Genetic differences in HLA-DQA1* and DQB1* allelic distributions between celiac and control children in Santiago, Chile.

Celiac disease is a permanent gluten intolerance strongly associated with HLA class II antigens. The over presentation of particular HLA alleles and haplotypes has been described in several populations. Different lines of evidence obtained during the last years suggest that a particular HLA-DQ heterodimer, encoded by the DQA1*0501 and DQB1*0201 genes in cis or trans conformation, confers the primary disease susceptibility. We report the HLA class II allelic distribution and DQA1/ DQB1 genotypes in 62 Chilean celiac patients compared with 124 control subjects in Santiago, Chile. We found a pronounced increase of the "susceptible" alleles :DQA1*0501 (0.480 vs 0.169, Pc < 0.0005), DQB1*0302 (0.430 vs 0.242, Pc = 0.002) and DQB1*0201 (0.250 vs 0.125, Pc = 0.037) in celiac patients in comparison with control children. As for "protective" alleles, we detected a high frequency of DQA1*0101 (0.310 vs 0.160, Pc = 0.01), DQA1*0201 (0.105 vs 0.010, Pc < 0.0075) and DQB1*0301 (0.250 vs 0.100, Pc = 0.010) in controls. In relation to risk haplotypes, the main combination observed was the conformation DQ8 (DQB1*0302/DQA1*0301) over DQ2 (DQB1*0201/DQA1*0501). In conclusion, results show that celiac disease in Chilean patients is primarily associated with DQ8 conformation. This is concordant with the high frequency of DR4 alleles (in linkage disequilibrium with DQB1*0302) detected in Amerind groups in Chile, where DQB1*0302 is more frequent than DQB1*0201.     

Allele and haplotype frequencies for HLA class II (DQA1 and DQB1) loci in patients with celiac disease from Spain

Celiac disease (CD) is a complex and multifactorial disease, defined as a malabsorptive disorder of the small intestine resulting from ingestion of gluten. Genetic susceptibility to CD has been associated with human leukocyte antigen (HLA)-DQ2 heterodimer, encoded by the DQA1*0501 and DQB1*02 genes. However, HLA risk factors do not explain the whole genetic predisposition: not all DQ2-encoding haplotypes confer equal susceptibility to CD. The aim of the present work was to confirm the aforementioned findings in a southern European population. With this purpose, 136 unrelated children diagnosed with CD were typed at the DNA level for HLA-DQA1 and -DQB1 loci. Patients are currently attended at the Donostia Hospital (province of Guipúzcoa, Spain). HLA class II typing was performed by polymerase chain reaction-sequence specific primer procedures. Conspicuous frequencies of the alleles associated with susceptibility to CD were observed (DQA1*0501: 0.592, DQB1*0201: 0.471). Accordingly, the haplotypes DQA1*0501-DQB1*0201 and DQA1*0201-DQB1*0202 revealed a strong linkage disequilibrium (18.84% and 18.75%, respectively) when compared with the Spanish general population. Of the total sample, 93.4% (127 individuals) were carriers of DQ2 heterodimer, either in homozygosis or in heterozygosis. This percentage coincides with figures reported in previous studies, implying the effect of other genes in the development of CD.     

HLA DQA1*0501 and DQB1*02 in Cuban celiac patients

Celiac disease (CD) susceptibility has been strongly associated with HLA-DQ2 and HLA-DQ8. The main objective of this study was to assess the distribution of HLA DQA1*0501 and DQB1*02 alleles (DQ2) for the first time in a group of Cuban celiac patients. We evaluated 22 patients, 54 first-degree relatives, and 60 controls for detection of antitissue transglutaminase (tTG)-specific antibodies in serum. We found that 100% of the probands and 19% of the first-degree relatives were positive for the antibodies in serum. We did not detect any specific response for the healthy control individuals. We observed a significant over-representation of DQ2 heterodimer, both in patients and relatives. In the group of patients, 86.3% were positive for DQA1*0501, 90.2% were positive for DQB1*02, and 86.3% were positive for both alleles. The frequencies in relatives and controls were as follows: 70%, 90%, and 70%; and 56.6%, 45%, and 20%, respectively. In conclusion, we found that the proportion of our celiac patients carrying DQ2 was similar to the proportion of CD patients reported in populations with different genetic backgrounds. These results underline the primary importance of HLA-DQ alleles in susceptibility to celiac disease.     

