MHC class I region plays a role in the development of diverse clinical forms of celiac disease in a Saharawi population

OBJECTIVE: The aim of this study was to investigate the association of MHC genes in the development of celiac disease (CD) and its diverse clinical forms in a Saharawi population. METHODS: One hundred and twenty-five CD patients and 98 healthy controls were selected from the Saharawi refugee camps in Tindouf. All were investigated for the presence of antitransglutaminase 2 antibodies. Patients were divided into two groups according to their clinical manifestations: 70 typical and 55 atypical. Patients and controls were typed for HLA-B, DRB1, DQB1, and DQA1, and for MICA transmembrane polymorphism. RESULTS: The frequency of HLA-DQ2 in Saharawi controls was notably increased compared with other populations. No differences in the distribution of DQ2 in either group of patients were found. However, the haplotype B8/DR3/DQ2 was notably overrepresented in atypical patients compared to typical ones (pc= 0.001). The MICA-A5.1 allele was increased in atypical CD patients compared to those with typical forms (pc= 0.0006). Finally, we found that the increased frequency of MICA-A5.1 in the atypical group was independent of the linkage disequilibrium with B8/DR3/DQ2 haplotype (p= 0.02). CONCLUSIONS: The elevated prevalence of CD in Saharawi seems to be related to the high frequency of HLA-DQ2 in this population. However, the development of atypical or typical forms of the disease may be due to a gene or genes located in the class I side of the haplotype B8/DR3/DQ2, especially MICA. This appears not to be implicated in the susceptibility to CD but may play an important role in the development of the different forms of the disease.     

Association of MHC class I related gene B (MICB) to celiac disease

BACKGROUND AND AIMS: Celiac disease (CD) is an enteropathic disorder characterized by strong association with HLA-DQ2. Our aim was to investigate whether MICB, a gene located in the MHC class I region, may contribute to CD susceptibility. PATIENTS AND METHODS: Total of 133 CD patients, previously reported to be associated with MICA-A5.1, and 116 controls were initially analyzed. Twenty-eight additional DQ2-negative CD patients were also studied. MICB was typed by PCR using sequence-specific primers. HLA-B, -DRB1, -DQA1, -DQB1, and MICA were also typed. RESULTS: The allele MICB0106 was strongly associated with CD (pc < 0.000001, odds ratio (OR) = 5.6, 95% confidence interval (CI) = 3.1-10.1) and it was overrepresented in atypical patients compared with typical ones (pc = 0.04, OR = 2.9, CI = 1.4-6.1). MICB0106 was part of DR3-DQ2 haplotype (B8-MICA-A5.1-MICB0106-DR3-DQ2), and consequently a strong linkage disequilibrium between MICB0106 with DQ2 (lambdas = 1) and MICA-A5.1 (lambdas = 0.55) was found. To analyze whether the association of MICB is independent of this haplotype, its association was also studied in DQ2-negative patients (n = 46). DQ8 (28%vs 9%, p = 0.0085, pc = NS) and MICB0104 (52%vs 30%, p = 0.01, pc = NS) were increased in DQ2-negative patients. MICA-A5.1 was significantly increased in atypical patients (p(c)= 0.001, OR = 6.4, CI = 2.2-18.4), and this association was independent of DQ2 and DQ8 (pc = 0.02, OR = 2.6, CI = 1.1-6.1). CONCLUSIONS: The expression of MIC genes on enterocytes under stressful conditions and their function as ligands of intraepithelial gammadelta and CD8 T cells, together with the data presented here suggest a potential role of MIC genes in the pathogenesis of CD.     

