Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring.
Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring.
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DOI：
10.1371/journal.pone.0149206
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gibran NS
中科院分区：
文献类型：
--
作者：
Sood RF;Arbabi S;Honari S;Gibran NS
肥厚性瘢痕形成（HTS）被假设具有遗传机制，但其遗传决定因素在很大程度上是未知的。丝裂原活化蛋白激酶（MAPK）途径是炎症信号的重要介质，实验证据表明MAPK参与HTS的形成。我们假设mapk通路基因的单核苷酸多态性（snp）与烧伤后HTS的严重程度有关。我们分析了烧伤后HTS的前瞻性队列全基因组关联研究数据。我们纳入了入院的深部分厚度烧伤患者，他们提供血液进行基因分型，并至少进行了一次温哥华疤痕量表（VSS）评估。在调整了HTS风险因素和人群分层后，我们在联合回归模型中测试了mapk通路基因snp与4个VSS变量的关联。除了个体snp分析外，我们还进行了基于基因的关联测试。我们的研究人群包括538名成年人（中位年龄40岁），他们主要是白人（76%）男性（71%），2007-2014年因小到中度烧伤（中位烧伤面积占体表总面积的6%）入院。在测试的2146个snp中，PTPN5基因的一个罕见错义变异（rs56234898；次要等位基因频率为1.5%）与烧伤后HTS严重程度的降低显著相关（P = 1.3×10−6）。在基于基因的分析中，PTPN5 （P = 1.2×10−5）和BDNF （P = 9.5×10−4）与HTS严重程度有显著相关性。我们报道PTPN5是一个与HTS严重程度相关的新基因位点。PTPN5是一种在神经元中表达的MAPK抑制剂，提示神经营养因子和神经炎症信号在HTS病理生理中的潜在作用。
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. 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. 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. 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.