Search

Background: Systemic inflammatory response syndrome (SIRS) is associated with organ failure and infectious complications after major burn injury. Recent evidence has linked melanocortin signaling to anti-inflammatory and wound-repair functions, with mutations in the melanocortin 1 receptor (MC1R) gene leading to increased inflammatory responses. Our group has previously demonstrated that MC1R gene polymorphisms are associated with postburn hypertrophic scarring. Thus, we hypothesized that MC1R single nucleotide polymorphisms (SNPs) would be associated with increased burn-induced SIRS and increased infectious complications., Methods: We performed a retrospective cohort study of adults (>18 y of age) admitted to our burn center with >20% total body surface area (TBSA) partial/full thickness burns between 2006 and 2013. We screened for five MC1R SNPs (V60L, V92M, R151C, R163Q, T314T) by polymerase chain reaction from genomic DNA isolated from blood samples. We performed a detailed review of each patient chart to identify age, sex, race, ethnicity, %TBSA burned, burn wound infections (BWIs), and 72-hr intravenous fluid volume, the latter a surrogate for a dysfunctional inflammatory response to injury. Association testing was based on multivariable regression., Results: Of 106 subjects enrolled, 82 had complete data for analysis. Of these, 64 (78%) were male, with a median age of 39 and median burn size of 30% TBSA. A total of 36 (44%) subjects developed BWIs. The median total administered IV crystalloid in first 72h was 24.6 L. In multivariate analysis, the R151C variant allele was a significant independent risk factor for BWI (adjusted prevalence ratio 2.03; 95% CI: 1.21-3.39; P = 0.007), and the V60L variant allele was independently associated with increased resuscitation fluid volume (P = 0.021)., Conclusions: This is the first study to demonstrate a significant association between genetic polymorphisms and a nonfatal burn-induced SIRS complication. Our findings suggest that MC1R polymorphisms contribute to dysfunctional responses to burn injury that may predict infectious and inflammatory complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The genetic determinants of post-burn hypertrophic scarring (HTS) are unknown, and melanocortin 1 receptor (MC1R) loss-of-function leads to fibrogenesis in experimental models. To examine the associations between self-identified race and MC1R single-nucleotide polymorphisms (SNPs) with severity of post-burn HTS, we conducted a prospective cohort study of burned adults admitted to our institution over 7 years. Subjects were evaluated using the Vancouver Scar Scale (VSS), asked to rate their itching, and genotyped for 8 MC1R SNPs. Testing for association with severe HTS (VSS>7) and itch severity (0-10) was based on multivariate regression with adjustment for known risk factors. Of 425 subjects analyzed, 77% identified as White. The prevalence of severe HTS (VSS>7) was 49%, and the mean itch score was 3.9. In multivariate analysis, Asian (prevalence ratio (PR) 1.54; 95% CI: 1.13-2.10), Black/African American (PR 1.86; 95% CI: 1.42-2.45), and Native American (PR 1.87; 95% CI: 1.48-2.35) race were independently associated with severe HTS. MC1R SNP R163Q was also significantly (P<0.001) associated with severe HTS. Asian race (linear regression coefficient 1.32; 95% CI: 0.23-2.40) but not MC1R SNP genotype was associated with increased itch score. We conclude that MC1R genotype may influence post-burn scarring.

Objective: To identify genetic variants associated with the severity of postburn hypertrophic scarring (HTS) using a genome-wide approach., Background: Risk of severe postburn HTS is known to depend on race, but the genetic determinants of HTS are unknown., Methods: We conducted a genome-wide association study (GWAS) in a prospective cohort of adults admitted with deep-partial-thickness burns from 2007 through 2014. Scar severity was assessed over time using the Vancouver Scar Scale (VSS), and DNA was genotyped with a >500,000-marker array. We performed association testing of single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) >0.01 using linear regression of VSS height score on genotype adjusted for patient and injury characteristics as well as population genetic structure. Array-wide significance was based on Bonferroni correction for multiple testing., Results: Of 538 patients (median age 40 years, median burn size 6.0% of body surface area), 71% were men and 76% were White. The mean VSS height score was 1.2 (range: 0-3). Of 289,639 SNPs tested, a variant in the CUB and Sushi multiple domains 1 (CSMD1) gene (rs11136645; MAF = 0.49), was significantly associated with decreased scar height (regression coefficient = -0.23, P = 7.9 × 10)., Conclusions: In the first published GWAS of HTS, we report that a common intronic variant in the CSMD1 gene is associated with reduced severity of postburn HTS. If this association is confirmed in an independent cohort, investigating the potential role of CSMD1 in wound healing may elucidate HTS pathophysiology.