Race and Melanocortin 1 Receptor Polymorphism R163Q Are Associated with Post-Burn Hypertrophic Scarring: A Prospective Cohort Study.
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ABSTRACT:
SUBMITTER: Sood RF
PROVIDER: S-EPMC4567912 | biostudies-literature | 2015 Oct
REPOSITORIES: biostudies-literature
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Project description:IntroductionAssociations between genetic variation and clinical conditions suggest that single nucleotide polymorphisms (SNPs) might correlate with postburn outcomes. COMT modulates catecholamine metabolism, and polymorphisms within the rs4680 allele result in variable enzyme activity. Catechol-amines are known to modulate the inflammatory process and may affect scar formation. The aim of this study was to determine whether variants in the rs4680 SNP of the COMT gene are associated with post-burn pruritus and scarring.MethodsAdult burn patients, admitted between 2007 and 2017, with deep partial-thickness burns or delayed healing provided blood samples for genotyp-ing and self-reported itch scores within 1 year of injury. Scarring was measured using the Vancouver Scar Scale (VSS). Itch scores ≥ 4 and VSS scores >7 were considered severe. Genomic deoxyribonucleic acid was genotyped for the rs4680 SNP using realtime polymerase chain reaction (PCR).ResultsMedian itch and VSS scores were highest for GG homozygotes and lowest for AA homozygotes. This difference was statistically significant for VSS score (P < 0.0001) and approached significance for itch (P = 0.052). After accounting for confounding variables, including race/ethnicity, age, sex, and burn size, the GG homozygotes demonstrated worse scarring (odds ratio 1.88, P = 0.005) compared to AG heterozygotes whereas the AA homozygotes trended towards a protective effect against scarring (odds ratio 0.71, P = 0.10). itch did not demonstrate a statistically significant difference between rs4680 genotype.ConclusionsOur analysis identifies a trend between COMT genotype with scarring, with rs4680 genetic variation constituting an independent risk factor for VSS score.
| S-EPMC8941635 | biostudies-literature
Project description: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.
| S-EPMC4752497 | biostudies-literature
Project description:Significance: Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) emanate from burn-injured tissue and enter systemic circulation. Locally and systemically, they activate pattern-recognition receptors, including toll-like receptors (TLRs), to stimulate cytokine secretion, which in the severest burns typically results in extreme systemic cytokine levels, a dysfunctioning immune system, infection, impaired healing, and excessive scarring. This system-wide disruption of homeostasis can advance to life-threatening, multiorgan dysfunction syndrome. Knowledge of DAMP- and PAMP-TLR signaling may lead to treatments that ameliorate local and systemic inflammation and reduce scarring and other burn injury sequela. Recent Advances: Many PAMPs and DAMPs, the TLRs they activate, and their downstream signaling molecules have been shown to contribute to local and systemic inflammation and tissue damage following burn injury. Critical Issues: Whether TLR-pathway-targeting treatments applied at different times postburn injury might improve scarring remains an open question. The evaluation of this question requires the use of appropriate preclinical and clinical burn models carried out until after mature scar has formed. Future Directions: After TLR-pathway-targeting treatments are evaluated in porcine burn wound models and their safety is demonstrated, they can be tested in proof-of-concept clinical burn wound models.
| S-EPMC5649422 | biostudies-literature
Project description:The physiological process of scarring is a common denominator of interest in a plethora of medical specialties. The molecular basis whereby this process results in pathological scarring for some individuals is poorly understood at present, with clues pointing towards individual predisposition for pathological scarring. Vitamin D and its subsequent pathway plays a key role in skin metabolism and homeostasis, with alterations in the level of vitamin D receptor (VDR) seen within pathological scars. The present study investigated the role of the rs2228570 polymorphism of VDR with regards to scar formation and evolution in a group of 71 female patients recovering from Caesarian section. Blood samples were taken at the time of surgery, and the follow-up was collected remotely at 3 and 6 months after surgery. The rs2228570 polymorphism was investigated using an RFLP-PCR protocol. The results demonstrated that the CC genotype, in combination with the Patient Observer Scar Assessment Scale (POSAS) and SCAR scores are associated with pathological scarring, with more studies being necessary to draw a firm conclusion.
