Association Study On Susceptibility Genes Of Keloid In Chinese Han Population

Background Keloid is a benign, proliferative dermal collagen growth that represent apathologic wound-healing response to skin injury, which is unique to humans. It ischaracterised by an excessive accumulation of extracellular matrix and especially byoverabundant collagen formation, which has escaped the boundaries of the originalwound to invade the surrounding normal skin and causes aesthetically displeasing andfunctionally disabling, even leading to the patients to suffer from both physical andpsychological distress. Keloid often occur sporadically, although it may affects in allraces, a common high incidence usually occur among the African-Americans and Asians.The risk of developing keloids is approximately15times higher in dark-skinnedindividuals compared with light-skinned individuals. The etiology of keloids isuncertain, however, the genetic factors had been considered that may contributes tokeloid formation. The genetically susceptible individuals of keloid is a familialcondition. So far, a definite mode of inheritance has not yet been established for keloid.Therefore, exploring the genetic pathogenesis and determining the susceptibility gene ofKeloid have been very positive guidance for establishing the basis of treatment of keloid.Several studies suggested the disease inheritance mode of keloid was autosomaldominant and autosomal recessive through different investigation of keloid pedigrees,Most scholars tend to think that keloids as an autosomal dominant inheritance, but is not a simple Mendelian monogenic inheritance.Some studies suggested the diseases wasdominant mode of inheritance with incomplete penetrance, and individuals carried thedominant allele does not necessarily express the phenotype.Recently, the genetic studies for keloid were more concentrated on the keloid relatedgene expression, which is more concentrated on the p53gene, FAS gene, c-myc, c-fos,ras gene and bcl-2family, and the ICE family of apoptotic genes, as well as HLA andcytokine TGF-beta, IL, but got no unified conclusion.The completion of the Human Genome Project (HGP) and the International HaplotypeMap Project (the HapMap) provides important biological information and analyticaltools for investigating complex disease susceptibility genes. The rapid development ofhigh-throughput genotyping technology and typing costs continue to decrease,genome-wide association analysis for seeking complex disease susceptibility genes(genome-wide association study--GWAS) study was availiable. GWAS is to use theprinciple of correlation analysis by comparing the difference between the allelefrequencies of the cases and controls,screening single nucleotide polymorphism (singlenucleotide polymorphism,SNP) which associated with disease traits from the geneticvariation at the genome-wide level. According to its position in the genome and linkagedisequilibrium, researchers speculated possible susceptibility genes, and verified therelationship between these genes and diseas. So far, only one article about keloid GWASresearch in the Japanese population was published in Nature Genetics in2010,whichidentified four SNPs rs873549, rs940187, rs1511412and rs8032158weresignificantly associated with keloid susceptibility in Japanese population. Of whichrs8032158is located in the NEDD4gene on chromosome15q21.3. Because there aresignificant racial and population differences in the incidence of keloid disease, weaimed to validate these genetic factors for keloid in Chinese population.Our studyshould lay a foundation for further elucidating the pathogenesis of keloids in ChineseHan population. Objective1. A large scale replication study was performed based on the result ofGWAS of keloid in the Japanese population to explore genetic susceptibility to Keloidof Chinese Han. Twelve SNPs were selected to genotype in Chinese Han cohorts (total714cases and2944controls).2. To study the NEDD4-1gene expression in keloid tissue.Methods1. Genotyped these SNPs in Chinese Han pouplation using SequenomMassarray system. Association analyses were performed using logistic regression withgender or sample cohorts as a covariate.2. Using RT-PCR and Western Blot method, to test the expression of NEDD4-1gene inkeloid, hyperplastic scar and normal skin tissues.Results1．One SNP was located in15q21.3were replicated and showed highsignificance with keloid in replication Chinese Han (P <0.05)(rs2271289: OR=0.6564,P=1.02E-11). Rs2271289was located in NEDD4gene.2．Two SNPs was located in1q41were replicated and showed high significance withkeloid in Chinese Han population (P <0.05)(rs873549, OR=2.05,95%CI:1.819-2.305, P=3.03E-33, Pcombined=9.09E-33; rs1442440, OR=0.56,95%CI:0.49-0.64, P=9.58E-18, Pcombined=2.87E-17, respectively).3. The expression of NEDD4-1gene has no obvious difference (P>0.05) in keloid,hyperplastic scar and normal skin.Conclusions1. Three SNPs were replicated and showed high significance with keloidin Chinese Han (P <0.05). Our study should shed new insight into the genetic basis ofkeloid in Chinese population, which not only indicated the existence of common genetic pathogenesis for keloid shared by Chinese Han and Japanese populations, but also existthe genetic heterogeneity between keloid patients in Chinese Han cohorts and Japanesein a certain degree. Further study focused on1q41and NEDD4should advance ourunderstanding on the pathogenesis of keloid.2. NEDD4-1gene can express in human pathological scar tissue and normal skintissues. It need to be further research.