Juvenile idiopathic arthritis (JIA) is primarily associated with HLA-DR8 but not DQ4 on the DR8-DQ4 haplotype

BACKGROUND: Juvenile idiopathic arthritis (JIA) is strongly associated with the DR8-DQ4 haplotype. The genes encoding DR8 and DQ4 are in strong linkage disequilibrium (LD) and occur together on the same HLA haplotype in almost all patients and controls. Because of the strong LD it is not clear whether DR8, DQ4, or both, are primarily associated with JIA. OBJECTIVE: To unveil the primary association of JIA--that is, with DR8 or DQ4. METHODS: DRB1, DQA1, and DQB1 alleles of 585 Norwegian and 47 Polish unrelated patients with JIA (categorised as pauciarticular and rheumatoid factor negative polyarticular JIA), and of 3155 Norwegian and 158 Polish unrelated controls, were typed using a polymerase chain reaction or oligonucleotide hybridisation and sequence-specific primers method. RESULTS: Several haplotypes which encoded DR8 (that is, carried DRB1*08) and which did not encode DQ4 (that is, did not carry DQA1*0401) were found. Such haplotypes were found in three Norwegian patients and two controls (p=0.029). In the Polish population such haplotypes were found among four patients with JIA and two controls (p=0.025). No haplotypes which carried DQA1*0401 and DQB1*0402 in the absence of DRB1*08 were found, either among patients with JIA (Polish and Norwegian) or among the controls (Polish). CONCLUSION: On the DR8-DQ4 haplotype the DRB1*08 allele is primarily associated with JIA.     

中国人群1型糖尿病HLA-DQ基因多态性的Meta分析

目的　综合评价中国人群HLA DQ基因多态性与 1型糖尿病 (DM)的关联性。方法　以 1型DM组和健康对照组的各HLA DQ等位基因频数(基因型频数、单倍型频数 )分布的OR值为统计量,全面检索相关文献;应用Meta分析软件包REVMAN4. 2,在基因分型水平上,对各研究的结果进行一致性检验和数据合并,并评估发表偏倚。结果　等位基因DQA1* 0301、DQA1* 0501、DQB1* 0201、DQB1* 0303、DQB1* 0401和DQB1* 0604是中国人群 1型DM的危险基因 (均P<0. 05), 他们的合并OR值分别为2. 83、2. 90、4. 17、1. 65、2. 00和 3. 00;基因型 (或单倍型 )DQA1* 0301 /DQB1* 0201、DQA1* 0301 /DQB1*0302、DQA1* 0501 /DQB1* 0201、DQA1* 0301 /DQB1* 0201 /DRB1* 0301和DQB1* 0302 /DRB1* 0405是中国人群 1型DM的危险基因型(或单倍型,均P<0. 05),他们的合并OR值分别为 8. 95、3. 09、6. 01、6. 57和 14. 85。而等位基因DQA1* 0101、DQA1* 0102、DQA1* 0103、DQA1* 0104、DQA1* 0201、DQA1* 0401、DQA1* 0601、DQB1* 0301、DQB1* 0501、DQB1* 0503、DQB1* 0601和DQB1* 0602是中国人群 1型DM的保护等位基因(均P<0. 05),他们的合并OR值分别为 0. 47、0. 38、0. 21、0. 07、0. 44、0. 39、0. 44、0. 19、0. 33、0. 32、0. 42和 0. 28; 基因型     

DR- and DQ-associated protection from type 1A diabetes: comparison of DRB1*1401 and DQA1*0102-DQB1*0602*

The transmission disequilibrium test was used to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type 1 diabetes repository (n = 1371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (n = 2441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P < 0.001, vs. the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P < 0.0001). Rare DQA1*0102-DQB1*0602 haplotypes without DRB1*1501 were never transmitted to affected offspring (n = 6). The DQA1*0101-DQB1*0503 haplotype was transmitted to 2 of 42 (4.8%) affected offspring (P < 0.001, vs. 50% expected transmission). Although DRB1*1401 is in linkage disequilibrium with DQB1*0503, neither of the two affected children who carried DQA1*0101-DQB1*0503 had DRB1*1401. However, all 13 nonaffected children who inherited DQA1*0101-DQB1*0503 had DRB1*1401. In a case-control comparison of patients from the Barbara Davis Center, DQA1*0101-DQB1*0503 was found in 5 of 110 (4.5%) controls compared with 3 of 728 (0.4%) patients (P < 0.005). Of the three patients with DQB1*0503, only one had DRB1*1401. Our data suggest that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type 1A diabetes.     