| S-EPMC8987945 | biostudies-literature
Project description:Variation in human skin/hair pigmentation is due to varied amounts of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of eu- and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many mammals. We have sequenced the MC1R gene in 121 individuals sampled from world populations with an emphasis on Asian populations. We found variation at five nonsynonymous sites (resulting in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). Interestingly, the human consensus protein sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency (7%) in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. The MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon was sequenced to study the evolution of MC1R. The ancestral human MC1R sequence is identical to the human consensus protein sequence, while MC1R varies considerably among higher primates. A comparison of the rates of substitution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest. In addition, the nucleotide diversity at the MC1R locus is shown to be several times higher than the average nucleotide diversity in human populations, possibly due to diversifying selection.
| S-EPMC1460552 | biostudies-other
Project description:Progenitor Biological Bandages (PBB) have been continuously applied clinically in the Lausanne Burn Center for over two decades. Vast translational experience and hindsight have been gathered, specifically for cutaneous healing promotion of donor-site grafts and second-degree pediatric burns. PBBs constitute combined Advanced Therapy Medicinal Products, containing viable cultured allogeneic fetal dermal progenitor fibroblasts. Such constructs may partly favor repair and regeneration of functional cutaneous tissues by releasing cytokines and growth factors, potentially negating the need for subsequent skin grafting, while reducing the formation of hypertrophic scar tissues. This retrospective case-control study (2010-2018) of pediatric second-degree burn patients comprehensively compared two initial wound treatment options (i.e., PBBs versus Aquacel® Ag, applied during ten to twelve days post-trauma). Results confirmed clinical safety of PBBs with regard to morbidity, mortality, and overall complications. No difference was detected between groups for length of hospitalization or initial relative burn surface decreasing rates. Nevertheless, a trend was observed in younger patients treated with PBBs, requiring fewer corrective interventions or subsequent skin grafting. Importantly, significant improvements were observed in the PBB group regarding hypertrophic scarring (i.e., reduced number of scar complications and related corrective interventions). Such results establish evidence of clinical benefits yielded by the Swiss fetal progenitor cell transplantation program and favor further implementation of specific cell therapies in highly specialized regenerative medicine.
| S-EPMC7997469 | biostudies-literature
Project description:Hypertrophic skin scarring following dermal injury causes extreme pain and psychological trauma for patients. Unfortuately, we do not have effective treatments to prevent or reverse skin scarring. Using RNA and ATAC sequencing of mouse and human fibroblasts, we show that JUN expressing fibroblasts are responsible for skin scarring by regulating CD36 expression. In summary, we show that CD36 antagonism by represent a therapeutic target to overcome JUN hypertrophic skin scarring.
2021-06-22 | GSE178562 | GEO
Project description:BACKGROUND: At present pathogenic mechanisms of cancer cachexia are poorly understood. Previous evidence in animal models implicates the melanocortin-4 receptor gene (MC4R) in the development of cancer cachexia. In humans, MC4R mutations that lead to an impaired receptor function are associated with obesity; in contrast, the most frequent polymorphism (Val103Ile, rs2229616; heterozygote frequency approximately 2%) was shown to be negatively associated with obesity. We tested if cancer patients that are homo-/heterozygous for the Val103Ile polymorphism are more likely to develop cachexia and/or a loss of appetite than non-carriers of the 103Ile-allele. METHODS: BMI (body mass index in kg/m2) of 509 patients (295 males) with malignant neoplasms was determined; additionally patients were asked about premorbid/pretherapeutical changes of appetite and weight loss. Cachexia was defined as a weight loss of at least 5% prior to initiation of therapy; to fulfil this criterion this weight loss had to occur independently of other plausible reasons; in single cases weight loss was the initial reason for seeing a physician. The average age in years (+/- SD) was 59.0 +/- 14.5 (males: 58.8 +/- 14.0, females 59.2 +/- 14.0). Blood samples were taken for genotyping of the Val103Ile by PCR- RFLP. RESULTS: Most of the patients suffered from lymphoma, leukaemia and gastrointestinal tumours. 107 of the patients (21%) fulfilled our criteria for cancer cachexia. We did not detect association between the Val103Ile polymorphism and cancer cachexia. However, if we exploratively excluded the patients with early leucaemic stages, we detected a trend towards the opposite effect (p < 0.05); heterozygotes for the 103Ile-allele developed cancer cachexia less frequently in comparison to the rest of the study group. Changes of appetite were not associated with the 103Ile-allele carrier status (p > 0.39). CONCLUSION: Heterozygotes for the 103Ile-allele are not more prone to develop cancer cachexia than patients without this allele; possibly, Ile103 carriers might be more resistant to cancer cachexia in patients with solid tumors. Further studies of the melanocortinergic system in cachexia of patients with solid tumors are warranted.
