HLA class II allele frequencies in type 1A diabetes mellitus Slovak patients (original) (raw)
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Associations between HLA class II alleles and type 1 diabetes mellitus in the Slovak population
Endocrine regulations, 2006
Several associations between HLA complex and diabetes mellitus type IA were found in various groups of patients of Caucasoid population. This study was therefore prompted to be conducted in Slovak population, since any such has not yet been performed in Slovak population. Patients suffering from DM-1A originated from all regions of Slovakia. Their age ranged from 1 to 42 years; but the criterion for including the subject to the study was the definition of diagnosis in older patients before their age of 15 (Table 1). The diagnosis was set up according to internationally accepted criteria. A total of 460 patients was typed for HLA-DQB1 alleles, among them 97 also for HLA-DQA1 and 146 for HLA-DRB1 alleles. HLA-typing was performed by a PCR-SSP method. Control group consisted of 196 (DQA), 143 (DQB1) and 130 (DRB1) unrelated blood donors aged 19-55 years old irrespective of their age or sex. The data obtained were expressed in a 2 x 2 contingency table and statistical significance was c...
European Journal of Immunogenetics, 2003
A combination of specific HLA class II antigens and the presence of type 1 diabetes (T1D)-related antibodies has a high positive predictive value for T1D but low sensitivity. The aim of the present study was to determine the frequencies of HLA-DRB-DQB deduced haplotypes associated with susceptibility and protection in Slovenian patients with established T1D, to evaluate the relationship between the HLA-DRB1-QBP-DQB1 haplotypes and the presence of insulin autoantibodies (IAA) and glutamic acid decarboxylase antibodies (GADA), and to access the possible impact of polymorphic QBP promoters on this relationship. A cohort of 135 patients with T1D (age 17.5 ± 7.0 years, duration of T1D 9.14 ± 6.3 years) was investigated. HLA-DRB1 and DQB1 alleles were typed using the polymerase chain reaction (PCR)-reverse line blot method. QBP promoter region alleles were determined using PCR-sequence-specific oligonucleotide hybridization (SSO) and PCR-sequence-specific primers (SSP). IAA and GADA antibodies were determined by enzyme-linked immunosorbent assay (ELISA). The chisquare test with Yates' correction was used for statistical analysis. Deduced haplotypes DRB1*0301-DQB1*0201 (P = 0.0001, OR = 3.4), DRB1*0401-DQB1*0302 (P = 0.0001, OR = 29.8), and DRB1*0402-DQB1*0302 (P = 0.008, OR = 4.7) were significantly more common, and DRB1*1501-DQB1*0602 (P = 0.0001, OR = 0.03) significantly less common in the investigated cohort than in a Slovenian control group. The highest risk and the strongest protective HLA-DR-DQ haplotypes found in Slovenian patients with T1D did not differ from those found in other Caucasian populations. While the DRB1*0301-QBP2.
Diabetologia, 1992
In Caucasians the predisposition to Type i (insulin-dependent) diabetes mellitus has been shown to associate with HLA-DR3,DQw2 and DR4,DQw8 and with the presence of amino acids other than aspartic acid at position 57 on the HLA-DQ[3 chain. In Finland the haplotypespecific absolute risk for developing Type i diabetes differs between various DR3 and DR4 positive haplotypes. The aim of our present analysis was to find out whether this variation is attributable to polymorphism at the DQ locus. As part of a nationwide prospective study including 757 serologically HLA genotyped families, we determined HLA-DQc~ and DQI3 restriction fragment polymorphisms in 17 selected families with important susceptibility haplotypes. Additionally, the DQA1 alleles were determined from 19 haplotypes using sequence-specific oligonucleotide probes, and the DQB1 second exon was sequenced from nine haplotypes. The DR3 as well as DR4 positive haplotypes frequently found in Type i diabetic patients showed no variation at the HLA-DQ locus, and they were DQw2 and DQw8, respectively. The absolute risk for Type 1 diabetes for DR4,DQw8 positive haplotypes A2,
International Journal of Immunogenetics, 2008