HLA class IIDRB, DQA1 and DQB1 polymorphisms in the Polish population from Wielkopolska

HLA DRB1, DQA1 and DQB1 alleles were determined by DNA PCR-SSO typing in a sample of 99 individuals originating from Wielkopolska (midwestern Poland). A high number of alleles (38 DRB1, 8 DQA1 and 14 DQB1) was detected at each locus, many of them presenting notable frequencies in this population. The three HLA loci are thus characterized by very high heterozygosity levels (93% for DRB1, 85% for DQA1, and 88% for DQB1), which confirms the results found for other European populations. A total of 6 DRB1-DQA1-DQB1 haplotypes are detected with an estimated frequency higher than 5%, namely, DRB1*1501-DQA1*0102-DQB1*0602, DRB1*0701-DQA1*0201-DQB1*0201, DRB1*0101-DQA1*0101-DQB1*0501, DRB1*1101-DQA1*0501-DQB1*0301, DRB1*03011-DQA1*0501-DQB1*0201, and DRB1*1301-DQA1*0103-DQB1*0603. A genetic distance analysis between the Polish and other world populations tested for HLA class II indicates that the Wielkopolska community is close to geographically close, rather than linguistically related populations from Europe. More generally, a good agreement between genetics and geography is found for DRB1 and DQB1 polymorphisms in Europe, suggesting that these two loci are highly informative for assessing historical relationships among humans.     

用PCR-SSP方法研究广西壮族HLA-DQA1和B1基因多态性

目的　检测广西壮族ＨＬＡＤＱＡ１ ,Ｂ１ 基因的多态性。方法　应用ＰＣＲＳＳＰ 方法对１４０ 名健康、无血缘关系广西壮族人的ＨＬＡＤＱＡ１ 和ＤＱＢ１ 进行基因分型。结果　共检出７ 个ＤＱＡ１ 等位基因和１６ 个ＤＱＢ１ 等位基因。在检出的ＤＱＡ１ 等位基因中,０３０１ 的基因频率最高（３５ ％ ） ,０４０１ 的基因频率最低（１ ．１ ％ ） 。在ＤＱＢ１ 等位基因中,０６０１（２２ ．１ ％ ） ,０３０１（２０ ．７ ％ ） ,０５０１（１３ ．９ ％ ） 最为常见。未检出的等位基因包括ＨＬＡＤＱＡ１ ＊ ０２０１ ,０３０２ ,０６０１ ,ＤＱＢ１ ＊ ０６０３ ,０６０５ 和０６０８ 。结论　广西壮族ＨＬＡＤＱＡ１ ,Ｂ１ 基因的多态性不仅有中华民族的特点,而且也有其独特性。     

Asp57-negative HLA DQ beta chain and DQA1*0501 allele are essential for the onset of DQw2-positive and DQw2-negative coeliac disease.

The genetic predisposition to coeliac disease is associated with the HLA DQw2 allele. Coeliac patients lacking the DQw2 allele are very rare and always exhibit the DR4-DQw3 haplotype. We performed oligotyping of polymerase chain reaction (PCR)-amplified DQA1 and DQB1 genes in six DQw2-negative and 30 DQw2-positive coeliac patients. The DQB analysis showed that all six DQw2-negative patients possessed the DQB1*0302 allele. The other DQB alleles found in five of these patients were DQB1*0501, DQB1*0604 and DQB1*0302. The DQ beta chains encoded from all these alleles have the replacement of aspartic acid residue at position 57 (Asp57), as well as the DQB1*0201 allele which was found in all 30 DQw2-positive coeliac patients. The DQw2-negative proband who lacked the homozygous Asp57 replacement exhibited the DQA1*0501 allele in the DQA1 gene. The DQA1*0501 allele was also found in 27 of the 30 DQw2-positive coeliac patients. Among this group of coeliacs, the four cases lacking the DQA1*0501 allele exhibited the homozygous Asp57 replacement in the DQ beta chain. Our results indicate that Asp57-negative DQ beta alleles are involved in both DQw2-positive and -negative coeliac patients. Moreover, when the Asp57-negative DQ beta chain is encoded from only one of the two DQB1 genes the DQA1*0501 allele is always present.     

