The Association Between SNPs Of NEDD4and The Susceptibility Of Keloid

【Background】Keloids is a common disease in plastic surgery, but its pathogenesis has not beenclearly stated yet and effective treatment has not been found either. Recently, the feature ofgenetic susceptibility of keloids becomes a new spotlight, and brings new ideas to explainthe pathogenesis of the disease. Meanwhile single nucleotide polymorphisms (SNP) iswidely studied in keloid disease as a third generation of genetic marker. Japanesereseachers found a SNP in the NEDD4gene that was associated with the geneticsusceptibility of keloids. At the same time, Nedd4protein which encode by NEDD4wasfound that it has been related to many molecules and signaling pathways which are alsoassociated with keloid. We mainly aim at the undiscovered SNPs in NEDD4gene, andwish to find a breakthrough to explain the pathogenesis of keloids. 【Objective】Based on the statistical analysis of samples collected from clinical keloids patients,we aim to discuss the association between the taget SNPs in NEDD4(ubiquitin ligase E3)and the genetic predisposition of keloids, which in turn could provide a new thought totackle some of the pathogenetic problem of keloids.【Methods】Firstly, under the supervision of experienced plastic surgeons that are familiar withkeloids, we continuously collected blood samples (from November2011to March2012)of the keloids Han patients (case group) as well as normal people (control group) from thedepartment of plastic surgery in Xijing hospital and then extracted the DNA from theblood samples. The standard to recruit patients to keloids group is that the scar mustextrude the epidermis and clearly grow beyond the scope of the original wound, theduration of the keloids must be more than1year. With the people recruited into the controlgroup, we must pay attention to the trauma and family history of them, the one withkeloids, proliferative scar or family history of keloids would not be included into controlgroup. Secondly, based on the SNPs’ information from the website of NCBI, we finallychose6SNPs on NEDD4: rs2303579, rs2303580, rs10518830, rs8032158, rs4774833andrs17819300. rs2303579and rs2303580are located in the exon missense region;rs10518830, rs4774833and rs17819300are located in the promoter region; rs8032158islocated in the intron area. Thirdly, under the support of MassArray MALDI-TOF MStechnology platform from Sequenom(United States), we analysed target SNPs’ genotypiesof the50samples of patients with keloid and the other52samples of normal people. Atlast, we analysed the data statistically to find the relationship between the taget SNPs andkeloids.【Results】1. rs2303579and rs2303580are relevant to the genetic predisposition of keloids.The statistic analysis showed that, in rs2303579, compared to the TT genotype, the people who carry the CT genotype (OR=1.56) and CC genotype (OR=2.50) are morelikely to have keloid disease (OR＞1，P=0.005); and the different distribution of C allelebetween case and control group showed the association with the genetic predisposition ofkeloids (P=0.001). In rs2303580, compared with CC genotype, the people who carry CTgenotype (OR=1.38) and the TT genotype (OR=2.50) are going to have a higher risk tosuffer from keloids (OR＞1，P=0.006); and the different distribution of T allele betweencase and control group showed the association with the genetic predisposition of keloids(P=0.001). In the additive model analysis, we observed that the C allele (OR=2.49, P=0.002) in rs2303579and the T allele (OR=2.44, P=0.003) in rs2303580are allcoincident with the assumption of additive model (P＜0.05), and are all dangerous factorsin the onset of keloid disease (OR＞1). In addition, in linkage disequilibrium analysis, thisstudy found that rs2303579and rs2303580are in a state of linkage disequilibrium (D’=1.000, r2=0979). On the haplotype analysis of rs2303579and rs2303580, the resultsshowed that when the allele C is in rs2303579and the allele T is in rs2303580, this kind ofhaplotype has a higher risk to suffer from the keloids (OR=2.72, P=0.0008); whereaswhen the situation is reversed, the haplotype is in a much lower possibility to suffer fromkeloids (OR=0.37, P=0.0008).2. rs10518830is relevant to the genetic predisposition of keloids.In rs10518830, compared with the people who carry GG genotype, the ones whocarry the CC genotype are more likely to have keloids (OR=2.44, P=0.013); and thedifferent distribution of C allele between case and control group showed the associationwith the genetic predisposition of keloids (P=0.001). In the additive model, C allele onrs10518830is accord with the assumption of additive model, and belongs to a dangerousfactor in the onset of keloids (OR=2.46, P=0.005).3. rs8032158is relevant to the genetic predisposition of keloids.In rs8032158, compared with the people who carry TT genotype, the ones who carrythe CT genotype (OR=2.02) and CC genotype (OR=2.28) are more likely to havekeloids (OR＞1, P=0.048); and the different distribution of C allele between case andcontrol group showed the association with the genetic predisposition of keloids (P= 0.012). In the additive model, C allele is accord with the assumption of additive model,and belongs to a dangerous factor in the onset of keloids(OR=2.01, P=0.02).4. rs4774833and rs17819300are not relevant with keloids.Through the analysis of our study, rs4774833(P=0.406) and rs17819300(P=0.669) were not associated with the genetic susceptibility of keloid (P＞0.05).【Conclusion】On the basis of case-control study, we found new functional SNPs on NEDD4genewhich are associated with the genetic predisposition of keloids. The rs2303579andrs2303580in the missense are relevant with keloid. Because these two loci are able tochange the downstream amino acid they encode, they could probably participate in thepathogenesis of keloid. The rs10518830which is located in the promoter region is alsoassociated with the genetic predisposition of keloids, and it would probably regulate theexpression level of NEDD4and participate the onset of keloids. rs8032158located in theintrons of NEDD4also has relevance with the genetic predisposition of keloids, but theresearches on the intron area of gene have been scarce, the function of rs8032158in theonset of keloid needs to be further studied. In conclusion, the newly found functionalSNPs on NEDD4which are associated with keloids are expected to partly explain thepathogenesis of keloid and provide some new ideas of the prevention and treatment ofkeloids.