Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
A Putative Functional Polymorphism in the IL21 3'-UTR Flanking Region Is Tagged by IL21 Lupus-Associated Variants and Alters Gene Expression in Vitro.
Travis, Hughes, Amr, H. Sawalha
We have previously reported, and recently localized, replicated and confirmed the genetic association between IL21 polymorphisms and the susceptibility to SLE with a genome-wide significance. Two SNPs located within IL21 and its 3'-UTR flanking region, rs907715 and rs6835457, explain the genetic association in this locus. Herein, we seek to identify putative functional polymorphisms for which the previously observed polymorphisms might serve as a proxy.
We conducted a scan for genetic polymorphisms in the IL21 locus that are in LD (r2>0.8) with the two previously reported lupus-associated markers (rs907715 and rs6835457) in Hapmap3 and among polymorphisms in the 1000 Genomes Project. We used luciferase reporter assays to interrogate the cis-acting effects of a putative functional polymorphism on IL21 gene expression.
We identified a total of 9 additional SNPs in high LD with the previously characterized genetic effect within the IL21 locus using the CEU European-derived samples. The observed LD block formed by these polymorphisms is centered around IL21 and does not extend to encompass other genes in the region. One polymorphism, rs2175679, is located within a putative regulatory region downstream of IL21 which is enriched for H3K4me1, H3K4me3, CTCF, and a number of transcription factor binding sites in ENCODE data sets. These data suggest this region to possess enhancer and/or insulator function downstream of IL21 which might be modified by this non-coding G/T polymorphism. Indeed, luciferase levels using constructs with the G-allele variant are significantly increased relative to those of the T-allele variant in rs2175679 (1.5-fold, P= 0.007). The G allele of rs2175679 is the allele which corresponds to the lupus-associated risk allele of both rs907715 and rs6835457.
A common non-coding variant in IL21 3'-UTR flanking region might contribute to increased lupus susceptibility by altering the transcriptional regulation of IL21.
To cite this abstract, please use the following information:
Travis, Hughes, Amr, H. Sawalha; A Putative Functional Polymorphism in the IL21 3'-UTR Flanking Region Is Tagged by IL21 Lupus-Associated Variants and Alters Gene Expression in Vitro. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :156