Abstract
BackgroundHypertrophic scarring (HTS) is hypothesized to have a genetic mechanism, yet its genetic determinants are largely unknown. The mitogen-activated protein kinase (MAPK) pathways are important mediators of inflammatory signaling, and experimental evidence implicates MAPKs in HTS formation. We hypothesized that single-nucleotide polymorphisms (SNPs) in MAPK-pathway genes would be associated with severity of post-burn HTS.MethodsWe analyzed data from a prospective-cohort genome-wide association study of post-burn HTS. We included subjects with deep-partial-thickness burns admitted to our center who provided blood for genotyping and had at least one Vancouver Scar Scale (VSS) assessment. After adjusting for HTS risk factors and population stratification, we tested MAPK-pathway gene SNPs for association with the four VSS variables in a joint regression model. In addition to individual-SNP analysis, we performed gene-based association testing.ResultsOur study population consisted of 538 adults (median age 40 years) who were predominantly White (76%) males (71%) admitted to our center from 2007–2014 with small-to-moderate-sized burns (median burn size 6% total body surface area). Of 2,146 SNPs tested, a rare missense variant in the PTPN5 gene (rs56234898; minor allele frequency 1.5%) was significantly associated with decreased severity of post-burn HTS (P = 1.3×10−6). In gene-based analysis, PTPN5 (P = 1.2×10−5) showed a significant association and BDNF (P = 9.5×10−4) a borderline-significant association with HTS severity.ConclusionsWe report PTPN5 as a novel genetic locus associated with HTS severity. PTPN5 is a MAPK inhibitor expressed in neurons, suggesting a potential role for neurotrophic factors and neuroinflammatory signaling in HTS pathophysiology.
Highlights
During the past 75 years, advances in modern burn care have led to dramatic improvement in the survival of patients with large burns [1]
We report PTPN5 as a novel genetic locus associated with hypertrophic scarring (HTS) severity
PTPN5 is a mitogen-activated protein kinase (MAPK) inhibitor expressed in neurons, suggesting a potential role for neurotrophic factors and neuroinflammatory signaling in HTS pathophysiology
Summary
During the past 75 years, advances in modern burn care have led to dramatic improvement in the survival of patients with large burns [1] Most of these survivors develop hypertrophic scarring (HTS), resulting in red, raised, stiff, contracted and often painful and pruritic scars that are both highly disfiguring and disabling [2]. Cutaneous injury leads to activation of the clotting and complement cascades and platelet aggregation, which promote the release of chemokines and cytokines that recruit and activate a variety of inflammatory cells such as neutrophils, macrophages, mast cells, T-lymphocytes [5] These cells in turn produce cytokines including transforming growth factor beta 1 (TGF-β1) that stimulate fibroblast differentiation into myofibroblasts, which contract wounds and deposit extracellular matrix (ECM) and have a central role in HTS formation [6].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