HLA-DQA1、DQB1、DRB1 02,07,09等位基因及单倍型在华东地区汉族人群的分布

应用ＰＣＲ－ＳＳＯ方法，对华东地区汉族人群进行了ＨＬＡ－ＤＱＡ１、－ＤＱＢ１和ＤＲＢ１＊０２，０７，０９基因分型。ＤＱＡ１中以ＤＱＡ１＊０３０１基因频率最高（０．３８４４），其次为＊０５０１（０．１４０６）和０１０２（０．１２１９），＊０４０１最低（０．０２８１）；ＤＱＢ１中以ＤＱＢ１＊０３０３基因频率最高（０．２３４２），其次为＊０３０１（０．１８９９）、＊０６０１（０．１２０３）和＊０２０１（０．１１０８），＊０５０１、＊０６０４和＊０６０５最低（均为０．０１２７）；ＤＲ９基因频率较高（０．２３１０），ＤＲ２中ＤＲＢ１＊１５０１占７３％，基因频率为０．０８５４，未见＊１６０１。ＤＱＡ１、ＤＱＢ１及ＤＲＢ１等位基因之间存在显著的连锁不平衡。ＤＲＢ１＊０９０１－ＤＱＡ１＊０３０１－ＤＱＢ１＊０３０３、ＤＱＡ１＊０１０３－ＤＱＢ１＊０６０１等为常见单倍型。本资料与我国其他汉族人群资料有可比性，也存在一定差异。     

Distribution of HLA class II alleles among Scandinavian patients with systemic lupus erythematosus (SLE): An increased risk of SLE among non[DRB1*03,DQA1*0501,DQB1*0201] Class II homozygotes?

HLA-DRB1, -DRB3, -DQA1 and -DQB1 alleles were determined by DNA typing in 51 Scandinavian patients with systemic lupus erythematosus (SLE) and 129 controls. DRB1*03,DRB3*0101,DQA1*0501,DQB1*0201 were significantly increased in the patient group, with relative risks (RR) of 2.80, 3.07, 3.55 and 2.12, respectively. These alleles are in strong linkage disequilibrium, and their possible relative contributions in predisposition to SLE are difficult to distinguish. The strongest association was found for DQA1*0501, which is in linkage disequilibrium with DRB1*03 as well as DRB1*11,12 (DR5). An increased frequency of DRB1*11,12 was observed (RR = 1.89, ns). No association with DRB1*15,16 (DR2) was found. The patients had a higher frequency of HLA class II homozygosity than the controls (RR = 5.05, p = 0.0005). When compared to the low-risk group (nonDRB1*03 class II heterozygotes), the cases homozygous for DRB1*03,DQA1*0501,DQB1*0201, known to be in linkage disequilibrium with the complement allele C4A*Q0, had the highest relative risk of developing SLE (RR = 16.39, p = 0.0002). However non[DRB1*03,DQA1*0501,DQB1*0201] class II homozygotes had a higher relative risk (RR = 4.68, p = 0.0147) than DRB1*03,DQA1*0501,DQB1*0201 heterozygotes, known to carry the C4A*Q0 allele (RR = 2.72, p = 0.0088). This may suggest that HLA class II molecules are directly involved in susceptibility to SLE.     

