Associations between Keloid Severity and Single-Nucleotide Polymorphisms: Importance of rs8032158 as a Biomarker of Keloid Severity

Ogawa, Rei; Watanabe, Atsushi; Naing, Banyar Than; Sasaki, Motoko; Fujita, Atsushi; Akaishi, Satoshi; Hyakusoku, Hiko; Shimada, Takashi

doi:10.1038/jid.2014.71

Cited by 59 publications

(54 citation statements)

References 8 publications

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“…The genetic causes of pathological scar development may be single nucleotide polymorphisms (SNPs): a genome-wide association study showed that four SNP loci in three chromosomal regions associate significantly with keloid development in the Japanese population [12]. Moreover, our study showed that one SNP (rs8032158) associates significantly with keloid clinical severity [13]. The rs8032158 SNP is located in intron 5 of the NEDD4 (Neuronal precursor cell-Expressed Developmentally Downregulated 4) gene on chromosome 15.…”

Section: Genetic Risk Factors That Increase Dermal Inflammationmentioning

confidence: 87%

Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis

Ogawa

2017

IJMS

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632

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Keloids and hypertrophic scars are caused by cutaneous injury and irritation, including trauma, insect bite, burn, surgery, vaccination, skin piercing, acne, folliculitis, chicken pox, and herpes zoster infection. Notably, superficial injuries that do not reach the reticular dermis never cause keloidal and hypertrophic scarring. This suggests that these pathological scars are due to injury to this skin layer and the subsequent aberrant wound healing therein. The latter is characterized by continuous and histologically localized inflammation. As a result, the reticular layer of keloids and hypertrophic scars contains inflammatory cells, increased numbers of fibroblasts, newly formed blood vessels, and collagen deposits. Moreover, proinflammatory factors, such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α are upregulated in keloid tissues, which suggests that, in patients with keloids, proinflammatory genes in the skin are sensitive to trauma. This may promote chronic inflammation, which in turn may cause the invasive growth of keloids. In addition, the upregulation of proinflammatory factors in pathological scars suggests that, rather than being skin tumors, keloids and hypertrophic scars are inflammatory disorders of skin, specifically inflammatory disorders of the reticular dermis. Various external and internal post-wounding stimuli may promote reticular inflammation. The nature of these stimuli most likely shapes the characteristics, quantity, and course of keloids and hypertrophic scars. Specifically, it is likely that the intensity, frequency, and duration of these stimuli determine how quickly the scars appear, the direction and speed of growth, and the intensity of symptoms. These proinflammatory stimuli include a variety of local, systemic, and genetic factors. These observations together suggest that the clinical differences between keloids and hypertrophic scars merely reflect differences in the intensity, frequency, and duration of the inflammation of the reticular dermis. At present, physicians cannot (or at least find it very difficult to) control systemic and genetic risk factors of keloids and hypertrophic scars. However, they can use a number of treatment modalities that all, interestingly, act by reducing inflammation. They include corticosteroid injection/tape/ointment, radiotherapy, cryotherapy, compression therapy, stabilization therapy, 5-fluorouracil (5-FU) therapy, and surgical methods that reduce skin tension.

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Section: Genetic Risk Factors That Increase Dermal Inflammationmentioning

confidence: 87%

Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis

Ogawa

2017

IJMS

Self Cite

632

616

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“…(2010) found four single-nucleotide polymorphisms in three chromosomal regions in Japanese patients with keloids. One of these four loci, rs8032158 SNP in chromosome 15, located in intron 5 of the neuronal precursor cell-expressed developmentally down-regulated 4 ( NEDD4 ) gene, is thought to affect keloid severity [8,9]. A study of admixture mapping identified potentially common genetic elements among a cohort of Black, Japanese and Chinese patients on chromosome 15q21.2–22.3, within which NEDD4 resides [10].…”

Section: The Cascade Of Fibrotic Eventsmentioning

confidence: 99%

Keloids: The paradigm of skin fibrosis — Pathomechanisms and treatment

et al. 2016

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Keloids, fibroproliferative dermal tumors with effusive accumulation of extracellular matrix (ECM) components, particularly collagen, result from excessive expression of growth factors and cytokines. The etiology of keloids is unknown but they occur after dermal injury in genetically susceptible individuals, and they cause both physical and psychological distress for the affected individuals. Several treatment methods for keloids exist, including the combination therapy of surgical incision followed by intralesional steroid therapy, however, they have high recurrence rate regardless of the current treatment method. Improved understanding of the pathomechanisms leading to keloid formation will hopefully identify pathways that serve as specific targets to improve therapy for this devastating, currently intractable, disorder.

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“…An increasing body of evidence indicated that genetic factors play an important role in the occurrence of KS (Nakashima et al, 2010;Shih and Bayat, 2010;Zhu et al, 2013). Several genetic markers have been identified to be associated with the diagnosis, prognosis, and development of KS (Wu et al, 2012;Yu et al, 2013;Ogawa et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Association of interleukin-6 gene polymorphisms and circulating levels with keloid scars in a Chinese Han population

Zhu¹,

Li²,

Li³

et al. 2017

Genet. Mol. Res.

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ABSTRACT. The aim of the present study is to explore the effect of IL-6 gene polymorphisms on the development of keloid scar (KS) in the Chinese Han population. Genotyping of IL-6 was performed by the polymerase chain reaction (PCR), followed by restriction fragment length polymorphism assays (PCR-RFLP). Serum level of IL-6 was measured using enzyme-linked immunosorbent assay (ELISA). Results indicated that when the IL-6 -572 CC homozygote genotype was used as the reference group, the GG genotype was found to be associated with a significantly increased risk of KS (GG vs CC: OR = 2.097, 95%CI = 1.100-3.995, P = 0.025). When the IL-6 -572 C allele was used as the reference group, the G allele was found to be associated with significantly increased risk of KS (G vs C: OR = 1.317, 95%CI = 1.002-1.730, P = 0.048). Furthermore, we observed a marked 2 X.J. Zhu et al. Genetics and Molecular Research 16 (2): gmr16029110 increase in serum IL-6 levels in KS patients with GG genotypes when compared to KS patients harboring the CC genotype. In conclusion, our results suggest that IL-6 gene polymorphism was associated with keloid scars in the southeastern Chinese Han population.

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Associations between Keloid Severity and Single-Nucleotide Polymorphisms: Importance of rs8032158 as a Biomarker of Keloid Severity

Cited by 59 publications

References 8 publications

Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis

Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis

Keloids: The paradigm of skin fibrosis — Pathomechanisms and treatment

Association of interleukin-6 gene polymorphisms and circulating levels with keloid scars in a Chinese Han population

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