Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource

Abstract

Genome-wide association (GWA) studies have identified over 300 regions associated with more than 70 common diseases1. However, identifying causal genes within an associated region remains a major challenge1,2. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of interleukin-2 (IL-2) receptor alpha-chain (IL-2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated to the autoimmune diseases type 1 diabetes (T1D) and multiple sclerosis2-4. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWA gene-phenotype investigations, and demonstrate the usefulness of a large bioresource of genotype-selectable normal donors from whom fresh, primary cells can be analyzed.

Genome‐wide association studies of multiple sclerosis

“…Nevertheless, there are clear examples of biologically plausible mechanisms: an eQTL for ankyrin D55 in CD4 + T cells colocalising with GWAS signals for MS, rheumatoid arthritis and Crohn's disease63; a specific DHS site driving risk to MS, type 1 diabetes and autoimmune thyroiditis in the MND1 locus64; and that T‐cell surface expression of IL‐12 receptor alpha (CD25) is associated with risk variants for both MS and type 1 diabetes 72. Such shared effects are interesting because they highlight more general processes of autoimmunity and therapies targeting them may show efficacy in multiple indications.…”

Variation in the Cd3ζ (Cd247) Gene Correlates with Altered T Cell Activation and Is Associated with Autoimmune Diabetes

“…This attenuated TCR/CD3 signaling could synergize with the 50% reduction in IL-2 abundance and correlate with the reduced function of regulatory T cells reported to be conferred by the NOD allele of the Idd3 locus (49). As recently discussed (50), such a scenario concurs with the quantal theory of immunity, stating that T cell responses depend on cells receiving a critical number of TCR-and IL-2R-mediated stimuli, which, in turn, may have consequences for the process of discrimination between self and nonself (51). The results are also consistent with recently published observations that haplotypes in the human IL2RA gene associated with human T1D and multiple sclerosis correlate with differences in the surface expression of IL-2Ra (50).…”

Where is the causal variant? On the advantage of the family design over the case–control design in genetic association studies

“…For the SNPs with the smallest P-values (SNPs 1-4, 21 and 24), the family-based P-values are lower than the case-control ones. However, the use of family data does not decrease P-value for all SNPs: for example, the SNP reported in the literature [21][22][23][24][25] as associated with MS, rs2104286 (SNP 23 in our numbering), is not associated using case-control data, and adding the IBD information does not decrease its P-value. After Bonferroni correction, the association is significant association only with rs3118470 (SNP 24) for both case-control and family designs, and, with rs12359875 (SNP 1) for family design only.…”