1. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease.
- Author
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Verlaan DJ, Berlivet S, Hunninghake GM, Madore AM, Larivière M, Moussette S, Grundberg E, Kwan T, Ouimet M, Ge B, Hoberman R, Swiatek M, Dias J, Lam KC, Koka V, Harmsen E, Soto-Quiros M, Avila L, Celedón JC, Weiss ST, Dewar K, Sinnett D, Laprise C, Raby BA, Pastinen T, and Naumova AK
- Subjects
- Adolescent, Asthma complications, Autoimmune Diseases complications, Base Sequence, Cell Line, Child, Chromosomes, Human, Pair 17 genetics, DNA Mutational Analysis, Egg Proteins metabolism, Female, Genes, Reporter, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Membrane Proteins metabolism, Molecular Sequence Data, Neoplasm Proteins metabolism, Pedigree, Polymorphism, Single Nucleotide genetics, Regulatory Sequences, Nucleic Acid genetics, White People genetics, Alleles, Asthma genetics, Autoimmune Diseases genetics, Chromatin Assembly and Disassembly genetics, Egg Proteins genetics, Membrane Proteins genetics, Neoplasm Proteins genetics
- 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.
- Published
- 2009
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