Both the human leucocyte antigen (HLA) DRB1 and the HLA DQB1 gene loci play a role in the development and progression of autoimmune diabetes mellitus (T1DM). Similarly, the insulin promoter variable number tandem repeats (INS-VNTR) polymorphism is also involved in the pathogenesis of diabetes mellitus (DM). We studied the association between each of these polymorphisms and DM diagnosed in patients older than age 35 years. Furthermore, we analysed possible interactions between HLA DRB1/DQB1 and INS-VNTR polymorphisms. Based on C-peptide and GADA levels we were able to distinguish three types of diabetes: T1DM, latent autoimmune diabetes in adults (LADA) and T2DM. INS-VNTR was genotyped indirectly by typing INS -23HphI A/T polymorphism. The genotype and allele frequencies of INS -23HphI did not differ between each of the diabetic groups and group of healthy subjects. We did, however, observe an association between the INS -23HphI alleles, genotypes and C-peptide secretion in all diabetic patients: A allele frequency was 86.2% in the C-peptide-negative group vs. 65.4% in the C-peptide-positive group (P corr. < 0.005); AA genotype was found to be 72.4% in the C-peptide-negative group vs. 42.6% in the C-peptidepositive groups (P corr. < 0.01). The HLA genotyping revealed a significantly higher frequency of HLA DRB1*03 allele in both T1DM and LADA groups when compared to healthy subjects: T1DM (25.7%) vs. control group (10.15%), odds ratio (OR) = 3.06, P < 0.05; LADA (27.6%) vs. control (10.15%), OR = 3.37, P < 0.01. The simultaneous presence of both HLA DRB1*04 and INS -23HphI AA genotype was detected in 37.5% of the T1DM group compared to only 9.2% of the healthy individuals group (OR = 5.9, P corr. < 0.007). We summarize that in the Central Bohemian population of the Czech Republic, the INS -23HphI A allele appears to be associated with a decrease in pancreatic beta cell secretory activity. HLA genotyping points to at least a partial difference in mechanism, which leads to T1DM and LADA development as well as a more diverse genetic predisposition in juvenile-and adult-onset diabetes. The simultaneous effect of HLA and INS-VNTR alleles/ genotypes predispose individuals to an increased risk of diabetes development.
Medicina, 2010
Objective: Type 1 diabetes mellitus is a slowly progressive autoimmune disease. The genetic background of type 1 diabetes mellitus is polygenic with the major disease locus located in the human leukocytes antigen (HLA) region. High risk and protective alleles, haplotypes, and genotypes have been determined in Lithuanian children with type 1 diabetes mellitus and healthy children. Material and methods: In this case-control study, 124 children with diabetes (55 males and 69 females; mean age, 9.2±3.9 years) were tested for HLA class II and compared with 78 healthy controls (43 males and 35 females; mean age, 10.8±3.4 years; range, 0-15 years). HLA DRB1, DQA1, and DQB1 alleles were genotyped using a polymerase chain reaction. Results: T1D risk-associated haplotypes (DR4)-DQA1*0301-DQB1*0302, (DR3)-DQA1*0501-DQB1*0201, and (DR1)-DQA1*0101-04-DQB1*0501 were more prevalent among children with diabetes than controls (50.0%, 41.1%, and 37.9% vs. 10.3%, 5.1%, and 24.4%, P<0.001). The haplotypes (DR4)-DQA1*0301-DQB1*0302 and (DR3)-DQA1*0501-DQB1*0201 increased T1D risk by 8.75 and 12.93 times, respectively (P<0.001). Protective haplotypes (DR2)-DQA1*0102-B1*0602, (DR11/12/13)-DQA1*05-DQB1*0301, and (DR13)-DQA1*0103-DQB1*0603 were significantly more prevalent among controls than children with diabetes (25.6%, 33.3%, 19.2% vs. 0%, 3.2%, 0%; P<0.001). These frequencies are quite similar to those from neighbor countries with varying incidence of type 1 diabetes mellitus. Conclusions: HLA class II haplotypes associated with type 1 diabetes mellitus positively or negatively were the same in Lithuanian children as in other European Caucasian populations. Differences in incidence and clinical manifestations of type 1 diabetes might be due to different environmental factors and/or lifestyle.
Genes and Immunity, 2003
Susceptibility to, and protection against development of type 1 diabetes (T1D) are primarily associated with the highly polymorphic exon 2 sequences of the HLA class II genes: DQB1, DQA1 and DRB1. However, several studies have also suggested that additional genes in the HLA complex influence T1D risk, albeit to a lesser degree than the class II genes. We have previously shown that allele 3 of microsatellite marker D6S2223, 4.9 Mb telomeric of DQ in the extended class I region, is associated with a reduction in risk conferred by the DQ2-DR3 haplotype. Here we replicate this finding in two populations from Sweden and France. We also show that markers in the HLA class II, III and centromeric class I regions contribute to the DQ2-DR3 associated risk of T1D, independently of linkage disequilibrium (LD) with both the DQ/DR genes and the D6S2223 associated gene. The associated marker alleles are carried on the DQ2-DR3-B18 haplotype in a region of strong LD. By haplotype mapping, we have located the most likely location for this second DQ2-DR3 haplotype-modifying locus to the 2.35 Mb region between HLA-DOB and marker D6S2702, located 970 kb telomeric of HLA-B.