Evidence for a protective role of the human leukocyte antigen class II region in early rheumatoid arthritis

OBJECTIVE: To analyse the distribution of predisposing DQ3 (DQB1*03(*04)/DQA1*03) and DQ5 (DQB1*0501/DQA1*01), shared epitope encoding and protective DRB1 alleles in patients with early rheumatoid arthritis (RA) and undifferentiated arthritis (UA). METHODS: Consecutive patients enrolled in an early arthritis clinic were DNA-typed for HLA-DQ and DR. RA patients (n=195), UA patients (n=160) and controls from the same region (n=306) were sorted according to their DQ-DR phenotypes: DQ3 vs DQ5 and the presence or absence of a protective DERAA-positive DRB1 molecule. The three groups were also sorted according to the shared epitope (SE) hypothesis. RESULTS: We observed the association of both DQ3 and DQ5 with RA. DQ3/3 homozygous individuals had the highest risk of developing disease [odds ratio (OR)=20.00]. Conversely DQ5, but not DQ3, was associated with undifferentiated arthritis (OR=2.15 vs 1.25). Consistent with these differences, DQ3-positive individuals had significantly more active disease at the first visit at the outpatient clinic than DQ5-positive patients. DRB1 alleles encoding a DERAA motif in their third hypervariable region provided a strong dominant protection against RA among DQ5-positive individuals and decreased arthritis activity among DQ3-positive patients. Individuals with SE-positive DR1, DR4 and DR10 alleles were also predisposed to RA, DR4/4 homozygous individuals having the highest risk of developing RA (OR=11.00). CONCLUSION: The DQ3-DR4/9 haplotypes are associated with RA. The DQ5-DR1/10 haplotypes are associated with less active disease, i.e. UA, and DERAA encoding DRB1 alleles modulate either predisposition to or the severity of RA. We propose that HLA polymorphism influences not only the initiation or perpetuation of RA but also protection against the disease.     

The HLA-DR3,DQ2 heterozygous genotype is associated with an accelerated progression of primary sclerosing cholangitis

BACKGROUND: An improvement of prognostic models in primary sclerosing cholangitis (PSC) is needed. In particular, inclusion of prognostic markers that are independent of the disease stage would be advantageous. We investigated whether HLA class II genes associated with PSC are also related to disease progression. METHODS: The study included 265 PSC patients from five European countries with a median follow-up of 9.1 years. The end-points were death (n = 38) or liver transplantation (n = 52). Thirty patients developed cholangiocarcinoma during follow-up. RESULTS: The DRB1*03,DQA1*0501, DQB1*02 (i.e. DR3,DQ2) heterozygous genotype was associated with an increased risk of death or liver transplantation (hazard ratio = 1.63; 95% confidence interval (CI) = 1.06-2.52). The presence of a DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in DR3,DQ2 negative individuals was associated with a reduced risk of death or liver transplantation (hazard ratio = 0.57; 95% CI = 0.36-0.88). There was a trend towards an increased risk of developing cholangiocarcinoma among DR4,DQ8 positive patients, but this did not reach significance (odds ratio = 2.27; 95% CI = 0.78-6.62). CONCLUSION: The DR3,DQ2 heterozygous genotype is associated with a more rapid progression of PSC, whereas HLA-DQ6 is associated with a retarded disease progression. It is possible that the DR4,DQ8 haplotype is related to cholangiocarcinoma development.     

Analysis by the polymerase chain reaction of histocompatibility leucocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus.

DNA sequence analysis of class II HLA from Caucasian and black patients with type 1 (insulin-dependent) diabetes mellitus has suggested that aspartic acid at position 57 (Asp 57) of the DQ beta chain provides protection against insulin-dependent diabetes mellitus (IDDM). In contrast, most Japanese patients with IDDM have Asp 57-positive alleles. To determine the reason for the differences and to localize the HLA-linked diabetogenic gene in Japanese, we studied the DQA1 and DQB1 genes of Japanese patients with IDDM and control subjects by the polymerase chain reaction in combination with restriction fragment length polymorphism analysis. Associations of DQA1*0301 and DQB1*0303 with IDDM were observed. DQA1*01 was associated negatively with IDDM. The HLA-DR9 haplotype, which is associated positively with IDDM in Japanese, was associated with DQA1*0301 and DQB1*0303, indicating that the Japanese DR9 haplotype is the same as that in caucasians but different from that in blacks. Of the loci on Japanese DR9 haplotypes, the DQA1*0301 allele showed the highest association with IDDM. DQB1*0303 was also positively associated with IDDM. Since DQB1*0303 is identical to DQB1*0302 except that it contains Asp 57, the data suggests that an Asp 57-positive allele confers susceptibility to IDDM when the whole molecule of the DQ beta chain is similar to other susceptible DQ beta chains. DQA1*0301 appears to be a marker of IDDM in all these populations: Japanese, caucasian, and black.     

