Genetic screening for individuals at high risk for type 1 diabetes in the general population using HLA Class II alleles as disease markers. A comparison between three European populations with variable rates of disease incidence

Hermann, Róbert; Bartsocas, C. S.; Soltész, G; Vazeou, Andriani; Paschou, Peristera; Bozas, Evangelos; Malamitsi‐Puchner, Ariadne; Simell, Olli; Knip, Mikael; Ilonen, Jorma

doi:10.1002/dmrr.455

Cited by 40 publications

(22 citation statements)

References 23 publications

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“…DQB1*0302 was strongly associated with, while DQB1* 030101 was largely protective of T1D. Similar associations were reported for northern Europe (8, 14-16), but not southern Europe (15,24) or Mediterranean countries (3), in which DQB1*0201 was reported as the major DQB1 susceptible allele. This lack of association of DQB1*0201 with T1D in Tunisians was supported by the finding that DQB1*0201 was linked with T1D susceptibility when present with DRB1* 030101 but was negatively associated with T1D when present with DRB1*070101 in a haplotype.…”

Section: Discussionsupporting

confidence: 72%

Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

Stayoussef

Benmansour

Al-Irhayim

et al. 2009

Clin Vaccine Immunol

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Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1* 110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1* 0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background.Type 1 (insulin-dependent) diabetes (T1D) is the most prevalent form of diabetes in children and young adults (12,17) and results from autoimmune CD4 ϩ and CD8 ϩ T-cell-directed destruction of insulin-producing pancreatic ß islet cells, leading to irreversible hyperglycemia and related complications (4,22). In addition to environmental factors, there is a strong genetic component to T1D pathogenesis, of which the human leukocyte antigen (HLA) locus, in particular the class II region (DR and DQ), account for 40 to 50% of T1D familial clustering (13,30). This was evidenced by the enrichment of DR3, DR4, DQ2, and DQ8, and the lower prevalence of DR15 or DQ6.2 alleles among T1D patients, thereby assigning a susceptible or protective role for these alleles in T1D pathogenesis, respectively (3, 16, 21).The fact that not all carriers of a specific high-risk DR or DQ variant develop the disease and the strong linkage disequilibrium between select DRB1 and DQB1 alleles (28) indicate that the pathogenesis of T1D results from the complex interaction between several genes within the class II region, in which specific DRB1-DQB1 haplotypes contribute to disease susceptibility. Accordingly, the enrichment ...

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Section: Discussionsupporting

confidence: 72%

Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

Stayoussef

Benmansour

Al-Irhayim

et al. 2009

Clin Vaccine Immunol

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“…The frequency of AGER −374 T/A polymorphism was strongly dependent on the HLA-DQB1 genotype, the frequency of which can vary in different populations [34], and therefore also the frequency of AGER −374 T/A polymorphism. The frequency of the 63 bp insertion/ deletion polymorphism was also lower in Scandinavian patients than in patients of other origins.…”

Section: Discussionmentioning

confidence: 97%

The −374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients

et al. 2006

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Aims/hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the −374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications. Methods The AGER −374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin. Results AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER −374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE −374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p<0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sightthreatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA 1c values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02). Conclusions/interpretation Our results show an association between the AGER −374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA 1c -dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.

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“…A comparable increase in incidence has occurred in the UK, although less well-documented, and the proportion of children under 15 years carrying the HLA genotype DR3-DQ2/DR4-DQ8 fell from 47% in 50-year survivors to 35% in recently diagnosed children, although there was no increase in those carrying protective genotypes [11]. In Finland, the proportion of affected children with the highest risk genotypes is small relative to that in countries with lower incidence rates, and suggests that the latter may be at an earlier stage of the same environmental process [12]. This implies that the influence of environmental change upon progression to diabetes within genetically susceptible subsets of the population can be tracked in space as well as over time.…”

Section: Environmental Anticipationmentioning

confidence: 92%

Spring harvest? Reflections on the rise of type 1 diabetes

Gale

2005

Diabetologia

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Genetic screening for individuals at high risk for type 1 diabetes in the general population using HLA Class II alleles as disease markers. A comparison between three European populations with variable rates of disease incidence

Cited by 40 publications

References 23 publications

Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

The −374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients

Spring harvest? Reflections on the rise of type 1 diabetes

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