Molecular characterization of HLA class II genes in celiac disease patients of Latin American caucasian origin

Abstract: In the present study, the polymorphic domain of HLA class II genes present in a pediatric population of Argentinian celiac disease patients was analyzed by hybridization to sequence-specific oligonucleotides and DNA sequencing. Sixteen out of 16 DR5/7 heterozygous patients bore the DQA1*0501 and DQB1*0201 alleles implicated in the DQ2 risk specificity. The second exon of DQA1, DQB1 and DRB1 genes from 2 DR5/7 patients was characterized by DNA sequencing. The following alleles were found in both patients: DRB1*1101 and DRB1*0701; DQB1*0301 and DQB1*0201; DQA1*0501 and DQA1*0201. Previous serological analysis in this population had shown the presence of DQ2 in 95% of the patients (40% in controls) and a negative association with DQ1 haplotypes, suggesting the presence of other "permissive" or neutral alleles. The following HLA-DQB1 alleles, besides DQB1*0201, were identified in 31 CD patients: DQB1*0301, 0302, 0401 and 0402. All these alleles share a common pattern of residues between positions 84 and 90, and distinct from that present in DQ1-related alleles.     

HLA-DRB1, DQA1 and DQB1 DNA polymorphisms in healthy Algerian and genetic relationships with other populations

Abstract: This study presents the results of HLA-DRB1, -DQA1, and -DQB1 sequence-specific oligonucleotide probe (SSOP) typings for a population sample of 47 individuals originating from Western Algeria. Allele and haplotype frequencies, as well as linkage disequilibria are computed by the standard methods used for the XIth International Histocompatibility Workshop data. A total of 24 alleles are detected at the DRB1 locus, where a very high heterozygosity level (0.914) is found. The highest DRB1 frequencies are 0.160, DRB1*1101, and 0.138, for DRB1*0301 and DRB1*0701. The DQA1 and DQB1 loci are less polymorphic. Among the 8 DQA1 alleles detected, DQA1*0501 is highly predominant with a frequency of 0.383. Thirteen DQB1 alleles are observed among which DQB1*0301 and DQB1*0201 are the most frequent (0.351 and 0.245, respectively). Three haplotypes predominate clearly: DRB1*1101-DQA1*0501-DQB1*0301 (0.138), DRB1*0701-DQA1*0201-DQB1*0201 (0.128) and DRB1*0301-DQA1*0501-DQB1*0201 (0.117). The two latter are among the most frequent haplotypes found in European and North American Caucasoid populations, but the DQA1*0501-DQB1*0201 association is not significant in Algerians. The genetic distances computed for each locus among a set of populations from different continents are significantly correlated to geography. They indicate that the Algerians are very close to South European populations, particularly to Sardinians, Italians, Romanians and French, with some intermediate characteristics between Europeans and sub-Saharan Africans. These results may serve as reference for future studies of HLA and disease in the Algerian population.     

The HLA DQB 1*0502 allele is neutrally associated with insulin-dependent diabetes mellitus in the Sardinian population

In the Sardinian population a very high incidence of insulin-dependent diabetes mellitus (IDDM) and the lack of HLA-DR2 protective effect due to the high frequency of the A2, Cw7, B17, 3F31, DR2, DQw1 extended haplotype has been reported. This haplotype, carrying a Serine at position 57 of the DQB1*0502 allele, has been previously reported to be underrepresented in patients when compared to controls. In order to provide an explanation for this finding, we defined by RFLP analysis the HLA haplotype of 45 Sardinian IDDM patients and 49 controls. All DR-2DQw1 subjects were molecularly characterized at the HLA DQA and DQB loci. All DR2-positive patients and the vast majority of the DR2-positive controls had the DQB1*0502 allele at the DR2-linked DQB1 locus, with no statistically significant difference between the two groups. All DQA1 genes were the ones expected, with only two exceptions. Nine out of 10 of the DR2-positive patients were compound heterozygotes for DQB1*0201/DQB1*0502 alleles; only this allele combination was significantly increased (p less than 0.0003). Our data suggests that a) the DQB1*0502 allele is neutral for IDDM development and b) the susceptibility to IDDM in our DR2-positive patients is related to the compound heterozygous state between the neutral DQA1*0102/DQB1*0502 and the susceptibility DQA1*0501/DQB1*0201 alleles.     