The HLA-DR3,DQ2 Heterozygous Genotype is Associated with an Accelerated Progression of Primary Sclerosing Cholangitis

Background: An improvement of prognostic models in primary sclerosing cholangitis (PSC) is needed. In particular, inclusion of prognostic markers that are independent of the disease stage would be advantageous. We investigated whether HLA class II genes associated with PSC are also related to disease progression. Methods: The study included 265 PSC patients from five European countries with a median follow-up of 9.1 years. The end-points were death (n = 38) or liver transplantation (n = 52). Thirty patients developed cholangiocarcinoma during follow-up. Results: The DRB1*03,DQA1*0501,DQB1*02 (i.e. DR3,DQ2) heterozygous genotype was associated with an increased risk of death or liver transplantation (hazard ratio = 1.63; 95% confidence interval (CI) = 1.06-2.52). The presence of a DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in DR3,DQ2 negative individuals was associated with a reduced risk of death or liver transplantation (hazard ratio = 0.57; 95% CI = 0.36-0.88). There was a trend towards an increased risk of developing cholangiocarcinoma among DR4,DQ8 positive patients, but this did not reach significance (odds ratio = 2.27; 95% CI = 0.78-6.62). Conclusion: The DR3,DQ2 heterozygous genotype is associated with a more rapid progression of PSC, whereas HLA-DQ6 is associated with a retarded disease progression. It is possible that the DR4,DQ8 haplotype is related to cholangiocarcinoma development.     

Contrasting molecular patterns of mhc class ii alleles associated with the anti-sm and anti-rnp precipitin autoantibodies in systemic lupus erythematosus

Objective. To find evidence of a potential genetic predisposition to the anti-Sm or anti-RNP precipitin autoantibody responses. Methods. HLA–DR and DQ alleles determined by restriction fragment length polymorphism and/or oligo-typing in 49 subjects with either anti-Sm alone or anti-RNP alone were compared with those in 139 race-matched normal control subjects and 59 race-matched lupus patients without anti-Sm and anti-RNP auto-antibodies. Results. Black patients with anti-Sm precipitin had increased frequencies of HLA-DR2 and the DQw6-associated DQA1*0102 (P = 0.007, odds ratio [OR] = 6.7) and DQB1*0602 (P = 0.001, OR = 9.1) chain alleles compared with normal black control subjects. Black patients with anti-RNP precipitin showed significant increases in the DQw5-associated DQA1*0101 (P = 0.03, OR = 5.5) and DQB1*0501 (P = 0.002, OR = 23.3) chain alleles compared with lupus patients without anti-Sm or RNP. White patients with anti-RNP precipitin showed an increased frequency of the DQw8-associated allele DQB1*0302 (P = 0.02, OR = 3.7) compared with normal controls, as well as an increased frequency of the DQw5-associated alleles DQA1*0101 and DQB1*0501 (P = 0.05, OR = 4.2) compared with lupus patients without anti-Sm or RNP. There were no specific HLA–DR2 or DR4 subtype associations found with either anti-Sm or RNP precipitin autoantibodies. Conclusion. There are distinct patterns of major histocompatibility complex class II allele associations with the anti-Sm versus the anti-RNP precipitin autoantibody responses, and HLA–DQ associations may be more primary than HLA–DR associations.     

