Type 1 diabetes genetic susceptibility encoded by HLA DQB1 genes in Romania

Guja, Cristian; Guja, Loreta; Nutland, Sarah; Rance, Helen E.; Sebastien, Martinez; Todd, John A.; Ionescu-Tîrgovişte, C

doi:10.1111/j.1582-4934.2004.tb00280.x

Cited by 20 publications

(25 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because DPT-1 was based on first-degree relatives of type 1 diabetic patients, allele frequencies in such families were bound to be enriched in susceptibility alleles, thus precluding the use of frequency data in healthy control subjects as a comparator. Thus, we inferred allele frequencies in the parental population of DPT-1 individuals based on the HLA allele frequencies of progressors (i.e., type 1 diabetic patients) and the known transmission disequilibrium biases of alleles to type 1 diabetes probands (33)(34)(35).…”

Section: Resultsmentioning

confidence: 99%

“…Because most showed no significance, P values reported here are not corrected for multiple sampling; those tests showing potential significance were reconsidered with a simple Bonferroni correction, based on the number of SNPs or alleles tested (for HLA alleles, we only corrected for frequent alleles or haplotypes, ignoring those present in Ͻ10 individuals). DPT-1 parental HLA allele frequencies were estimated based on published transmission disequilibrium of HLA alleles to type 1 diabetes probands (33)(34)(35), according to the following formula: ProAF ϭ ParAF 2 ϩ [ParAF ϫ (1 Ϫ ParAF) ϫ (%transmission to probands/50%)], where ProAF and ParAF are the proband and parental allele frequencies, respectively. Hazard ratios for INS-23 genotype subsets were computed by Cox proportional modeling.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

et al. 2008

View full text Add to dashboard Cite

the DPT-1 Study Group OBJECTIVE-The unfolding of type 1 diabetes involves a number of steps: defective immunological tolerance, priming of anti-islet autoimmunity, and destruction of insulin-producing ␤-cells. A number of genetic loci contribute to susceptibility to type 1 diabetes, but it is unclear which stages of the disease are influenced by the different loci. Here, we analyzed the frequency of type 1 diabetes-risk alleles among individuals from the Diabetes Prevention Trial-Type 1 (DPT-1) clinical trial, which tested a preventive effect of insulin in at-risk relatives of diabetic individuals, all of which presented with autoimmune manifestations but only one-third of which eventually progressed to diabetes. RESEARCH DESIGN AND METHODS-In this study, 708individuals randomized into DPT-1 were genotyped for 37 single nucleotide polymorphisms in diabetes susceptibility loci.RESULTS-Susceptibility alleles at loci expected to influence immunoregulation (PTPN22, CTLA4, and IL2RA) did not differ between progressors and nonprogressors but were elevated in both groups relative to general population frequencies, as was the INS promoter variant. In contrast, HLA DQB1*0302 and DQB1*0301 differed significantly in progressors versus nonprogressors (DQB*0302, 42.6 vs. 34.7%, P ϭ 0.0047; DQB*0301, 8.6 vs. 14.3%, P ϭ 0.0026). Multivariate analysis of the factors contributing to progression demonstrated that initial titers of anti-insulin autoantibodies (IAAs) could account for some (P ϭ 0.0016) but not all of this effect on progression (P ϭ 0.00038 for the independent effect of the number of DQB*0302 alleles). The INS-23 genotype was most strongly associated with anti-IAAs (median IAA levels in TT individuals, 60 nU/ml; AT, 121; and AA, 192; P ϭ 0.000037) and only suggestively to the outcome of oral insulin administration.CONCLUSIONS-With the exception of HLA, most susceptibility loci tested condition the risk of autoimmunity rather than the risk of failed immunoregulation that results in islet destruction. Future clinical trials might consider genotyping INS-23 in addition to HLA alleles as disease/treatment response modifier.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

et al. 2008

View full text Add to dashboard Cite

show abstract

“…CMH contribute at least 30% of familial aggregation in insulin-dependent diabetes mellitus, systemic lupus erythematous and rheumatoid arthritis [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…It should be noted, however, that the same HLA allele may provide protection for a disease and at the same time, to confer susceptibility to another -for example alleles DQA1 * 0102, DQB1 * 0602 associated to HLA-DR2 are rare in patients with diabetes type 1, but is associated with multiple sclerosis [1,2].…”