HLA DQ AND DP IN FINNISH FAMILIES WITH CELIAC DISEASE

We studied DQA1, DQB1, and DPB1 alleles in 31 Finnish families with celiac disease (CD). All healthy first-degree relatives underwent clinical investigation, including in most cases biopsy, to establish whether clinically silent CD was present. Our results indicate that all patients, having either full clinical CD or its silent form, had the susceptibility alleles DQA1*0501 and DQB1*0201. The different clinical outcomes of CD were therefore not directly determined by the DQ alleles. The frequency of DPB1*0101 was also higher in CD patients, but the association appeared secondary to those of DQA1*0501 and DQB1*0201 (DQ2). The primary association of CD with the DQA1*0501 and DQB1*0201 alleles, rather than with HLA haplotypes, was confirmed in multiplex families.     

HLA-DQ1 haplotype ruin the effect of cis complementation of DQA10501-DQB10201 in association with trichosanthin-induced immunosuppression

CD8 cell-mediator (M+) or non-mediator (M−) are distinguishable for healthy subjects according to whether their CD8 T cells keep the down-regulatory function in Trichosanthin (Tk)-induced immunosuppression. Tk is a plant protein of 247 amino acid residues purified from a Chinese medicinal herb. The M+ phenotype has been shown in our previous work to be strongly associated with HLA-DQ2. By genotyping with PCR-based techniques, the essential alleles of the DQ2 were identified as DQA1^*0501 and DQB1^*0201, which were either in cis (DR3) or in trans (DR5, DR7) position. A more detailed examination of the HLA association pattern with M+/M− in 42 Chinese candidates, however, revealed another two points of interest. 1) The cis complementation did not work if another DQA1^*01- or DQA1^*02-related haplotype (e.g. DRB1^*0101-DQA1^*0101-DQB1^*0501) were combined. The later seemed to behave like a ‘negative’ factor superimposed on the ‘positive’ role of DQA1^*0501-DQB1^*0201 haplotype in heterozygous condition. 2) In addition to DQA1^*0501, the DQB1^*0201 was actually able to combine all available DQA1 alleles except DQA1^*01 family to form the trans complementation. Again, the DQ1 haplotype acted negatively. It is thus likely that the cis and trans complementary association of DQA1^*0501-DQB1^*0201 could only be detected conditionally or only appeared as a special case in the Tk-induced immunosuppression.     

HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease

Celiac disease (CD) has a strong genetic association with human leukocyte antigens (HLA). The primary susceptibility for CD is HLA-DQA1*05 DQB1*02 (also known as DQ2), with the remainder of cases primarily HLA-DQA1*03 DQB1*03 (also known as DQ8). In a set of nine Bedouin multiplex celiac disease families and one simplex, we genotyped DNA samples at HLA DQA1 and DQB1. Nineteen celiac disease patients had at least one DQA1*05 DQB1*02 genotype (= DQ2), 4 affecteds had the second most common genotype of DQA1*03 DQB1*0302 (= DQ8), 9 were DQ2 and DQ8, and 4 had at least one copy of DQB1*02 without the DQA1*05 genotype. Using transmission disequilibrium testing, we observed a significant over-representation in affecteds of the DQA1*05 DQB1*02 genotype (p = 0.0089), as well as over-representation of the DQA1*03 DQB1*0302 genotype (p = 0.078). The HLA DQA1 DQB1 high-risk genotypes associated with celiac disease are similar in these Bedouin families with CD to what is observed in Northern and Southern Europeans.     

A study of Italian pediatric celiac disease patients confirms that the primary HLA association is to the DQ(alpha 1*0501, beta 1*0201) heterodimer.

