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A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects. | LitMetric

AI Article Synopsis

  • The cortactin gene (CTTN) has SNPs linked to severe asthma in Black patients and plays a key role in maintaining endothelial cell (EC) integrity, crucial for lung function during respiratory distress conditions.
  • A specific SNP (Ser484Asn) was found in a study involving Black patients with severe sepsis, indicating that carriers of this SNP had a higher risk of mortality from sepsis.
  • Lab studies showed that the S484N variant negatively affects EC barrier recovery and contributes to increased lung permeability, suggesting that this genetic change is linked to worse outcomes in inflammatory lung injuries among Black patients.

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119916PMC
http://dx.doi.org/10.1016/j.trsl.2022.02.002DOI Listing

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