HLA DPB1*0201 gene confers disease susceptibility in japanese with childhood onset type I diabetes, independent of HLA-DR and DQ genotypes

HLA is an important etiologic genetic factor in Type I diabetes and specific HLA-class II genes are closely related to the onset of the disease. Many differences in the patterns of susceptible and resistant DRB1, DQA1, and DQB1 genes have been observed among various ethnic groups. We have previously shown that DRB1*0405, DRB1*0901 and DQA1*0301-DQB1*0302 were the major susceptible alleles or haplotype to Type I diabetes while DR-DQ haplotype studies suggested the important role of DR and DQ alleles in susceptibility and resistance in Japanese patients. Based on the analysis of 90 Japanese patients with childhood onset Type I diabetes and 136 unrelated healthy Japanese controls by polymerase chain reaction-restriction fragment polymorphism method (PCR-RFLP), we report here the association of Type I diabetes with DPB1*0201 (relative risk = 2.29; Pc = 0.027) in this population. Comparison of linkage disequilibrium patterns between patients and controls showed that the significantly high prevalence of DPB1*0201 among patients cannot be attributed simply to linkage disequilibrium with susceptible DRB1 alleles and DQA1-DQB1 haplotypes. Our results suggest that in addition to alleles at the DRB1, DQA1, DQB1 loci, polymorphism at DPB1 locus also influences the risk of Type I diabetes.     

汉族类风湿关节炎患者HLA—DR和—DQ基因分型研究

为探讨ＨＬＡ－ＤＲ和－ＤＱ等位基因与我国汉族类风湿关节炎（ＲＡ）的相关性，采用聚合酶链反应－限制性内切酶片段长度多态性分析（ＰＣＲ－ＲＦＬＰ）方法对汉族人群中３５例ＲＡ患者和１００名健康人的ＤＲ和ＤＱ位点进行ＤＮＡ定型分析。结果发现，ＤＲ４频率在正常人为２４．０％，在ＲＡ患者为５１．４％（Ｐ＜０．０１，ＲＲ＝３．３０）；ＤＲ４亚型位点分析发现２组均以ＤＲＢ１＊０４０５占多数，但ＤＲＢ１＊０４０５频率在ＲＡ组为３１．４％，高于正常人的１０．０％（Ｐ＜０．０１）。ＤＱ４频率在全部ＲＡ患者为３７．１％，在ＤＲ＋４ＲＡ患者为７２．２％，均高于全部正常人的１０．０％（Ｐ＜０．０１）和ＤＲ＋４正常人的４１．６％（Ｐ＝０．０３７６）；ＤＲ＋４－ＤＱ＋４ＲＡ患者的病情重于ＤＲ－４患者。结果提示，ＤＲ４、主要是ＤＲＢ１＊０４０５与ＲＡ相关，ＤＱ４可增加ＤＲ４对ＲＡ的易感性，ＤＲ＋４－ＤＱ＋４单倍型是ＲＡ病情严重程度的标志。     

Risk variation in celiac disease in a population from Southern Spain: evaluating the influence of the DQB1*02:02 allele frequency

Objectives: To date, the greatest genetic risk factor known for celiac disease (CD) is the presence of HLA-DQ2 heterodimers, specifically DQ2.5 in state of homozygosis or heterozygosis. DQ2.2 variants are the second most important risk factor when carried trans to DQ2. This study aimed to determine the prevalence and risk genotypes of HLA-DR-DQ.

Material and methods: A total of 196 patients with CD and 206 healthy controls from the Province of Málaga (southern Spain) were included. The corresponding risk gradient in our population was established in accordance with the odds ratios (ORs) found.

Results: The heterozygous genotype for DR7-DQ2.2/DR3-DQ2.5 presented the highest risk (OR =6.404, p?=?.0001) followed by the DR3-DQ2.5 homozygous genotype (OR =4.721, p?=?.001). An intermediate risk was found for the DQ2.5 heterozygous genotype with no other DQ risk variant (DQ8 or DQ2.2). Similarly, these three genotypes had also an increase in the risk of associated-autoimmune diseases. The DQB1*02:01 allele was the most widely represented among patients with CD respect to the control group (f?=?0.479, p?=?.0001), with the second most common being DQB1*02:02 (f?=?0.209, p?=?.0001).

Conclusions: In addition to the gene dosage effect confirmed in our report, and in contrast with previous studies, we found a raised risk for those patients with DQ2.2 heterodimers in trans configuration to DQ2.5 compared to DQ2.5 homozygous individuals. Therefore, in our population of patients with CD the frequency of DQ2.2 acts as a factor that increases the genetic risk of developing CD.     