Celiac disease (CD) has been recently reported to be primarily associated with the DQ(alpha 1*0501, beta 1*0201) heterodimer encoded in cis on DR3 haplotype and in trans in DR5,7 heterozygous individuals. The high incidence of DR5,7 heterozygotes, reflecting the high frequency of the DR5 allele in Italy, makes the analysis of the Italian CD patients critical. Polymerase chain reaction-amplified DNA from 50 CD patients and 50 controls, serologically typed for DR and DQw antigens, was hybridized with five DQA1-specific oligonucleotide probes detecting DQA1*0101 + 0102 + 0103, DQA1*0201, DQA1*0301 + 0302, DQA1*0401 + 0501 + 0601, and DQA1*0501 and a DQB1-sequence-specific oligonucleotide probe recognizing DQB1*0201 allele. As expected by the DR-DQ disequilibria, DQA1*0201 [62% in patients versus 26% in controls, relative risk (RR) = 5] and DQA1*0501 (96% versus 56%, RR = 19) show positive association with the disease. Of CD patients, 92% (50% DR3 and 42% DR5,7) compared to 18% of the controls carry both DQA1*0501 and DQB1*0201 alleles, so that the combination confers an RR of 52, higher than both the risks of the single alleles (DQA1*0501 RR = 19, DQB1*0201 RR = 30), confirming the primary role of the dimer in determining genetic predisposition to CD both in DR3 and in DR5,7 subjects.     

Characterization and epitope mapping of four HLA class II reactive mouse monoclonal antibodies using transfected L cells and human cells transfected with mutants of DQB1*0302

Abstract: To study epitopes of HLA class II molecules, four mouse monoclonal antibodies (mAbs) 13B6, 17F8, 19A1 and 12G6 were made using HLA-DQ8, DP2 and DP4 expressing mouse transfectants for immunization. Three of the mAbs, 13B6, 17F8 and 19A1, bound to all DQ1, 4, 8 or 9 positive B-lymphoblastoid cell lines (B-LCLs) and transfectants tested, i.e. cells carrying the DQB1 genes 0302-3, 0401-2, 0501-3, 0601-4 and 0609 irrespective of the accompanying DQA1 gene. These DQB1 genes code for the shared amino acids (aa) GVY in position 45–47 of the DQ β chain. DQ1+4+8+9 specific (IIB3) and DQ3 specific (IVD12) reference mAbs inhibited binding of all three mAbs. Testing 13B6, 17F8 and 19A1 with cells made using aa substitutions in various positions of DQP1*0302 indicated involvement of aa 45 in the epitopes of all three mAbs. The last mAb (12G6) bound to all B–LCLs and all DP transfected cells. However, only some DR transfectants and a single DQ transfectant (carrying DQA1 *0201 and DQB1*0202) bound mAb 12G6. This reactivity pattern correlates with a shared sequence of aa (RFDSDVGE) in position 39–46 of DR-and DQ- and 37–44 of DP p chains.     

系统性红斑狼疮临床表现与HLA Ⅱ类单倍型关联的研究

目的 探讨系统性红斑狼疮（ＳＬＥ）易感基因致病的模式。方法 利用多聚酶链反应／特异寡核控针杂交（ＰＣＲ／ＳＳＯＰＨ）方法检测１１３例确诊ＳＬＥ病人的ＨＬＡⅡ基因型并进行单倍型分析。结果 ＳＬＦ病人的单倍型具有特定的结构特征,即以２个或３个重型ＳＬＥ相关基因共同组成１个单倍型;反之,２个或３个轻型ＳＬＥ相关基因组成另１个单倍型;重型基因和轻型基因之间很少有强连锁不平衡。ＤＱＡ１＊０３０１－ＤＱＢ１＊     

Motif analysis of HLA class II molecules that determine the HPV associated risk of cervical carcinogenesis