| S-EPMC2359760 | biostudies-literature
Project description:Hypertrophic scars or keloid form as part of the wound healing reaction process, and its formation mechanism is complex and diverse, involving multi-stage synergistic action of multiple cells and factors. Adipose stem cells (ASCs) have become an emerging approach for the treatment of many diseases, including hypertrophic scarring or keloid, owing to their various advantages and potential. Herein, we analyzed the molecular mechanism of hypertrophic scar or keloid formation and explored the role and prospects of stem cell therapy, in the treatment of this condition.
| S-EPMC8770320 | biostudies-literature
Project description:BackgroundPatient survival after severe burn injury is largely determined by burn size. Modern developments in burn care have greatly improved survival and outcomes. However, no large analysis of outcomes in paediatric burn patients with present treatment regimens exists. This study was designed to identify the burn size associated with significant increases in morbidity and mortality in paediatric patients.MethodsWe undertook a single-centre prospective observational cohort study using clinical data for paediatric patients with burns of at least 30% of their total body surface area (TBSA). Patients were stratified by burn size in 10% increments, ranging from 30% to 100% TBSA, with a secondary assignment made according to the outcome of a receiver operating characteristic (ROC) analysis. Statistical analysis was done with Student's t test, ?(2) test, logistic regression, and ROC analysis, as appropriate, with significance set at p<0·05.Findings952 severely burned paediatric patients were admitted to the centre between 1998 and 2008. All groups were comparable in age (mean 7·3 [SD 5·3] years, ranging from 6·1 [5·1] years in the 30-39% TBSA group to 9·6 [5·4] years in the 90-100% TBSA group) and sex distribution (628 [66%] boys, ranging from 59% [73/123] in the 60-69% TBSA group to 82% [42/51] in the 90-100% TBSA group). 123 (13%) patients died (increasing from 3% [five of 180] in the 30-39% TBSA group to 55% [28/51] in the 90-100% TBSA group; p<0·0001), 154 (16%) developed multiorgan failure (increasing from 6% [ten] in the 30-39% TBSA group to 45% [23] in the 90-100% TBSA group; p<0·0001), and 89 (9%) had sepsis (increasing from 2% [three] in the 30-39% TBSA group to 26% [13] in the 90-100% TBSA group; p<0·0001). Burn size of 62% TBSA was a crucial threshold for mortality (odds ratio 10·07, 95% CI 5·56-18·22, p<0·0001).InterpretationWe established that, in a modern paediatric burn care setting, a burn size of roughly 60% TBSA is a crucial threshold for postburn morbidity and mortality. On the basis of these findings, we recommend that paediatric patients with greater than 60% TBSA burns be immediately transferred to a specialised burn centre. Furthermore, at the burn centre, patients should be treated with increased vigilance and improved therapies, in view of the increased risk of poor outcome associated with this burn size.FundingShriners Hospitals for Children, US National Institutes of Health, US National Institute on Disability and Rehabilitation Research, Institute for Translational Sciences, CFI Leaders Opportunity Fund, Physicians' Services Incorporated Foundation.
| S-EPMC3319312 | biostudies-literature