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A cis-Acting Regulatory Variant in the IL2RA Locus¹

Hui-Qi Qu,^* Dominique J. Verlaan, Bing Ge, Yang Lu,^* Kevin C. L. Lam, Rosemarie Grabs,^* Eef Harmsen, Thomas J. Hudson, Hakon Hakonarson, Tomi Pastinen, and Constantin Polychronakos^2*

^*Endocrine Genetics Lab, The McGill University Health Center and Montreal Children’s Hospital, McGill University and Genome Québec Innovation Centre, Montréal, Québec, Canada, Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada; and Center for Applied Genomics, and Department of Pediatrics and Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104

The mechanism for the association of type 1 diabetes (T1D) with IL2RA remains to be clarified. Neither of the two distinct, transmission-disequilibrium confirmed loci mapping to this gene can be explained by a coding variant. An effect on the levels of the soluble protein product sIL-2RA has been reported but its cause and relationship to disease risk is not clear. To look for an allelic effect on IL2RA transcription in cis, we examined RNA from 48 heterozygous lymphocyte samples for differential allele expression. Of the 48 samples, 32 showed statistically significant allelic imbalance. No known single nucleotide polymorphism (SNP) had perfect correlation with this transcriptional effect but the one that showed the most significant (p = 1.6 x 10^–5) linkage disequilibrium with it was the SNP rs3118470. We had previously shown rs3118470 to confer T1D susceptibility in a Canadian dataset, independently of rs41295061 as the major reported locus (p = 5 x 10^–3, after accounting for rs41295061 by conditional regression). Lower IL2RA levels consistently originated from the T1D predisposing allele. We conclude that an as yet unidentified variant or haplotype, best marked by rs3118470, is responsible for this independent effect and increases T1D risk through diminished expression of the IL-2R, likely by interfering with the proper development of regulatory T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funding by the GRiD Project from Genome Canada, Génome Québec and by the Juvenile Diabetes Research Foundation International. H.Q.Q. holds a fellowship from the Canadian Institutes of Health Research. T.P. holds a Canada Research Chair (tier 2).

² Address correspondence and reprint requests to Dr. Constantin Polychronakos, The McGill University Health Center and Montreal Children’s Hospital, 2300 Tupper, Montréal, Quebec H3H 1P3, Canada. E-mail address: constantin.polychronakos{at}mcgill.ca

³ Abbreviations used in this paper: T1D, type 1 diabetes; SNP, single nucleotide polymorphism; LCL, lymphoblastoid cell line; AE, allelic expression.