title: Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring.
abstract: BACKGROUND
  Hypertrophic 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Surgery, UW Medicine Regional Burn Center, Harborview Medical Center, Seattle, WA, United States of America.
authors.forename: Ravi F
authors.initials: RF
authors.lastname: Sood
authors.affiliation: Department of Surgery, UW Medicine Regional Burn Center, Harborview Medical Center, Seattle, WA, United States of America.
authors.forename: Saman
authors.initials: S
authors.lastname: Arbabi
authors.affiliation: Department of Surgery, UW Medicine Regional Burn Center, Harborview Medical Center, Seattle, WA, United States of America.
authors.forename: Shari
authors.initials: S
authors.lastname: Honari
authors.affiliation: Department of Surgery, UW Medicine Regional Burn Center, Harborview Medical Center, Seattle, WA, United States of America.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Gibran
mesh_terms: D000328:Adult; D002056:Burns / Q000150:complications*; D017439:Cicatrix, Hypertrophic / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology*; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000276:immunology
chemical_list: D020928:Mitogen-Activated Protein Kinases; C489930:PTPN5 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor