ArticleTranslational research : the journal of laboratory and clinical medicine2022
A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects.
Article in Translational research : the journal of laboratory and clinical medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it, 8 citations in OpenAlex.
- Genetic Variation and Sickle Cell Disease Severity: A Systematic Review and Meta-Analysis.JAMA network open · 2023Pooled it
- Lung Lymphatics in Edema, Inflammation, and Thrombosis.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- Genetic and epigenetic regulation of cortactin (CTTN) by inflammatory factors and mechanical stress in human lung endothelial cells.Bioscience reports · 2024Article
- A Razor's Edge: Vascular Responses to Acute Inflammatory Lung Injury/Acute Respiratory Distress Syndrome.Annual review of physiology · 2024Review
- Risk Variants in the Exomes of Children With Critical Illness.JAMA network open · 2022Article
- Cortactin in Lung Cell Function and Disease.International journal of molecular sciences · 2022Review
- Septin and actin contributions to endothelial cell-cell junctions and monolayer integrity.Cytoskeleton (Hoboken, N.J.)Review
Corrections and comments
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Authors and funding
24 authors at 6 institutions in 1 country.
Funding
Abstract
The cortactin gene (CTTN), encoding an actin-binding protein critically involved in cytoskeletal dynamics and endothelial cell (EC) barrier integrity, contains single nucleotide polymorphisms (SNPs) associated with severe asthma in Black patients. As loss of lung EC integrity is a major driver of mortality in the Acute Respiratory Distress Syndrome (ARDS), sepsis, and the acute chest syndrome (ACS), we speculated CTTN SNPs that alter EC barrier function will associate with clinical outcomes from these types of conditions in Black patients. In case-control studies, evaluation of a nonsynonymous CTTN coding SNP Ser484Asn (rs56162978, G/A) in a severe sepsis cohort (725 Black subjects) revealed significant association with increased risk of sepsis mortality. In a separate cohort of sickle cell disease (SCD) subjects with and without ACS (177 SCD Black subjects), significantly increased risk of ACS and increased ACS severity (need for mechanical ventilation) was observed in carriers of the A allele. Human lung EC expressing the cortactin S484N transgene exhibited: (i) delayed EC barrier recovery following thrombin-induced permeability; (ii) reduced levels of critical Tyr486 cortactin phosphorylation; (iii) inhibited binding to the cytoskeletal regulator, nmMLCK; and (iv) attenuated EC barrier-promoting lamellipodia dynamics and biophysical responses. ARDS-challenged Cttn+/- heterozygous mice exhibited increased lung vascular permeability (compared to wild-type mice) which was significantly attenuated by IV delivery of liposomes encargoed with CTTN WT transgene but not by CTTN S484N transgene. In summary, these studies suggest that the CTTN S484N coding SNP contributes to severity of inflammatory injury in Black patients, potentially via delayed vascular barrier restoration.
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Registered trials
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