1.15.1 Keloid prone individuals show a genetic predisposition to keloid formation Individuals with an inherited tendency to form keloids and those expressing atypical genetic features during dermal wound healing are at high risk of keloid formation. Although there are no clearly defined genetic loci indicating risk for keloids, there is strong support for the genetic susceptibility to keloid formation.
17 1.15.2 Predominance in Black ethnic groups
A genetic predisposition to keloid formation is supported by the finding that keloids are 5-15 times more predominant in ethnic groups with darker pigmented skin than Whites (80). It is estimated that 15-20% of Blacks (African-American, African-Caribbean and Africans), Hispanics and Oriental individuals are inflicted with keloidal growths (80). These darker skinned ethnic groups were reported to be 15 times more likely to develop keloids and this predilection was attributed to the enhanced action of melanocyte stimulating hormone (MSH) in the highly pigmented skin. The following findings support this assumption:
• Highly pigmented individuals of various races are more prone to keloid formation
• Melanocyte numbers are high at the main locations of keloid formation
• During puberty and pregnancy increased hormone production by the pituitary gland stimulates melanocyte proliferation and synthetic activity. This increased activity is associated with increased pigmentation and the incidence of keloids is higher during this period.
• The positive response of keloids to treatment with steroids is thought to be associated with the inhibition of MSH production. This assumption is supported by association between hypopigmentation, steroid injection and MSH suppression (58).
1.15.3 Familial inheritance
The existence of keloids within families and in twins suggests that genetic elements contribute to keloid formation. A report effectively illustrating the inherited familial propensity to form keloids, presented the cases of 3 European Caucasian brothers who developed keloids as teenagers following surgery, ear piercing and chicken pox scarring in the eldest to the youngest respectively (81).
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Another study showed that 96 of the 341 family members displayed keloid formation; 36 were male and 60 were female and the age of infliction ranged from early childhood to late adulthood (82). The severity of keloids in the affected members varied from small earlobe keloids to very severe large keloids affecting different areas of the body (82). In twins keloid formation was found in 4 sets of identical twins and occurred simultaneously in a pair of twins at their vaccination sites (40, 82). The modes of inheritance in families and twins were found to be autosomal dominant or recessive, but there is greater evidence for the autosomal dominant mode. This type of inheritance in keloid patients displayed incomplete penetrance and genetic expression (83). In addition, familial inheritance studies have reported that aggressive keloid disease and multiple-site keloid development was associated with a positive family history and black African ethnic origin (84).
Other factors favouring a genetic predisposition in keloid formation are the higher rate of keloid development in people with type A blood and the following tissue compatibility antigens:
HLA B14, Bw16, B21, Bw35, DR5, DRB1*, DQA1, DQB1 [20-23]. Keloids are often concomitant with many common genetic diseases of connective tissue including scleroderma, progeria, Ehlers-Danlos syndrome or Rubinstein-Tabi syndrome [24].
1.15.4 Genetic polymorphisms in keloid tissue
In analysing genetic polymorphisms in keloid tissue, chromosome loci that positively correlated with keloid formation were: 2q23, 7p11 and 14q22-q23 (72, 80, 85). Comparative analysis of gene expression in fibroblasts of keloids and reactive scars revealed differences in 500 genes of various metabolic and cellular pathways. Genes that were abundantly expressed in keloid fibroblasts were genes for insulin-like growth factor binding protein (IGFBP) and connective tissue growth factor (CTGF) while genes that exhibited the most distinct differences were genes
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for nerve growth factor β (NGF-β), cyclin D2 , receptor genes for thrombin and thrombin-like growth factor (F2R and F2RL2 respectively) as well as for TGF-β receptor I (72, 85).
Many genes encoding second messengers in intracellular pathways regulating cell growth and differentiation were also excessively expressed in keloids. These included dishevelled-associated activator of morphogenesis 1 – activator from the Wnt protein family (DAAM1), JAG-1, encoding second messengers of the Notch signalling pathway as well as nucleus factor of transcription 1B (NF1B) (72, 85). Excessive expression of genes encoding extracellular matrix components were COL1A1 gene encoding type I collagen, ELN gene encoding elastin and genes encoding collagen types: V, VI, X, XV and XVI and also periostin, thrombospondin 4, lumican, mimecan, versican, syndecan-2 and decorin (72, 85). Another gene that showed excessive expression in keloid fibroblasts was the gene for 311 protein but, its function is not fully understood. However, it is thought to be an oncogene as neoplasms of the central nervous system (astrocytomas) show an excessive expression of this protein (72).
1.15.5 Keloid fibroblasts show reduced expression of many genes
There is diminished expression of many genes in keloid fibroblasts mainly, genes for inhibitors in intracellular signalling pathway of the Wnt protein family (DKK1, DKK3 and SFRP1 and 2), and for inhibitors in the cyclin signalling pathway (CDKN1C, CDKN3) (72). Another group of genes showing decreased expression in keloids included: interleukin 1 receptor (IL1R) gene and interleukin 1 controlled genes, encoding chemokines and their ligands (CXCL1, CXCL12 and CXCL14) (72). Also, there was reduced expression of genes encoding interleukin-7 (IL-7) and interleukin-8 (IL-8). Exceedingly diminished expression was reported for genes encoding metalloproteinases (extracellular matrix proteins degrading enzymes); these included matrix metalloproteinase 3 (MMP3) and membrane metalloendopeptidase (MME).
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Other genes exhibiting significantly decreased expression were the receptor II encoding gene for TGF-β type 2 and a family of HOX genes (72). Genes of this family regulate precise differentiation of germ layer cells during the early stage of embryogenesis and many of these genes regulate fibroblast proliferation in adults. Research shows that specific “silencing” of some of these genes is associated with the development of adenocarcinoma in the lung (72).