Polymorphic variants of the <i>IL2RA</i> gene and susceptibility to type 1 diabetes in the Polish population

Fichna, Marta; Żurawek, Magdalena; Fichna, Piotr; Januszkiewicz, Danuta; Nowak, Jerzy

doi:10.1111/j.1399-0039.2011.01828.x

Cited by 12 publications

(16 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 Moreover, healthy controls carrying the T1D-associated rs12722495 susceptible genotype (GG) have diminished IL-2 responsiveness in Tregs, as measured by phosphorylation of STAT5. 14,15 A genotype containing the rs3118470 SNP was shown to be significantly protective in T1D-affected sibling-pair families 16 and this observation has been replicated in Japanese 17 and Polish 18 populations. The rs3118470 SNP has also been associated with differential allele expression of IL2RA messenger RNA.…”

Section: Introductionmentioning

confidence: 77%

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

et al. 2017

View full text Add to dashboard Cite

T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3lo Tregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3+IL-17+ cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3+IL-17+ cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.

show abstract

Section: Introductionmentioning

confidence: 77%

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…A total of 10 studies 5,9,13–17,19,20 with 19 outcomes met the inclusion and exclusion criteria (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies

Tang

Cui

Jiang

et al. 2015

J Cellular Molecular Medi

View full text Add to dashboard Cite

Single nucleotide polymorphisms (SNPs) in the interleukin 2 receptor alpha (IL2RA) gene have been suggested to be associated with type 1 diabetes (T1D) susceptibility. However, the results from individual studies are inconsistent. To explore the association of IL2RA polymorphisms with T1D, including rs11594656, rs2104286, rs3118470, rs41295061 and rs706778, a meta-analysis involving 10 independent studies with 19 outcomes was conducted: five studies with a total of 10,572 cases and 12,956 controls were analysed for rs11594656 with T1D risk, three studies with 7300 cases and 8331 controls for rs2104286, three studies with 3880 cases and 5409 controls for rs3118470, five studies with 11,253 cases and 13,834 controls for rs41295061 and three studies with 1896 cases and 1709 controls for rs706778 respectively. Using minor allelic comparison, the five investigated SNPs were all observed to have a significant association with T1D: For rs11594656, fixed effect model (FEM) odds ratio (OR) 0.87, 95% confidence interval (CI) 0.83, 0.91; rs2104286, FEM OR 0.81, 95% CI 0.77, 0.85; rs3118470, FEM OR 1.23, 95% CI 1.16, 1.31; rs41295061, random effect model (REM) OR 0.67, 95% CI 0.60, 0.76 and rs706778 FEM OR 1.20, 95% CI 1.08, 1.33. Similar results were obtained when all the included studies were calculated by a REM. Our meta-analysis suggests that all five SNPs in the IL2RA gene are risk factors for T1D risk, and rs11594656, rs2104286 and rs41295061 are the most associated SNPs in the populations investigated. This conclusion warrants confirmation by further studies.

show abstract

“…As Tregs prevent the expansion of CD4 ϩ , CD8 ϩ , and natural killer (NK) lymphocytes, decreased CD25 expression on Tregs would be consistent with higher activation of CD4 ϩ cells in our stimulated conditions (I 0 ). Interestingly, IL2RA polymorphisms and haplotypes (1 including rs10795791 and the other rs11594656, although each associated with 2 different SNPs) have been associated with several autoimmune diseases (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Of course, this hypothesis deserves further exploration.…”

Section: Cd8mentioning

confidence: 99%

Tacrolimus Pharmacodynamics and Pharmacogenetics along the Calcineurin Pathway in Human Lymphocytes

et al. 2014

View full text Add to dashboard Cite

BACKGROUND Although therapeutic drug monitoring has improved the clinical use of immunosuppressive drugs, there is still interpatient variability in efficacy and toxicity that pharmacodynamic monitoring may help to reduce. To select the best biomarkers of tacrolimus pharmacodynamics, we explored the strength and variability of signal transduction and the influence of polymorphisms along the calcineurin pathway. METHODS Peripheral blood mononuclear cells from 35 healthy volunteers were incubated with tacrolimus (0.1–50 ng/mL) and stimulated ex vivo. Inhibition of NFAT1 (nuclear factor of activated T cells 1) translocation to the nucleus and intracellular expression of interleukin-2 in CD4+ and CD8+ T cells and the surface activation marker CD25 in CD3+ cells were measured by flow cytometry. We sequenced the promoter regions of immunophilins and calcineurin subunits and characterized selected single nucleotide polymorphisms in the genes of the calcineurin pathway with allelic discrimination assays. RESULTS All responses closely fitted an I/Imax sigmoid model. Large interindividual variability (n = 30) in I0 and IC50 was found for all biomarkers. Moreover, strong and statistically significant associations were found between tacrolimus pharmacodynamic parameters and polymorphisms in the genes coding cyclophilin A, the calcineurin catalytic subunit α isoenzyme, and CD25. CONCLUSIONS This study demonstrates the consistency and large interindividual variability of signal transduction along the calcineurin pathway, as well as the strong influence of pharmacogenetic polymorphisms in the calcineurin cascade on both the physiological activity of this route and tacrolimus pharmacodynamics.

show abstract

Polymorphic variants of the IL2RA gene and susceptibility to type 1 diabetes in the Polish population

Cited by 12 publications

References 41 publications

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells

Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies

Tacrolimus Pharmacodynamics and Pharmacogenetics along the Calcineurin Pathway in Human Lymphocytes

Contact Info

Product

Resources

About