| Scar is the inevitable outcome in the process of wound repair in human body, and also is the general designation of post-traumatic appearance shape and histopathological changes of the skin tissue. But the unrestricted growth of scar will lead appearance destruction and functional disorder and bring the patient the physical and psychological damage. Hyperplastic scar and keloid which are called pathological scar are the serious form of the scar. So far, there is no authoritative interpretation of the pathomechanism and criterion of treatment for the pathological scar, especially for the keloid. Although keloid often occurs sporadically, there appear racial differences and genetic predisposition, it affects the human in all races. The proportion of familial keloid is not high, but it is so important in the study of the etiology of keloid. In previous studies of the genetic inheritance of the family keloid, the researcher discovered part of inheritance regularity and found many of the susceptibility gene loci in keloid patients from different areas and ethnic groups through genetic research techniques such as genome-wide association, gene chip technology etc. The studies had revealed numerous genes that may be associated with keloid, such as rs980504、rs1866744、p53, human leukocyte antigen(HLA), series of TGF-β, SMAD etc and conducted intensive research of their mechanism and expression product. However, due to the diversity and complexity of the keloid, the mechanism of keloid is not completely clear. There are a large number of patients with pathological scar in Han Chinese population, and number of scholars had verified the existence of partial susceptibility loci in Han Chinese patients. Regrettably, gene mutation sites detected from keloid of Han population are rare. We find four cases of keloid pedigrees through our clinical work and take a comprehensive clinical investigation on them. Subsequently, we detect some single nucleotide polymorphisms and other genetic characteristics gene variant from one keloid pedigrees through whole genome re-sequencing. To find out the clear role of gene variant in the formation of keloid, we verify part of the SNPs which associated with keloid in the DNA of patients with keloids and Hyperplastic scars.PartⅠ Data collection and genetic survey on Han Chinesekeloid familiesObjective:To study the clinical and genetic characteristics of keloid through investigating on four Han Chinese pedigrees.Methods:Collecting the pedigree information and clinical data from Han Chinese keloid pedigrees which consist of 22 patients of 127 members, and then constructing the charts of these pedigrees according to the datum. And analyze the genetic model and summarize the clinical features of the disease in the families through genetic methods.Results:Four Han Chinese keloid pedigrees were discovered. The three pedigree spans are 3 generations and one is 4 generations. Incidence of KD in the consanguinity family member is 20.6%,and 18.3% in male KD, 23.4% in female. Incidence of anterior chest KD is 40.9%. The inheritance pattern observed in these four Han Chinese keloid pedigrees is consistent with an autosomal dominant inheritance with incomplete penetrance, and its incompletepenetrance is 12%.Conclusion:The pattern of inheritance observed in these four Han Chinese keloid pedigrees is similar with previous reports and no gender differences in the incidence of disease, but differences in pathogenic site. Pedigree investigation helps to reveal the genetic characteristics of keloid.Part Ⅱ DNA extraction and whole-genome sequencing on onecase of Han familial keloidsObjective:To analyze pathogenic mutations information of keloid pedigrees through whole genome re-sequencing.Methods:Collecting information and clinical data of keloid pedigrees and constructing charts of these pedigrees. The DNA were extracted from 5 peripheral venous samples of the same pedigree including four keloid and one normal sample to sequence the whole genome.Results:27 disease-associated SNPs,9 INDEL,2SVs and 15 CNVs were screened out. Variations were associated to a total of 51 genes and 19 genes were selected by the GO annotation similarity and pathway analyses.Conclusion:The inheritance pattern observed in this Han Chinese keloid pedigrees is consistent with an autosomal dominant inheritance with incomplete penetrance, and the new disease-associated genes filtrated through the WGS will provide a new direction for KD research.Part Ⅲ Detection and analysis of expression of 4 SNPs in Keloidand Hyperplastic scars in Chinese Han PopulationObjective:To verify genotype of four new SNPs associated with family keloid and the impact on the Keloid and Hyperplastic scar.Methods:We selected 4 SNPs(based on the whole genome re-sequencing we has done) for replication in DNA samples of 71 KDs and 50 HSs by using PCR-Massarray system.Results:We found significant association evidence at rs181924090, P= 0.0075; rs183178644, P=0.0151 and rs151091483, P=0.0073. But at rs141156594, there was no significant association between KD and HS(P=0.7893).Conclusion:rs181924090(11p15.5, SIRT3), rs151091483(17p13.1, MYH8) and rs183178644(6p25.3, HUS1B) are new potential SNPs and genes associated with KD and HS, especially closely related with tumor behaviors as KD has and contracture character as HS has. While rs141156594(18q22.2, RTTN) is a new SNPs involving in early abnormal proliferation of scar and the ECM formation in wound healing. |
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