Abstract
Genome-wide association studies (GWASes) revealed several single-nucleotide polymorphisms (SNPs) in the human 17q12-21 locus associated with autoimmune diseases. However, follow-up studies are still needed to identify causative SNPs directly mediating autoimmune risk in the locus. We have chosen six SNPs in high linkage disequilibrium with the GWAS hits that showed the strongest evidence of causality according to association pattern and epigenetic data and assessed their functionality in a local genomic context using luciferase reporter system. We found that rs12946510, rs4795397, rs12709365, and rs8067378 influenced the reporter expression level in leukocytic cell lines. The strongest effect visible in three distinct cell types was observed for rs12946510 that is predicted to alter MEF2A/C and FOXO1 binding sites.
Highlights
The study of human 17q12-21 locus began with the discovery of its association with inheritable predisposition to breast cancer [1]
Since the identification of the first single-nucleotide polymorphisms (SNPs) in the locus that strongly correlate with susceptibility to childhood asthma and ORMDL3 gene expression level [3], 17q12-21 has been the most replicated and most significant asthma locus defined by genome-wide association studies (GWASes) and meta-analyses of GWASes, and the list of candidate genes was substantially extended [4]
Of 136 polymorphisms analyzed by Schmiedel et al, we chose SNPs highlighted by the authors for their overlap with DNase I hypersensitivity sites highly specific for lymphocytes (Figure 3a in [17])
Summary
The study of human 17q12-21 locus began with the discovery of its association with inheritable predisposition to breast cancer [1]. Autoimmunity-associated SNPs in the 17q12-21 locus overlap with several genes: NEUROD2, PPP1R1B, STARD3, TCAP, PNMT, PGAP3, ERBB2, MIR4728, MIEN1, GRB7, IKZF3, ZPBP2, and GSDMB The role of these genes in the immune system is not obvious, with the exception of IKZF3 that encodes Aiolos transcription factor and is important for normal development and function of B cells [12]. We used fine-mapping results of Farh et al [16] and Schmiedel et al [17] to select the most probable causative autoimmunity-associated SNPs in the human 17q12-21 locus for experimental validation We studied their effect on transcription in the luciferase reporter system which is most suited for analysis of one or few loci and enables detection of regulatory activities of long sequences that depend on cooperative binding of different transcription factors [18]. We found four SNPs that significantly influenced the reporter expression level in lymphoid and monocytic cell lines
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