Genetic Testing and Molecular Biomarkers, 2013
To assess the contribution of the HLA class II region for susceptibility to type 1 diabetes mellitus (T1DM), we investigated the association of HLA class II alleles-DP, DQ, and DRB1. Here, we present an extensive molecular typing for HLA class II alleles and their haplotypes in a Bengali-speaking Indian population of T1DM patients (n = 151) and controls (n = 151) from West Bengal. HLA typing was done by DNA sequencing using a 3730 DNA Analyzer. The individual analysis of each gene gave the following alleles to be higher in cases than in controls, thus making them susceptible alleles-DPA1*020103, DPB1*020102, DQA1*050101, DQA1*0201, and DQB1*020101G. Similarly, the following alleles are protective alleles in our study-DPA1*010602, DPB1*040101, DQA1*010201, DQA1*0103, and DRB1*15. Our result confidently establishes that HLA-DP allelic, and its haplotypic, diversity contributes significantly to the risk for T1DM. The DQA1*0103 allele is a novel allele with a significant association with the protection from T1DM. Among the various haplotypes tested, the DQA1*0201:DQB1*020101G, DQA1*050101:DQB1*020101G, and DQA1*0201:DQB1*030101G were the most frequently found in T1DM patients. In India, very few investigations have been undertaken to study the impact of the genetic background on the risk to develop T1DM in its population, where the annual average incidence is 10.5/100,000/year. In conclusion, the present study highlights the genetic effect of HLA haplotypes that contributes to the susceptibility to T1DM.
HLA-DRB1, -DQB1 and -DPB1 polymorphism in the Slovak population
Tissue Antigens, 1998
Aim of the study was to investigate an association between HLA class II alleles and type 1 diabetes mellitus in the Slovak population. Methods. 460 patients suffering from diabetes were typed for DQB1 alleles; 97 out of them also for DQA1 and 146 for DRB1 alleles, respectively. The HLA-typing was performed by a PCR-SSP method. Primer sets originated from the GenoVision (Olerup SSP TM AB Sweden). Results. Out of DQA1 and DQB1 alleles, the most frequent were found: DQA1*0301 (30.93% compared to 17.09 % in the healthy population; P < 0.0002), DQA1*0501 (34.02% compared to 25.76% in the healthy population; P < 0.0413, DQB1*0201 (22.93% vs. 12.94%, P < 0.0002), and DQB1*0302 (30.33 % vs. 5.59 %; P < 0.0001). Similarly, DRB1*0301 and DRB1*0401, respectively, were found to have the highest occurrence rates among 13 DRB1 alleles tested (DRB1*03: 26.37 % vs. 9.62 %, P < 0.0001; DRB1*04: 34.93% vs. 11.16 %, P < 0.0001). Statistically significant decreased occurrence rates were also observed, too: DQA1*0102 (8.76% vs. 16.58 %, P < 0.0111), DQA1*0201 (6.18% vs. 13.51 %, P < 0.0077), DQB1*0602 (2.17% vs. 10.14 %, P < 0.0001), DRB1*15 (2.74% vs. 12.31 %, P < 0.0001) and DRB1*07 (7.18% vs. 14.23%, P < 0.0081). The DQB1*0302 and DQA1*0301, respectively, were present in the same individual in all DRB1*0401 positive patients, suggesting they belong to the haplotype DQB1*0302-DQA1*0301-DRB1*0401. The same situation was observed with the alleles DQB1*0201, DQA1*0501, and DRB*0301, respectively, forming the haplotype DQB1*0201-DQA1*0501-DRB1*0301. These findings are in concordance with similar studies done in Czech, Polish or other Caucasoid populations. However, some findings, i.e. decreased frequencies of DQA*0301, DQA1*0603, and DRB*11 were not reported till now. Conclusion. The results of our study confirm previous studies done in various Caucasoid populations that HLA-DQ2, -DQ8, -DR3, and DR4 represent for autoimmune diabetes mellitus susceptible and HLA-DQ6, DR15, and DR7 protective molecules