exon 3 were characterized as DRB1^∗14 like alleles. Further analysis of the sequences using Simplot software suggested that an intergenic recombinant event (i.e. exchange of sequence between non-allelic genes) may have occurred between DRB3^∗02 allele and DRB1^∗14 like allele, and the recombination sites are located at intron 1 and the boundary of exon 2 and intron 2 of DRB1. There are 5 CGGGG sequences flanking each side of exon 2 could serve as potential recombination site. Moreover, the full-length cDNA of the novel allele has been identified. The exon 1 and exon 3 to exon 6 share the same sequence as DRB1^∗14 like alleles. At the mRNA level, the new allele has no significant difference when compared with the other DRB1 allele. This novel recombinant allele is also found to be paternally inherited. In conclusion, this is the first report of a DRB1 and DRB3 intergenic recombination event involving whole exon 2, which generate a new DRB1^∗14:141.     

The association of HLA -A, -B,and -DRB1 genotypes with Graves' disease in Taiwanese people

Graves' disease has been associated with different human leukocyte antigen (HLA) genes in different races. To evaluate the association of HLA type in Taiwanese with Graves' disease, the HLA-A, -B, and -DRB1 alleles in a total of 236 Taiwanese adults with Graves' disease and 533 racially matched normal control subjects were examined using the PCR-SSOP (sequence specific oligonucleotide probe) technique. The prevalence of HLA-A*0207, -B*2704, -B*4601, and -DRB1*0901 among patients with Graves' disease was found to be increased, with odds ratios (OR) of 2.21, 3.82, 1.76 and 1.62, respectively. However, after correction for multiple comparisons, the relative risk of HLA-A*0207 susceptibility to Graves' disease remained statistically significant and the haplotype HLA-A*3303 -B*5801 -DRB1*0301 had a significantly protective effect. None of the other 2- or 3-locus haplotypes showed any significantly increased risk. Although HLA-DRB1*1405 showed an increased relative risk in patients with GO (Graves' opthalmopathy) (OR 4.61) when compared with patients without GO, the relative risk after adjusting for the number of comparisons was not significant. Taiwanese patients with Graves' disease have HLA-associated susceptibility genes which are similar to those found in Chinese patients in Hong Kong and Singapore. However, the finding in this study of a higher frequency of HLA-A*0207 in Taiwanese with Graves' disease has not been documented in any other ethnic group.     

Identification of a novel HLA-DRB1 allele, HLA-DRB1*12:27, in a Chinese individual

Nucleotide sequence of HLA-DRB1*12:27 allele was different from that of HLA-DRB1*12:02:01 by three-nucleotide substitution at position 165A>C, 171G>C, and 175C>T.     

Meta-analysis of the association between HLA-DRB1 allele and rheumatoid arthritis susceptibility in Asian populations

The aims of this study were to summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in Asians and to determine if the shared epitope (SE) hypothesis could explain the meta-analysis results. Among the papers published between January 1987 and July 2006 on RA susceptibility in Asian-Mongoloid populations (Korean, Japanese, Chinese, and Thai), 12 were selected for the metaanalysis. Mongoloid-Asian patients with RA had significantly higher frequencies of HLA-DRB1*0101, *0401, *0410, and *1001 than controls (OR 1.5-2.1, p<0.05 for association). When analyses were restricted to more ethnically homogeneous populations, HLA-DRB1*0405 showed a significant susceptibility to RA in Koreans (OR 5.65, 95% CI 4.32-7.39), whereas the HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 alleles showed protective association with RA (OR 0.32-0.70, p<0.05 for association). In conclusion, it was found that HLA-DRB1 *0101, *0401, *0405, *0410, and *1001 are susceptible, while HLA-DRB1* 0301, *0403, *0406, *0701, *1301, and *1405 are protective in Asian-Mongoloids. All the RA-associated alleles except DRB1*0301 could be explained by the structural model supporting the SE hypothesis that RA susceptibility is determined by the combination of amino acid residues at HLA-DR beta71 and beta74, not by beta71 alone.     

Pocket 4 in the HLA-DRB1 antigen-binding groove: an association with atopy

BACKGROUND: Many studies have attempted to identify an association between HLA genes and atopy, given the role of HLA molecules in the regulation of the immune response. In the case of house-dust mites, it is difficult to find an association with a particular HLA allele, due to the complexity of the allergen. The objective was to investigate whether HLA-DRB1 functional groups are better correlated with the atopic disease in our population than DRB1 alleles. METHODS: The method was reanalysis of the HLA-DRB1 data of a previous case/ control study. RESULTS: The "Dr" group was found to be associated with the atopic disease in our population. CONCLUSIONS: Grouping HLA-DRB1 alleles into functional categories may assist in the search for predictive factors in relation to atopic disease.     

Identification of three novel alleles of HLA-DRB1 and HLA-A in the Brazilian population

Two human leukocyte antigen (HLA)-DRB1 (HLA-DRB1*1376 and -DRB1*1465) and one HLA-A (HLA-A*2471) novel alleles have been identified in individuals from the Brazilian Bone Marrow Donor Registry. DNA sequencing of exon 2 for HLA-DRB1 alleles showed two and five nucleotide substitutions in -DRB1*1376 and -DRB1*1465, compared with closely related alleles, respectively. These substitutions result in a change of amino acid residues in HLA-DRB1*1376 at position 74 (Arg --> Glu) and in -DRB*1465 at positions 47 (Tyr --> Phe), 57 (Asp --> Ser) and 74 (Glu --> Ala). On the other hand, sequence analysis of exons 2 and 3 for HLA-A*2471 showed a single substitution, leading to a single amino acid change at position 151 (His --> Arg). These three novel alleles may have originated from other HLA alleles by gene conversion. However, it is also possible that HLA-A*2471 has evolved from one of the alleles of the HLA-A*2402 group through a point mutation.