In previous studies, the HLA class II haplotype HLA DRB1*0401-DQB1*0301 was shown to correlate with susceptibility to HPV infection, CIN and cervical cancer while DRB1*0101-DQB1*0501 indicated protection. The present study was designed to identify naturally processed peptide sequences bound to the susceptibility and protective HLA DR-DQ molecules, and use this for T-helper epitope prediction from HPV 16. The HLA class II molecules were obtained by immuno-affinity purification of Epstein-Barr virus B lymphoblastoid cell lines (BCL) homozygous for HLA DQA1*0301-DQB1*0301 and HLA DQA1*0101-DQB1*0501. Peptide pools eluted from the HLA molecules were sequenced by Edman degradation. On the basis of the peptide sequence data obtained, the E6, E7, L1 and L2 proteins of HPV 16 were examined to identify sequences which are likely to bind to HLA DQB1*0301 and DQB1*0501. In addition, motif prediction as well as the binding affinity of predicted peptide motifs for HLA DRB1*0401 and DRB1*0101, the DR alleles associated with susceptibility and protection respectively, was accomplished using published data and a prediction algorithm for the naturally processed peptide sequences bound to these molecules. The HLA DQB1*0501 peptide ligand sequence showed that proline gives an outstanding signal at position 2, Asn/Arg at P1, aliphatic/aromatic amino acids in the central portion, a hydrophobic cluster at P5 with a small contribution by small polar residues and another cluster of aromatic residues towards the C-terminus. The HLA DQB1*0301 sequence also showed that proline gives an outstanding signal at position 2, Thr/Arg at P1, aliphatic/aromatic amino acids in the central portion and an aliphatic cluster with a small contribution by small polar residues at P5. There were no differences in the number of HPV peptides that were predicted as being capable of binding to HLA DQB1*0301 and HLA DQB1*0501, but more HPV peptide motifs were predicted to bind with high affinity to HLA DRB1*0101 than DRB1*0401. The results suggest that HPV 16 peptide epitopes bind with higher affinity to the protective than to susceptible HLA DR-DQ molecules which may lead to a more effective immune response.     

HLA CLASS II AND SUSCEPTIBILITY AND RESISTANCE TO INSULIN-DEPENDENT DIABETES MELLITUS IN A POPULATION FROM THE NORTHWEST OF SPAIN

The role of HLA class II alleles in genetic predisposition to insulin-dependent diabetes mellitus(IDDM) was examined using Polymerase Chain Reaction/oligonucleotide probe typing (PCR/SSOs) of eight HLA class II loci in 58 IDDM patients and 50 healthy controls from the Northwest of Spain (Asturias). We compared the distribution of HLA class II alleles, haplotypes and genotypes between IDDM patients and controls, and tested three recently proposed HLA-IDDM susceptibility theories. By using the aetiologic fraction (δ) as an almost absolute measure of the strongest linkage of disequilibrium of a HLA marker to the putative Type I susceptibility locus, it has been found that the strength of association of the HLA markers may be quantified as follows: DQA1 *03-DQB1 *0302 or DQA1 *0501-DQB1 *0201 > DR3 or DR4; presence of more than one dimer DQαβ of the six proposed by Rønningen > non-Asp57 DQβ and Arg52 DQα > Arg52 DQα > non-Asp57 DQβ/non-Asp57 DQβ > DRB1*0301; DQA1*0501-DQB1*0201 > DQA1*03-DQB1*0302; DQB1*0302. The presence of at least one Asp57 DQβ allele was the best protection HLA marker to IDDM in our population. Therefore, the above data confirm that IDDM susceptibility to HLA locus is linked more to DQ than DR.     

Impaired binding of a DQ2 and DQ8-binding HSV VP16 peptide to a DQA1*0501/DQB1*0302 trans class II heterodimer

DQalpha and DQbeta trans heterodimeric HLA-DQ molecules form in individuals heterozygous for the DQ2 and DQ8 specificities. Unique functions and disease associations have been postulated for such trans-dimers, which may be different from cis-encoded DQ molecules encoded by the corresponding haplotypes. We analyzed the ability of the trans-dimer encoded by HLA-DQA1*0501/DQB1*0302 to bind a peptide antigen which interacts with DQ molecules encoded by both parental haplotypes. Markedly impaired binding was observed, consistent with both the use of different anchor residues and with changes in levels of DQ cis-dimer availability for peptide binding interactions.