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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
A cis-acting regulatory variant in the IL2RA locus
Hui-Qi Qu1, Dominique J Verlaan, Bing Ge
1Endocrine Genetics Lab, The McGill University Health Center and Montreal Children's Hospital, Montréal, Québec, Canada.
Journal of Immunology (Baltimore, Md. : 1950)
|October 2, 2009
Summary
Type 1 diabetes (T1D) risk is linked to IL2RA gene variants. A specific SNP, rs3118470, is associated with lower IL2RA expression, potentially impacting regulatory T cell development and increasing T1D susceptibility.
Area of Science:
- Immunogenetics
- Molecular genetics
- Autoimmune diseases
Background:
- The genetic basis for Type 1 Diabetes (T1D) association with the IL2RA gene is not fully understood.
- Previous studies identified T1D susceptibility loci within IL2RA but could not attribute them to coding variants.
- Reported effects on soluble IL-2 receptor alpha (sIL-2RA) levels lack clear causal links to disease risk.
Purpose of the Study:
- To investigate the allelic effect on IL2RA gene transcription in cis.
- To identify the specific variant or haplotype responsible for the independent T1D risk associated with IL2RA.
- To clarify the mechanism by which IL2RA variants influence T1D pathogenesis.
Main Methods:
- Analysis of RNA from 48 heterozygous lymphocyte samples to assess differential allele expression.
- Examination of allele-specific expression patterns and their correlation with known single nucleotide polymorphisms (SNPs).
- Statistical analysis, including linkage disequilibrium and conditional regression, to evaluate the association of SNP rs3118470 with T1D susceptibility and IL2RA expression.
Main Results:
- Statistically significant allelic imbalance in IL2RA expression was observed in 32 out of 48 samples.
- SNP rs3118470 showed the strongest linkage disequilibrium (p = 1.6 x 10(-5)) with the observed transcriptional effect.
- Lower IL2RA expression levels consistently originated from the T1D predisposing allele, independent of other known T1D loci.
- rs3118470 conferred T1D susceptibility in a Canadian dataset, even after accounting for the major reported locus rs41295061.
Conclusions:
- An unidentified variant or haplotype, strongly associated with rs3118470, independently increases T1D risk.
- This risk is likely mediated by diminished expression of the IL-2 receptor (IL-2R).
- Reduced IL-2R expression may impair the development of regulatory T cells, contributing to T1D pathogenesis.
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