The DOI matches its Crossref record; 69 of the 70 references it cites were found in a registry or an index.
Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease
Open accessAbstract
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.
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“We note that such comparisons should be made with the understanding that transcription factor binding sites may differ between species (70).”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [70]
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Metadata
- Authors
- Verlaan, D. J., Berlivet, S., Hunninghake, G. M., Madore, A.-M., Larivière, M., Moussette, S., Grundberg, E., Kwan, T., Ouimet, M., Ge, B., Hoberman, R., Swiatek, M., Dias, J., Lam, K. C. L., Koka, V., Harmsen, E., Soto-Quiros, M., Avila, L., Celedón, J. C., Weiss, S. T., Dewar, K., Sinnett, D., Laprise, C., Raby, B. A., Pastinen, T., & Naumova, A. K.
- Affiliations
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- McGill University (CA)
- Brigham and Women's Hospital (US)
- Université du Québec à Chicoutimi (CA)
- McGill University and Génome Québec Innovation Centre (CA)
- Research Institute of the McGill University Health Centre (CA)
- Corresponding author
- Pastinen, Tomi
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 85
- Issue
- 3
- Pages
- 377-393
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2771592
- OpenAlex
- W2041155293
- Cited by
- 297
- References
- 70
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 13 · 2023: 18 · 2022: 14 · 2021: 16 · 2020: 16 · 2019: 13 · 2018: 17 · 2017: 18 · 2016: 18 · 2015: 32 · 2014: 17 · 2013: 18 · 2012: 28
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL04370, HL66289, T32 HL07427, U01HL065899, R01HL066289, K08HL092222, R37HL066289, K01HL004370, U01HL075419, R01HL086601, P01HL083069, U01 HL65899, T32HL007427)
- National Human Genome Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Asthma and respiratory diseases
- Keywords
- asthma, autoimmune disease, type 1 diabetes, primary biliary cirrhosis, Crohn's disease, cis-regulatory variation, long-range chromatin interactions, allele-specific expression, nucleosome occupancy, CTCF binding, insulator proteins
- MeSH terms
- Gasdermins, Adolescent, Alleles, Asthma, Autoimmune Diseases, Base Sequence, Cell Line, Child, Chromosomes, Human, Pair 17, DNA Mutational Analysis, Egg Proteins, Female, Haplotypes, Humans, Male, Membrane Proteins, Molecular Sequence Data, Neoplasm Proteins, Pedigree, Regulatory Sequences, Nucleic Acid, Genes, Reporter, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Chromatin Assembly and Disassembly, White People
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