Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Missense Variant in MAPK Inactivator PTPN5 is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring
Ravi F. Sood, MD, Anne M. Hocking, PhD, Lara A. Muffley, BS, Maricar Ga, BS, Shari Honari, RN, BSN, Reiner P. Alexander, MD, MSc, Nicole S. Gibran, MD.
UW Medicine Regional Burn Center, Seattle, WA, USA.

PURPOSE: Hypertrophic scarring (HTS) is a common and often devastating sequela of burn injury, resulting in disfigurement, chronic pain, intractable pruritis, and functional impairment that can severely decrease quality of life. Although it is thought to result from an exaggerated inflammatory response to injury, its precise pathogenesis is unknown, limiting the development of effective therapies. Risk of HTS is known to depend on race, suggesting a genetic mechanism. However, the genetic determinants of HTS have not been identified. Mitogen-activated protein-kinases (MAPKs) are key mediators of inflammation, and inhibition of p38 MAPK decreases fibroproliferative scarring in a porcine model. The purpose of this study was to test whether single-nucleotide polymorphisms (SNPs) in MAPK-pathway genes would be associated with HTS severity following burn injury.
METHODS: Adults (age 18 or older) admitted to our institution with at least deep-partial-thickness burns were prospectively enrolled from 2007 to 2014. Blood was drawn for genomic DNA isolation, and scarring was evaluated after hospital discharge using the Vancouver Scar Scale (VSS). Genotyping was performed using Illumina HumanCoreExome BeadChips. All SNPs corresponding to genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) MAPK pathway were included in the analysis after filtering based on standard minor-allele-frequency (MAF)-, missingness-, and Hardy-Weinberg-equilibrium thresholds. Principal component analysis was performed to assess and subsequently adjust for population substructure. Association testing was performed for each SNP using all four VSS sub-scores jointly in an inverted regression model including age, sex, number of operations, burn size, and the first two principal components as adjustment covariates. To control for multiple testing, p-values were adjusted by the Bonferroni method.
RESULTS: Of 538 subjects with complete genotype- and clinical data, 71% were male and 76% were white, with median age of 40 years and median burn size of 6.0% total body surface area. Median follow-up was 6.4 months. Mean VSS sub-scores were as follows: height, 1.2 (range: 0-3); pliability, 2.3 (range: 0-5); pigmentation, 1.8 (range: 0-2); and vascularity, 2.0 (range: 0-3). After filtering, 2200 SNPs in 219 genes were included in the analysis. Regression analysis revealed a single SNP, rs56234898, that was significantly associated with decreased HTS severity (raw p = 1.3×10-6, adjusted p = 0.0029). This variant is a missense mutation in an exon region of the protein tyrosine phosphatase, non-receptor type 5 (PTPN5) gene, which encodes a phosphatase that inactivates MAPKs. The minor allele frequency of rs56234898 in our study subjects was 0.015.
CONCLUSION: We report rs56234898 as the first genetic variant to be associated with decreased severity of post-burn hypertrophic scarring. This polymorphism results in an amino-acid substitution in PTPN5, a specific inactivator of MAPKs including p38 MAPK. Thus, it may attenuate hypertrophic-scar formation by decreasing MAPK signaling through PTPN5 gain of function. Although rs56234898 is a rare variant, understanding the role of PTPN5 in hypertrophic-scar pathophysiology may aid in the development of new therapies.


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