Comparison of HLA class II antigens between three type 1 diabetes groups in the central region of Algeria : research article
Rachida RaacheAmel BenyahiaHabiba AmrounNadine AttalW. HamianeM. AzzouzL. LacetSimone Elisabeth HaworthA. BoudibaM.C. Abbadi
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Abstract:
In human type 1 diabetes (T1D), both genetic and environmental factors are involved in the pathogenesis of the disease. The strongest genetic contribution has been mapped to the major histocompatibility complex (MHC) on the short arm of chromosome 6, which encodes the human leukocyte antigens (HLA). It is estimated that HLA class II gene polymorphisms account for 20 to 50% of familial aggregation of type 1 diabetes. Several studies have clearly demonstrated that there are susceptibility and protective markers at HLA-DR and -DQ.
In this study, HLA class II antigens were investigated using a serological method in 210 T1D patients from the central region of Algeria, and compared to 140 healthy controls. Marker frequencies were compared between three groups of diabetics : children, juveniles and adults with latent autoimmune diabetes (LADA), and the control group.
The frequency was calculated for HLA-DR and -DQ. Significant differences were detected between T1D patient and the control groups for the frequencies of HLA-DR3, -DR4, -DQ2 and -DQ8 (DQ3) but there were no significant differences in these antigen frequencies between the three T1D groups versus the controls, with the respective frequencies of HLA-DR3 (71.76, 66.67, 70% vs 31.43%), HLA-DR4 (64.71, 48.89, 52.50% vs 26.43%), HLA-DQ2 (76.47, 66.67, 75% vs 39.29%) and HLA-DQ8 (3) (64.71, 46.67, 47.50% vs 19.29%).
Mantel-Haenszel tests were used to calculate the odds ratio for the presence of type 1 diabetes in association with HLA-DR3, -DR4, -DQ2 and -DQ8 (3). The values for each respective HLA antigen were as follows : for the T1D children (OR: 5.54; 5.1; 5.02; 7.67) for the juveniles (OR: 4.36; 2.66; 3.09; 3.66) and for LADA (OR: 5.09; 3.08; 4.64; 3.79). The heterozygous phenotype HLA-DR3/DR4 increased the risk (conferred the highest susceptibility) (OR: 8.79, 2.68, 4.23 for children, juveniles and the LADA group, respectively).
These results confirm the positive association between T1D and HLA class II antigens, as previously reported in other populations in the central region of Algeria.Keywords:
HLA-DQ
Histocompatibility
Pathogenesis
Genetic predisposition
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Forty-four Japanese patients with IgA nephropathy and their relatives were typed for HLA-A, B, C, DR and DQ antigens and their HLA haplotypes were determined. The frequency of DQ4 increased significantly in the patients as compared with that in 100 healthy control persons (Pc < 0.01). DR4 frequency was higher than in the control subjects but revealed no significant difference (p < 0.05, Pc > 0.05). The incidence of DR4-DQ4 haplotype was increased in the patients (54.5%) and A24Cw-B52DR2DQ1 haplotype which is very common in the Japanese population was decreased as compared with controls of general Japanese population. Thirty-nine cases of 44 (88.6%) had DR4 or DR9 and HLA genotypes of DR4/DR 5, 6, 8 and DR9/DR5, 6, 8 were significantly increased as compared with those in the control subjects (P < 0.001). The incidence of DR4 was significantly higher in the patients with macroscopic hematuria as compared with those without (P < 0.01). No specific HLA antigens or HLA haplotypes were related to the prognosis of IgA nephropathy. These findings suggested that HLA haplotypes associated with DR4-DQ4, DR4-DQ3 and DR9-DQ3 as well as those associated with DR5, 6, 8 might be involved in susceptibility to IgA nephropathy, while A24Cw-B52DR2DQ1 haplotype might be resistant to the disease development.
