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Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource
Calliope A Dendrou1, Vincent Plagnol, Erik Fung
1Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, UK.
Nature Genetics
|August 25, 2009
Summary
Identifying causal genes after GWAS is hard. This study links immune cell IL-2 receptor alpha (CD25) expression to autoimmune disease risk genes, aiding gene-phenotype correlation research.
Area of Science:
- Immunology
- Genetics
- Computational Biology
Background:
- Genome-wide association studies (GWAS) identify disease-associated genetic regions but struggle to pinpoint causal genes.
- Dissecting gene-phenotype correlations is crucial for understanding disease mechanisms.
- The interleukin-2 receptor alpha (IL2RA, CD25) gene region is linked to autoimmune diseases like type 1 diabetes and multiple sclerosis.
Purpose of the Study:
- To investigate the relationship between IL2RA (CD25) surface protein expression and specific haplotypes in immune cells.
- To establish gene-phenotype correlations for post-GWAS investigations.
- To demonstrate the utility of a bioresource for analyzing fresh, primary cells from genotype-selectable donors.
Main Methods:
- Polychromatic flow cytometry to measure cell surface protein expression.
- Analysis of gene-phenotype correlations, including allele-specific expression (ASE) at the RNA level.
- Utilizing a bioresource of normal donors with selectable genotypes.
Main Results:
- Differences in IL-2 receptor alpha (CD25) surface expression were cell-type specific.
- These expression differences correlated with specific IL2RA region haplotypes previously associated with type 1 diabetes and multiple sclerosis.
- Allele-specific expression (ASE) confirmed the strongest gene-phenotype correlation at the RNA level.
Conclusions:
- Gene-phenotype correlations, particularly involving cell surface markers like CD25, can help identify causal genes in GWAS-associated regions.
- The study provides a framework for post-GWAS gene discovery using functional assays and accessible bioresources.
- This approach aids in understanding the genetic basis of autoimmune diseases.