Section: Introductionmentioning

confidence: 99%

HLA typing in autoimmune diseases

Martinescu¹,

Franciuc²,

Aftenie³

2012

ARS Medica Tomitana

View full text Add to dashboard Cite

Genome scan, linkage and association studies have identified CMH genes in the genetic determinism of most autoimmune diseases, affecting approximately 5% of the population. The susceptibility conferred by HLA alleles does not influence the development of autoimmunity in general, but rather the probability of some disorders. From extremely high number of known HLA alleles, less than 30 are associated with diseases, and fewer than 10 are involved in the strongest associations. The aim of this study was to determine HLA genes in autoimmune diseases. The method used for the assignment of HLA alleles was molecular genotyping, primarily by the sequence specific oligonucleotide hybridization method (SSO), and when required, by the sequence specific primers method (SSP). Molecular genotyping was performed in 282 cases of diabetes mellitus type 1, Hashimoto thyroiditis, Graves' disease and ankylosing spondylitis. HLA typing in patients with autoimmune diseases is important for determining prognosis and genetic counseling. In ankylosing spondylitis HLA typing is used for differential diagnosis. In such studies it's important to be aware that there is a particular HLA gene expression depending on the geographic area.

show abstract

“…Polymorphisms in peptidylarginine deaminase (PADI) and insulin genes (INS) are associated with RA and IDDM respectively [53,54] whereas variants of PDCD1 (encoding programmed cell death 1), SLC22A4 (within cytokine gene cluster), FCRL3 (encoding receptors with homology to the Fc-receptors of Ig), SUMO4 (small ubiquitin-like modifier 4), and CD25 (encoding a subunit of the IL-2 receptor complex) have been shown to be associated with several autoimmune conditions including SLE, RA, IDDM, Crohn's disease and autoimmune thyroid disorders [3,4,6,7,41,55,56]. Also, genetic lesions including point mutations in AIRE as well as complement deficiency have been vastly shown to be associated with an increased chance of autoimmunity [57][58][59][60][61][62][63][64][65][66].…”

Section: Genetic Basis Of Autoimmunitymentioning

confidence: 99%

Autoimmunity and Apoptosis - Therapeutic Implications

Rashedi

Panigrahi²,

Ezzati³

et al. 2007

CMC

View full text Add to dashboard Cite

Acquisition of a complex immune system during evolution provided organisms with the most effective defense mechanism against "foreign" or "non-self" invaders. This efficient protection against pathogens, however, has been achieved at the expense of a higher risk for "self"-directed reaction or autoimmunity. Establishment of self-tolerance and homeostasis in the immune system is regulated at different physiological stages of immune cells development. The breakdown in discrimination between "self" and "non-self" causes an aberrant immune response against autoantigens that promote damage to the "self" cells and tissue(s), resulting in various autoimmune phenotypes. Whereas activation and clonal proliferation of autoreactive T-and B-lymphocytes underlies the pathogenesis of autoimmune diseases, the mechanism by which self-tolerance is lost and autoimmune responses are induced is not clear yet. Autoimmunity is a multi-step process that occurs as a consequence of complex interaction between genetic susceptibility and non-genetic factors. Programmed cell death, as a key mechanism to regulate immune system function, has a crucial influence on both the selection process of immune cells and the maintenance of this immune tolerance in peripheral repertoire. Thus, defects in apoptotic death pathways may contribute to the development of autoimmune response in susceptible individuals in certain conditions.

show abstract

Type 1 diabetes genetic susceptibility encoded by HLA DQB1 genes in Romania

Cited by 20 publications

References 28 publications

Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

HLA typing in autoimmune diseases

Autoimmunity and Apoptosis - Therapeutic Implications

Contact Info

Product

Resources

About