Comparative genomic hybridisation analysis of keloid tissue in Caucasians suggests possible involvement of HLA-DRB5 in disease pathogenesis

Abstract

Keloid disease (KD) is a common fibroproliferative disorder that can occur following cutaneous injury in genetically susceptible individuals. Familial predisposition, high prevalence in certain populations and occurrence in twins suggest a strong genetic component to KD. However, to date no single causative gene has been identified. Copy number variations (CNVs) in genes have been associated with several human diseases including common skin disorders. The objective of this study was, therefore to determine if CNVs in the human genome may contribute to the development of KD. Agilent SurePrint G3 one Million microarrays were used to detect DNA copy number differences in keloid scars of four Caucasian females and compared to commercial reference DNA samples. Subsequent validation was performed with quantitative polymerase chain reactions (qPCR) using 15 KD cases and 27 Caucasian controls. Further validation using a second cohort was carried out with an additional 11 Caucasian controls and 10 KD cases developed from minor skin puncture wounds (caused by acne, vaccination or chickenpox). HLA-DRB1*15 was typed using allele-specific primers in PCR. Five CNV regions located at chromosome (chr) 6p21.32, chr11q11, chr17q12, chr8p23.1, chr22q13.1, chr19p13.1 and chr2q14.3 were selected for validation with qPCR. When comparing controls to subgroups of KD, according to their cause of scarring, chr6p21.32 (primer design targetting HLA-DRB5) was significantly (P < 0.005) associated with KD developed from minor skin puncture wounds, which is further validated using a larger sample size (P < 0.001). The presence of HLA-DRB5 was associated with HLA-DRB1*15 status; 18 out of 19 individuals were positive for both HLA-DRB5 and HLA-DRB1*15 allele. In conclusion, these preliminary findings further support the possible contribution of the HLA genes in KD pathogenesis.

Copy number variations of &lt;italic&gt;HLA-DRB5&lt;/italic&gt; is associated with systemic lupus erythematosus risk in Chinese Han population

“…Here, we found that CNVS of HLA-DRB5 was associated with SLE disease susceptibility. A recent study has revealed the involvement of HLA-DRB5 CNVS in the development of Keloid disease through minor puncture wounds in Caucasians [17]. For the first time, we discovered that HLA-DRB5 CNVS was genetically associated with SLE in Han Chinese.…”

German S2k guidelines for the therapy of pathological scars (hypertrophic scars and keloids)

“…Due to familial tendency to develop keloids, for several years several genetic factors have been discussed (e.g. genes regulating apoptosis, mitogen‐activated protein kinase, TGF‐β signal cascade, interleukin‐6, plasminogen activator inhibitor‐1) [10].…”

Keloid incidence in Asian people and its comorbidity with other fibrosis-related diseases: a nationwide population-based study

“…In addition, the human leukocyte antigen (HLA) system has been demonstrated to be a crucial factor in keloid pathogenesis among various ethnic groups. Previous studies on Caucasians have indicated that a positive association exists between the HLA-DRB1*15 allele and keloid susceptibility [8], and that the HLA-DRB5 copy number is associated with keloid development at sites of minor puncture wounds [37]. In addition, the HLA-DQA and DQB alleles have been reported to be associated with keloid susceptibility in ethnic Chinese populations [28].…”