HLA genotyping is useful in the evaluation of the risk for coeliac disease in the 1st-degree relatives of patients with coeliac disease

OBJECTIVE: Coeliac disease (CD) is a common disease with a strong heredity. About 10-20% of 1st-degree relatives of probands develop CD. Relatives should be screened for CD, because if not treated, CD exposes patients to numerous complications. The heterogeneity of symptoms and the lifetime-spanning risk of CD render the timing of CD antibody and/or gastroscopy screenings difficult. As CD susceptibility has been shown to be strongly associated with the HLA alleles DQA1*0501 and DQB1*0201 (together encoding the DQ2 heterodimer) and DRB1*04 (associated with the DQ8 heterodimer), our aim was to investigate whether HLA genotyping might be useful in the identification of 1st-degree relatives of CD patients who do not need further screening for CD. MATERIAL AND METHODS: The study comprised 54 Finnish CD families including 54 CD probands and 382 living 1st-degree relatives. All subjects who were willing to participate were screened for CD (duodenal and skin biopsies; endomysial, reticulin and gliadin antibodies). The DQA1*0501, DQB1*0201 and DRB1*04 allele frequencies of CD patients and the 1st-degree relatives were determined. RESULTS: Altogether 17.6% (5.9% of the parents, 15.7% of the siblings, 25.8% of the offspring) of the investigated 1st-degree relatives (n = 245) did not carry any of the alleles studied. All of the CD patients (n = 136) with the exception of one (0.7%) carried at least one of the alleles investigated. CONCLUSIONS: By using the HLA genotyping a considerable proportion of 1st-degree relatives of CD probands could be excluded from further screening for CD.     

MICA rather than MICB,TNFA, or HLA-DRB1 is associated with susceptibility to psoriatic arthritis

OBJECTIVE: To analyze the genetic contribution of HLA in development of psoriatic arthritis (PsA) and to study whether MICA is primarily associated with PsA or whether its association is secondary to linkage disequilibrium with centromeric genes, such as MICB, TNFA, or HLA-DRB1. METHODS: DNA samples from 81 Spanish patients with PsA and 110 healthy controls were examined by polymerase chain reaction (PCR) sequence-specific primers to type HLA-Cw and HLA-DRB1, PCR sequence-specific oligonucleotides to determine HLA-B, and PCR restriction fragment length polymorphism for tumor necrosis factor-alpha promoter polymorphisms at positions -238 and -308. Analysis of microsatellite polymorphisms in the transmembrane region of MICA and in intron 1 of MICB was also carried out. RESULTS: HLA-Cw*0602 was significantly increased in PsA [60% vs 17%; p(c) < 0.00002, OR 7.33, etiological fraction (EF) 0.52]. MICA-A9 (60% vs 30%; p(c) = 0.0002, OR 3.57, EF 0.43) and the microsatellite MICB-CA-22 allele (23% vs 7%; p(c) = 0.028, OR 3.9, EF 0.17) were also significantly increased in PsA. MICA-A9 was in linkage disequilibrium with MICB-CA-22 (delta = 0.6). The association of MICA-A9 was independent of MICB-CA-22 and Cw*0602, since it was also associated in MICB-CA-22 negative (p(c) = 0.0015, OR 2.96, EF 0.34) and in Cw*0602 negative patients (p(c) = 0.034, OR 2.83, EF 0.34). TNFA and DRB I alleles were not significantly associated with PsA. CONCLUSION: Cw*0602 and MICA-A9 appear to be the strongest genetic susceptibility factors for PsA. However, MICA-A9 was associated independently of Cw6. HLA-B alleles and MICB-CA22 are associated secondarily to linkage with MICA. TNFA and HLA-DRB1 were not associated with PsA susceptibility, and our data suggest that their reported association may only reflect the linkage disequilibrium with MICA-A9 among the different populations studied.     

Polymorphism of major histocompatibility complex extended haplotypes bearing HLA-DR3 in patients with rheumatoid arthritis with gold induced thrombocytopenia or proteinuria.

