ArticleHuman molecular genetics2012
Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers, 5 of them syntheses that pooled it.
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Who cites it
100 citing papers in PubMed, 5 syntheses or guidelines pooled it, 196 citations in OpenAlex.
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- Integrative genomics identifies new genes associated with severe COPD and emphysema.Respiratory research · 2018Pooled it
- Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.American journal of respiratory cell and molecular biology · 2017Pooled it
- Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis.The Lancet. Respiratory medicine · 2014Pooled it
- Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.American journal of respiratory and critical care medicine · 2012Pooled it
- A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC genetics · 2015Trial
- Telomere dysfunction and mucociliary impairment drive idiopathic pulmonary fibrosis susceptibility: insights from a Sardinian whole-exome study.BMJ open respiratory research · 2026Article
- HHIP's dynamic role in epithelial wound healing reveals a potential mechanism of COPD susceptibility.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Single-cell atlas of human lung aging identifies cell type dyssynchrony and increased transcriptional entropy.Nature communications · 2026Article
- Dissecting Hhip1 FunctionActa histochemica et cytochemica · 2025Article
- Review
- Hedgehog-interacting protein orchestrates alveologenesis and protects against bronchopulmonary dysplasia and emphysema.Science advances · 2025Article
- HHIP protein interactions in lung cells provide insight into COPD pathogenesis.Human molecular genetics · 2025Article
- Characterisation of a COPD-associated nephronectin (The European respiratory journal · 2025Article
- Article
- POU5F1 bridges Hedgehog signaling and epithelial remodeling in COPD.Frontiers in cell and developmental biology · 2025Article
- Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.American journal of respiratory and critical care medicine · 2024Article
- HHIP's Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility.bioRxiv : the preprint server for biology · 2024Article
- Breathing new life into the study of COPD with genes identified from genome-wide association studies.European respiratory review : an official journal of the European Respiratory Society · 2024Review
- Identification of a distal enhancer regulating hedgehog interacting protein gene in human lung epithelial cells.EBioMedicine · 2024Article
40 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
22 authors at 4 institutions in 1 country.
Funding
Abstract
Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHIP) on chromosome 4q31 have been strongly associated with pulmonary function levels and moderate-to-severe chronic obstructive pulmonary disease (COPD). However, whether the effects of variants in this region are related to HHIP or another gene has not been proven. We confirmed genetic association of SNPs in the 4q31 COPD genome-wide association study (GWAS) region in a Polish cohort containing severe COPD cases and healthy smoking controls (P = 0.001 to 0.002). We found that HHIP expression at both mRNA and protein levels is reduced in COPD lung tissues. We identified a genomic region located ∼85 kb upstream of HHIP which contains a subset of associated SNPs, interacts with the HHIP promoter through a chromatin loop and functions as an HHIP enhancer. The COPD risk haplotype of two SNPs within this enhancer region (rs6537296A and rs1542725C) was associated with statistically significant reductions in HHIP promoter activity. Moreover, rs1542725 demonstrates differential binding to the transcription factor Sp3; the COPD-associated allele exhibits increased Sp3 binding, which is consistent with Sp3's usual function as a transcriptional repressor. Thus, increased Sp3 binding at a functional SNP within the chromosome 4q31 COPD GWAS locus leads to reduced HHIP expression and increased susceptibility to COPD through distal transcriptional regulation. Together, our findings reveal one mechanism through which SNPs upstream of the HHIP gene modulate the expression of HHIP and functionally implicate reduced HHIP gene expression in the pathogenesis of COPD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.