Association Of HLA Allele And Haplotype With Keloids In Chinese Hans

Background Keloids are benign, proliferative dermal collagen growths that represent a pathological wound-healing response to skin injury in susceptible persons. They are thick scar tissue of human skin, which have escaped the boundaries of the original wound to invade the surrounding normal skin. Although keloids are common among the darker pigmented races, but the epidemiology of keloids in general is variable. The rported incidence of keloids in the general population ranges from a high of 16% among the adults in Zaire to a low of 0.09% in England. A number of hypotheses such as high skin tension, hypoxia, endocrine dysfunction, fatty acid, autoimmune and genetic hypotheses have been proposed in the past to explain the keloid phonomanon. Keloids are hypothesized to be an immune disease with genetic predisposition and an environmental trigger.HLA genes on human chromosome 6 code for the major histocompatibility complex (MHC) proteins that are important in presentation of antigens and self recognition by immune cells. HLA is now recognized as a major contributing factor for susceptibility to autoimmune diseases. Some HLA alleles were reported association with keloids, however, the literature concerning HLA associations with keloid is often in disagreement, with discrepancies seen in the allelic distribution for different ethnic groups. There is limited data on HLA haplotype in keloid. No report has been published about HLA alleles and haplotype associated with keloid in Chinese Hans.Objective To investigate the distribution of HLA-A, B, C, DQA1, DQB1 and DRB1 allele and haplotype in Chinese Hans keloids patients, and to explore the correlation of the HLA allele and haplotype profile with single site and multiple site, severity and family history.Methods The polymerase chain reaction–sequence-specific primer (PCR-SSP) method was used to study the distribution of HLA-A, B, C, DQA1, DQB1 and DRB1 alleles in 192 patients with keloids and 273 healthy controls in Chinese Hans. The method of case-control study was used to analyze the correlation of the HLA allele and haplotype profile with single site and multiple site, severity and family history.Results1. The distribution of HLA-A, B, C, DQA1, DQB1 and DRB1 alleles and haplotypes were analyzed in Chinese Hans normal people. The A1 (38.10%), B40 (16.67%), Cw*0304(12.09%), DQA1*0301 (18.85%), DQB1*0602 (23.61%), HLA-DRB1* 07(13.00%), A2-DQA1*0104 (5.16%) were respectively the most frequent ones in every gene and all haplotypes.2. The correlation of the HLA allele and haplotype profile with keloids. The frequencies of HLA-A3 (Pc<10-7), -A25 (OR=2.54, Pc=0.0111 ), -B07 (OR=3.40,Pc=0.0080), -Cw*0802 (OR=2.52, Pc=0.0004), -DQA1*0104 (OR=2.13, Pc=0.0063), -DQB1*0501 (OR=14.42, Pc<10-7 )和-DQB1*0503 (OR=6.09, Pc<10-7 ), HLA-DRB* 15 (OR=2.10, Pc=0.0247) were significantly higher in patients than in controls. The 10 two-locus haplotypes and 2 extended haplotypes were found as high-risk ones in developing keloids in this study.3. The correlation of the HLA allele and haplotype profile with single site and multiple site of keloids. The frequencies of HLA-A * 03, HLA-DQB1*0501 and DQB1*0503 was increased not only in single-site group of patients(Pc <10-7), but also in multiple-sites grou(Pc <10-5), whereas the frequency of HLA-A*01 was decreased in these two subgroups compared with control group (all Pc <10-7 ).The significant decreased frequencies of HLA-DQA1*0501 (OR = 0.43, Pc = 0.0234) and DQB1*0201 (OR = 0.23, Pc = 0.0003) in single site group were observed. We found that the frequencies of HLA-B*07 , Cw*0802 and HLA-DQA1*0104 (Pc<0.05 ) were significantly higher only in single site group than in controls, whereas the frequency of HLA-A*25 and DRB1* 15 were increased only in multiple-sites group (Pc<10-5).4. The correlation of the HLA allele and haplotype profile with severity of keloids. We analyzed the distribution of HLA alleles in the different severity of patients versus controls. HLA-A*01, A*03, DQB1*0501 and DQB1*0503 were associated with all subgroup of patients regardless of severity of keloids (all pc<0.05).The frequencies of HLA-A*25 (Pc = 0.0027),Cw*0802 (Pc = 0.0007),DQA1*0104 (Pc = 0.0090)were increased only in the moderate-severity group, whereas HLA-DRB1*15 was increased not only in the moderate-severity group (Pc=0.02652) but also in severe group (Pc= 0.0455). The frequencies of DQB1*0201 (Pc = 0.0018) and DQB1*0402 (Pc = 0.0270) were decreased in moderate group. 5 haplotypes HLA-A*25-B*07, B*07-DRB1*15, DQA1*0104-DQB1*0503, B*07-Cw*0802-DQB1*0501 and Cw*0802- DQB1* 0501- DRB1*15 only were found to be associated with moderate keloids compared with the controls, whereas the frequencies of haplotypes B*07-DQB1*0501, DQA1* 0104- DQB1*0501 and DQB1*0503-DRB1*15 haplotypes were significantly increased in all subgroups of keloid patients. No haplotype was only associated with severe keloids. 5. The correlation of the HLA allele and haplotype profile with a positive family history of keloids. The frequencies of A*03-B*07, A*03-Cw*0802, A*25-Cw*0802, B*07- Cw*0802, DQA1*0104-DQB1*0501, DQA1*0104-DQB1*0503 and DQB1* 0503- DRB1*15 were obviously increased in both negative family history and a positive family history, whereas the frequency of A*25-B*07 and B*07-DRB1*15 were obviously increased only in patients with a positive family history. There were B*07-DQB1*0501, B*07-Cw*0802-DQB1*0501 and Cw*0802-DQB1 *0501-DRB1* 15 only associated with patients without a positive family history.The significant increase the frequency of HLA-A*03, HLA-DQB1*0501 and DQB1*0503 were in these two subgroups compared with the control group, whereas DQB1*0201 were decreased.The frequencies of HLA-A*25, B*07 and Cw*0802 and DQA1*0104 were increased in subgroup without a positive family history. Whereas the significant increase in the frequency of HLA-DRB* 15 was in subgroup with a positive family history.Conclusion1. This study provides the database of HLA-A, B, C, DQA1, DQB1 and DRB1 alleles and haplotypes in Chinese Hans normal people.2. We first studied HLA alleles and haplotypes association with keloids patients in Chinese Hans.The HLA-A3, -A25, -B07, -Cw*0802, -DQA1*0104, -DQB1*0501 and -DQB1*0503, HLA-DRB1* 15 may be markers for general susceptibility to keloids. The 10 two-locus haplotypes and 2 extended haplotype were found as high-risk ones in developing keloids in this study.3. The study showed a detailed account of the HLA correlation with different phenotypes. The different phenotypes of keloids may have different genetic backgrounds.4. The results of the study provide information for researching association of HLA with keloids and seaching for susceptibility gene further.