RGD Reference Report - Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring. - Rat Genome Database

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Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring.

Authors: Lao, T  Glass, K  Qiu, W  Polverino, F  Gupta, K  Morrow, J  Mancini, JD  Vuong, L  Perrella, MA  Hersh, CP  Owen, CA  Quackenbush, J  Yuan, GC  Silverman, EK  Zhou, X 
Citation: Lao T, etal., Genome Med. 2015 Feb 14;7(1):12. doi: 10.1186/s13073-015-0137-3. eCollection 2015.
RGD ID: 11552596
Pubmed: PMID:25763110   (View Abstract at PubMed)
PMCID: PMC4355149   (View Article at PubMed Central)
DOI: DOI:10.1186/s13073-015-0137-3   (Journal Full-text)

BACKGROUND: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. METHODS: We exposed Hhip haploinsufficient mice (Hhip (+/-) ) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. RESULTS: We detected more severe airspace enlargement in Hhip (+/-) mice vs. wild-type littermates (Hhip (+/+) ) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip (+/-) vs. Hhip (+/+) mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip (+/-) mice compared to Hhip (+/+) mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip (+/-) mice after CS exposure. CONCLUSIONS: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HHIPHumanpulmonary emphysema  ISOHhip (Mus musculus)DNA:haplotype insufficiency: :RGD 
HhipMousepulmonary emphysema  IMP DNA:haplotype insufficiency: :RGD 
HhipRatpulmonary emphysema  ISOHhip (Mus musculus)DNA:haplotype insufficiency: :RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hhip  (Hedgehog-interacting protein)

Genes (Mus musculus)
Hhip  (Hedgehog-interacting protein)

Genes (Homo sapiens)
HHIP  (hedgehog interacting protein)


Additional Information