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Coeliac disease (CD) has one of the strongest class II HLA association of any human disease. The goal of this study was to establish the frequency of HLA-DR and DQ antigens, as well as common HLA-DR-DQ haplotypes among CD patients. No similar study has previously been done in Croatian patients.There were 58 biopsy proven patients with CD. The control groups comprised 502 and 118 healthy person for HLA-DR and HLA-DQ typing, respectively.The class II HLA-DR and DQ antigens typing were carried out by standard microcytotoxicity assay for B cells. Only antisera to three specificities (DQ1, 2 and 3) were available to us at the time of the study.We confirmed the high frequency of HLA-DR3 (84.48%; RR = 23.7; p < 0.00001) in our patients with CD. As reported in other populations, most of the patients negative for DR3, were heterozygous for DR7 and DR5 (10.34%) or DR4/DR5, DR4/DR6 (3.44%). CD was significantly correlated with the presence of HLA-DQ2 (96.55%, RR = 75.9; p < 0.00001). Correlation with CD was strongly dependent on homozygosity, 15 out of 58 (25.86%) of the patients and 4 (2.87%) of the controls being homozygotes for DQ2 (RR = 11.9; p < 0.00001). The remaining two patients were DR4-DQ3 positive. Among extended haplotypes only DR2-DQ1 was under-represented (RR = 0.3; p < 0.0033).The results suggest that in Croatia CD is primarily associated with HLA-DQ2 specificities on the DR3-DQ2 haplotype.
HLA-DQ
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The Basques were previously shown to present a high frequency of HLA—B18 and Bf Fl. which are known to be associated with insulin dependent diabetes mellitus (IDDM). During the VIII International Histocompatibility Workshop, we studied HLA‐A, B, C, DR; Bf, C4 and GLO.I polymorphisms in 51 unrelated French Basque IDDM patients and in 50 controls. Haplotypes were established by family studies in all controls and some patients. Two haplotypes were frequently found in the controls: HLA‐ A1, Bw57, Bf S, C4 FIS, DR7 and HLA‐ Aw30, Cw5, B18, Bf Fl, C4 Fs°, DR3. The first one was not found in the patients. All the components of the second haplotype had increased frequencies possibly as a consequence of linkage disequilibrium with HLA— DR3 : a highly significant association between IDDM and HLA‐DR3 was observed (90.2% vs 24.0%, relative risk (RR) = 29.1. P < 10 −11 ). The HLA‐DR4 frequency was slightly increased (37.3% vs 16.0%). and HLA—DR2 was not found. The silent allele C4 s ° was particularly associated with early diagnosed IDDM (86.7% in patients with age at onset under 20 years vs 57.1% in other patients, P < 0.02). The high relative risk for HLA‐DR3/DR4 heterozygous vs that of individuals, possibly HLA‐DR3 homozygous, supported the hypothesis that two HLA‐DR linked genetic factors could be involved in the inheritance of IDDM susceptibility.
Linkage Disequilibrium
HLA-A
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A possible association of Crohn's disease (CD) with MHC (major histocompatibility complex) markers was investigated in families with more than one affected member. HLA-A, B, C, DR and DQ typing was performed in 21 CD families with two or more CD patients. The following HLA-antigens showed increased relative risk (RR) values for CD: B44 (RR = 2.43; B15 (Bw62, Bw63) (RR = 2.03); DR7 (RR = 1.85); DR4 (RR = 1.06). Three of 44 patients were DR4- and four DR7-homozygous. The risk haplotype B44/DR7 was observed in four and Bw62/DR4 in three CD patients, respectively. CD affected family members (female greater than male) shared HLA haplotypes more frequently than expected by mendelian laws. None of the differences reached statistical significance.
Histocompatibility
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Shared susceptibility alleles in the HLA region contribute to the co-existence of type 1 diabetes (T1D) and celiac disease (CD). The aim of our study was to identify HLA genotype variations that influence co-occurrence of T1D and CD (T1D + CD) and the order of their onset. Totally 244 patients, 67 with T1D, 68 with CD and 69 with T1D + CD, (split into "T1D first" and "CD first"), were analyzed. Control group consisted of 130 healthy unrelated individuals. Two-tailed Fisher's exact test was used for statistical analysis. The genetic background of Slovenian CD patients resembled more northern than southern European populations with DR3-DQ2/DR3-DQ2 (odds ratio [OR] = 19.68) conferring the highest risk. The T1D + CD was associated with DR3-DQ2/DR3-DQ2 (OR = 45.53) and even more with DR3-DQ2/DR4-DQ8 (OR = 93.76). DR3-DQ2/DR7-DQ2 played a neutral role in susceptibility for T1D + CD. The order of the onset of T1D or CD in patients with co-occurring diseases was not influenced by HLA risk genotype profile. DR3-DQ2/DR3-DQ2 was associated with an increased risk for developing CD in patients with T1D, whereas patients with CD carrying DR3-DQ2/DR4-DQ8 were at higher risk for developing T1D. In addition to other genetic factors including HLA class I alleles present on DR3-DQ2 extended haplotype, the second extended haplotype may moderate the risk for T1D + CD conferred by DR3-DQ2. Our results suggested that individuals carrying high-risk genotypes DR3-DQ2/DR3-DQ2 or DR3-DQ2/DR4-DQ8 would more likely develop both T1D and CD than either disease alone.
HLA-DQ
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It is well known that certain genes in the HLA‐D region confer increased susceptibility to insulin‐dependent diabetes mellitus (IDDM), Previous studies have documented an increased risk associated with the HLA‐DRβ chain alleles, DR3 and DR4, and the DQβ chain allele DQB1*0302 (formerly DQw8). Since DQα is also polymorphic and has been strongly implicated as the primary IDDM susceptibility locus in other races, we wanted to assess the contribution of DQα to IDDM in Caucasians, This information would enable us to define more precisely the class II association with IDDM as well as gain insight into issues of cu versus trans association of DQ heterodimers in this disease. To this end, the DQa genotype was determined for a large group of diabetic and normal Caucasian individuals who had been HLA‐DQβ and HLA‐DR typed previously. Using the polymerase chain reaction and a set of twelve oligonucleotide probes, we determined the DQα genotype of 323 patients with IDDM and 182 normal subjects. We found that certain DQα alleles are decreased in the diabetic population compared with normal subjects (i.e. DQA1*102 and 0103), while others are significantly increased in patients with IDDM (i.e. DQA 1*0301 and *0501), In addition, certain combinations of DQα alleles are associated with increased susceptibility to disease (i.e. DQA 1*0301, *0501), These results parallel our findings at the DQβ locus; however, because of the various associations between DQα and DQβ chains, the risks conferred by DQα are generally lower than those at DQβ, Moreover, our data indicate that, in Caucasians, no single DQα allele accounts for the highest degree of susceptibility to IDD M as in other races, although DQα analysis may be informative in a few cases. When done in combination, however, oligonucleotide analyses at both DQβ and DQα complement each other and provide a more complete assessment of the HLA‐associated component of disease susceptibility in IDDM
HLA-DQ
Genetic predisposition
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Common variable immunodeficiency (CVID) is a heterogeneous heritable disease
characterized by arrest in B cell differentiation. An association between CVID and two HLA
haplotypes, haplotype I (HLA-A1, HLA-B8, HLA-DR3) and haplotype II (HLA-A29, HLA-B44, HLADR7)has been previously documented. In the present study, we have attempted to find an association between susceptibility to CVID and HLA class I and II antigens in Iranian population. Seventeen Iranian patients with CVID (mean age 17, range 3-28 years; 12 male and 5 female), including two couples of brothers and 100 healthy controls were studied. All subjects were typed for HLA class 1, and 12 patients and all controls were typed for HLA class II, using microdroplet lymphocytotoxicity technique. Out of 12 CVID patients typed for HLA-DR and DQ specificities, five patients presented DR-1, which showed an increased frequency in patient (41.6% vs. 12% in controls), and 3 presented DQ-2, which also showed an increased frequency (25% vs. 4% in controls), both of which reached statistical significance (P = 0.018 and P = 0.026, respectively). HLA-DR10 was present in 2 patients
(16.6%), which was markedly more frequent compared to controls, but this difference was not
significant statistically. Our results suggest that HLA-DR1 and DQ-2 may contribute to susceptibility to CVID. We did not find any significant association between HLA-A1, B8 and DR3 that has been previously reported to be associated with CVID.
Common Variable Immunodeficiency
HLA-DQ
Immunogenetics
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This study focused on the immunogenetic aspect of Parkinson's disease (PD). The frequencies of HLA‐A, ‐B, ‐C, ‐DR and ‐DQ antigens were determined in 40 patients with idiopathic PD, and were compared with those in a representative sample of the Turkish population ( n =160). Compared with values for the Turkish population, the frequencies of HLA‐B22 and HLA‐DR14 (6) antigens were higher in the PD group, with relative risks (RR) of 9.55 and 15.48, respectively. These frequency differences were statistically significant. The frequency of HLA‐A24 (9) was also higher in the PD patients, but to a lesser extent than the antigens noted earlier (RR=2.38). The frequencies of HLA‐DQ7 (3), HLA‐DQ4, HLA‐DR11 (5), HLA‐DR1 and HLA‐DR7 were lower in the PD group, with RR values of 0.177, 0.187, 0.69, 0.85 and 0.93, respectively. None of these frequency differences were statistically significant. The frequency of the HLA‐DQ4 antigen in the PD group was significantly lower than that in the Turkish population, and this difference was significant when the corrected P ‐value was used.
Turkish population
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