The distribution of DR3 and of extended haplotypes bearing DR3 was studied in three groups of subjects: 35 patients with rheumatoid arthritis (RA) with gold induced thrombocytopenia or proteinuria, 185 patients with RA without these side effects, and 300 normal healthy controls. The extended haplotypes bearing DR3 were analysed with cDNA probes for DR alpha, DR beta, DQ alpha, and DQ beta genes. The data showed that the prevalence of DR3 was significantly higher in patients who developed gold induced thrombocytopenia or proteinuria than in normal controls or patients with RA without these side effects. Distribution of three extended haplotypes bearing DR3 (B8, DR3; B18,DR3; non-B8,non-B18,DR3) in patients with RA with thrombocytopenia or proteinuria was significantly different from that in normal controls, but not from that in patients with RA without these toxic reactions. Southern blot analysis of DR, DQ genes with cDNA probes showed that the extended haplotype bearing B8,DR3, which carries DQA2.1 and DQB2.1 genes, was present in a significantly higher proportion of patients with RA with gold induced thrombocytopenia or proteinuria (22/24, 92%) than in patients with RA without these side effects (32/45, 71%) or normal subjects (40/61, 66%). The data suggest that the genomic region on chromosome 6 involved in susceptibility to gold induced thrombocytopenia or proteinuria should be extended to the DQA2, DQB2 gene loci.     

HLA class II alleles associated with susceptibility and resistance to Crohn's disease in the Jewish population

Previous studies have suggested that susceptibility to Crohn's disease (CD) is associated with the histocompatibility complex (HLA) class II alleles DR1, DQ5, and DR13 in the Caucasian population, DR7 in the French and German populations, and DR4 and DQ4 in the Japanese population. However, little is known about the relationship between HLA class II alleles and CD in the Jewish population since these previous studies included few Jewish individuals. In order to determine whether the HLA associations observed with predominantly non-Jewish populations were also present in the Jewish CD population and whether there were any HLA class II alleles uniquely associated with CD in the Jewish population, 132 CD patients, of which 82 were Ashkenazi Jewish, were HLA-typed using serologic and DNA methods. Ethnically matched controls were similarly typed. No association with DR1 or DR13 was observed in the Jewish CD population although an association with DR13 (OR [odds ratio] = 5.3, p = 0.02) was observed in the non-Jewish CD population. However, an association with DR15 (OR = 2.7, p = 0.03), which is normally associated with ulcerative colitis, was observed in the Jewish, but not non-Jewish, CD group. In addition, a strong negative association was observed with DR3, which was especially striking in the Jewish population (OR = 0.35, p = 0.025); similar negative associations with DR3 have been observed by others using non-Jewish populations. Furthermore, a significant negative association with DR7 (OR = 0.45, p = 0.04) was observed in the Jewish, but not non-Jewish, population. Consistent with this was the negative association with DQ2 (OR = 0.38, p = 0.005), which is in strong linkage disequilibrium with both DR3 and DR7, in the Jewish, but not non-Jewish, population. These studies support previous suggestions that susceptibility to CD in Jewish and non-Jewish populations is determined by distinct genes and provide further support to the hypothesis that a gene on the DR3 haplotype may protect against CD. Furthermore, protection is conferred by the same or another gene found on Jewish, but not non-Jewish, DR7 haplotypes.     

HLA DQA1 and DQB1 study in Algerian type 1 diabetes families.

The distribution of HLA class II alleles associated with insulin-dependent diabetes mellitus (Type 1) in the Algerian population is poorly known. We have typed 36 Algerian Type 1 diabetic probands and their families using DQA1 and DQB1 oligonucleotide probes. Fifty-nine parental haplotypes non transmitted to diabetic offspring served as controls. The frequencies of DQA1 and DQB1 alleles and haplotypes and their associations with Type 1 diabetes were, except minor differences, similar to those reported in French. Susceptibility DQA1 (Arg52+) and DQB1 (Asp57-) alleles were significantly increased among patients versus controls (90% vs 53%, RR = 8.4, p < 10(-6), and 94% vs 64%, RR = 9.4, p < 10(-5), respectively). 85% of Type 1 diabetics versus 34% of control haplotypes were either DR3DQw2 or DR4DQw8 susceptibility haplotypes (DQA1 Arg52+, DQB1 Asp57-) (RR = 10.8, p < 10(-7). 75% of the probands vs 14% of the controls (RR = 18, p < 10(-5)) and 73% of affected siblings versus 24% of unaffected siblings (RR = 8.4, p < 0.02) possessed a genotype composed of these two susceptibility haplotypes in the homozygous or heterozygous state. 42% of the probands were DR3DQw2/DR4DQw8, corresponding to Hardy-Weinberg expectations. The lack of excess of heterozygotes could be due to the consanguine families in this sample, as among the patients with consanguine parents the frequency of DR3, 4 heterozygotes was lower (27% vs 48% in non-consanguine patients, NS) and that of DR3 homozygotes increased (45% vs 12%, respectively, p < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA DRB1/DQA1/DQB1 haplotype determines thyroid autoimmunity in patients with insulin-dependent diabetes mellitus

OBJECTIVE  Thyroid autoimmunity is frequently associated with insulin-dependent diabetes mellitus (IDDM). The genetic factors which contribute to thyroid autoimmunity and IDDM have been described but vary between different races. We have therefore investigated the effect of class II HLA genes at both loci and the HLA haplotypes on the presence of autoimmunity in patients with IDDM in Taiwan.
SUBJECTS AND MEASUREMENTS  Eighty-three patients with IDDM and 105 unrelated normal controls were recruited for the measurement of thyroid autoantibodies and for genotyping of HLA DRB1, DQA1 and DQB1 by polymerase chain reaction-based DNA typing techniques.
RESULTS  Among 83 patients with IDDM, 23 (27.7%) were positive for antithyroid autoantibodies. Compared to those without thyroid autoimmunity, there was a female preponderance for IDDM with thyroid autoimmunity (female: male, 3:20 vs 29:31). Among the DR specificities, DR6 was associated with a weak protective effect against thyroid autoimmunity in IDDM patients. Upon detailed analysis of class II HLA haplotypes, the DRB1*0301/DQA1*0501/DQB1*0201 haplotype was found to be associated with an increased risk of IDDM regardless of thyroid autoimmunity, while DRB1*0405/DQA1*0301/DQB1*0401 was significantly increased only in the IDDM patients with thyroid autoimmunity. IDDM individuals with the HLA DRB1*0405/DQA1*0301/DQB1*0302 haplotype were not at risk of thyroid autoimmunity.
CONCLUSIONS  Our data indicated that there was a generalized genetic factor within or associated with the DRB1*0301/DQA1*0501/DQB1*0201 haplotype, and a more restricted effect with the DRB1*0405/DQA1*0301/DQB1*0401 haplotype which led to thyroid autoimmunity in patients with insulin-dependent diabetes mellitus.     

Respective weight of genotypes DQA1 and DQB1 associated with insulin-dependent diabetes in French children]

Genetic susceptibility alleles have been identified at the DQ HLA region. The aim of the present study was to confirm the value of these markers, and to evaluate the respective weight in the risk of the different alleles at the DQA1 and DQB1 levels, identified by restriction mapping after polymerase chain reaction on exon 2. A significant enrichment in DQB1 alleles encoding for an aminoacid different from Aspartic acid at position 57 (NA) was observed in diabetic (n = 213) in comparison to control (n = 93) children (94% vs 52%; p < 10(-8)). Not all the given NA/NA allelic combinations were equally and positively associated to the disease. Homozygous "Ala/Ala" combinations carried the highest relative risk (OR = 12.3; p < 10(-8)), and among them, the *0201/*0302 genotype was more positively associated to type 1 diabetes (OR = 66; p < 10(-8)). A significant enrichment in DQA1 alleles encoding for Arginine at position 52 in diabetic children was also observed (82% vs 40%; p < 10(-8)). The *0301/*0501 (Arg/Arg) genotype was significantly associated to Type 1 diabetes (OR = 16.2; p < 10(-4)). The highest risk was carried by the whole genotype, a result which could be expected from the known linkage desequilibrium between HLA-DQA1 and DQB1, DRB1 loci. The frequency of Ala DQB1 alleles was low in the background non-at-risk population, although the incidence of the disease is low in our country.