Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease

Abstract

Common SNPs in the chromosome 17q12-q21 region alter the risk for asthma, type 1 diabetes, primary biliary cirrhosis, and Crohn disease. Previous reports by us and others have linked the disease-associated genetic variants with changes in expression of GSDMB and ORMDL3 transcripts in human lymphoblastoid cell lines (LCLs). The variants also alter regulation of other transcripts, and this domain-wide cis-regulatory effect suggests a mechanism involving long-range chromatin interactions. Here, we further dissect the disease-linked haplotype and identify putative causal DNA variants via a combination of genetic and functional analyses. First, high-throughput resequencing of the region and genotyping of potential candidate variants were performed. Next, additional mapping of allelic expression differences in Yoruba HapMap LCLs allowed us to fine-map the basis of the cis-regulatory differences to a handful of candidate functional variants. Functional assays identified allele-specific differences in nucleosome distribution, an allele-specific association with the insulator protein CTCF, as well as a weak promoter activity for rs12936231. Overall, this study shows a common disease allele linked to changes in CTCF binding and nucleosome occupancy leading to altered domain-wide cis-regulation. Finally, a strong association between asthma and cis-regulatory haplotypes was observed in three independent family-based cohorts (p = 1.78 x 10(-8)). This study demonstrates the requirement of multiple parallel allele-specific tools for the investigation of noncoding disease variants and functional fine-mapping of human disease-associated haplotypes.

17q21 variants modify the association between early respiratory infections and asthma

“…Among the 12 SNPs studied, one belongs to ORMDL3 while the other ones are intergenic (three SNPs) or belong to other genes, IKZF3 (one SNP), involved in the regulation of lymphocyte development, ZPBP2, or zona pellucida-binding protein 2 (one SNP), and GSDML (six SNPs), encoding one of the gasdermin proteins implicated in epithelial barrier function and skin differentiation [24]. These 17q21 SNPs are strongly associated with transcript levels of ORMDL3 [13], and, as found more recently, with transcript levels of GSDML, indicating that both ORMDL3 and GSDML are coregulated by cis-acting genetic variants [25]. Therefore, our epidemiologic observations are consistent with biological findings which suggest that genetic variants act over a large genomic region, playing a role in transcriptional activity of at least three genes (ZPBP2, GSDML and ORMDL3) [25].…”

Sex-biased genetic effects on gene regulation in humans

“…rs2872507 is associated with RA (Stahl et al 2010) and Crohn's disease (Barrett et al 2008). The GWAS-reported locus on 17q12-q21 is a region under complex gene regulation and harbors multiple disease signals (Verlaan et al 2009). Most studies have focused on the potential role of IKZF3 and ORMDL3 in disease, but we report the eQTL-gene ZPBP2 and bring this gene to the fore as a potential mediator of the disease association.…”

17q21 locus and ORMDL3: an increased risk for childhood asthma

“…GSDMB and ORMDL3 have received the most attention and their genotype-mediated expression is also affected by rhinovirus infection, one of the most common and powerful triggers for asthma exacerbations (8). It has further been suggested that these two genes might be coregulated, as their transcript levels seem connected (10).…”