γ- Secretase Expression And TNFA-308 Gene Polymorphism Abnormality Acne Lesions In Acne Vulgaris Analysis And Correlation Of Meta

BackgroundsAcne inversa (AI, Hidradenitis suppurativa,Follicular occlusion triad) is a chronic inflammatory skin disease that presents with comedones, painful nodules, abscesses, and sinus tracts in apocrine gland-bearing areas. Longstanding disease can result in fibrosis, dermal contractures, significant scarring, formation of fistulae, and rarely malignant transformation to squamous cell carcinoma.AI affects most commonly the axillae, submammary folds, abdominal fold, groin, buttocks, and neck. AI typically occurs after puberty and can be either familial or sporadic. Familial AI usually shows an autosomal dominant inheritance pattern.The pathogenesis is obscure, but suggested contributory factors include a genetic predisposition, immunologic abnormality,smoking,obesity and androgens.y-Secretase is an intramembranous protease complex capable of cleaving in excess of30type-I transmembrane proteins including amyloid precursor protein, Notch receptors, CD44,N-cadherin, and E-cadherin. The complex is composed of four hydrophobic proteins, presenilin, presenilin enhancer-2, nicastrin,and anterior pharynx defective-1, encoded by PS-1/PS-2, PSEN-2,NCT, and APH-la/APH-lb, respectively. Presenilin can be encoded by PS-1or PS-2and anterior pharynx defective-1can be encoded by APH-1A or APH-1B, but only one of each can be present in any one y-secretase complex, and thus at least six differenty-secretase variants exist and these may be tissue-or cell-specific.In our previous study,we collected samples from six Han Chinese families with features of AI, and identified a frameshift mutation in PS-1in one family, a frameshift mutation in PSEN-2in two families, nonsense mutation,frameshift mutation and splicing mutation in NCT.These mutations highlighted y-secretase to have an integral role in AI. Basic questions, such as the expression of the y-secretase subunits in human skin, need to be addressed.Objectives(1) To verify the differential expressions of PS-1, PS-2, PSEN-2, NCT and APH-la between AI lesional skin tissues and normal skin tissues.(2) To localize the sites of differential expressions of PS-1, PS-2, PSEN-2and NCT between AI lesional skin tissues and normal skin tissues. Methods(1) The total protein lysates were obtained from AI lesional skin tissues and normal skin tissues and were analysed by Western bloting to detect the expressions of PS-1, PS-2, PSEN-2, NCT and APH-la.(2) Immunohistochemistry (IHC) was used to localize the sites of differential expressions of PS-1, PS-2, PSEN-2and NCT between AI lesional skin tissues and normal skin tissues.Results(1) Low expression of PS-2protein was found in sweat glands and epidermis of AI lesional skin tissues(sweat glands:t=-11.145, p=0.000<0.05; epidermis:t=-3.051, p=0.038<0.05).Expreesion of NCT protein was reduced in hair follicle and epidermis of AI lesional skin tissues (hair follicle:t=2.594, p=0.08<0.1; epidermis:t=-2.376, p=0.098<0.1)(2) No expression of NCT protein was observed in two AI lesional skin tissues (HS3, HS4) and one normal skin tissues (FVD5).(3)No expression of APH-la protein was noticed in two normal skin tissue (IVD4,IVD5)Conclusions(1) Low expression of PS-2in sweat glands and epidermis is likely to play a role in the pathogenesis of AI. Likewise, low expression of NCT in hair follicle and epidermis may also play a role in the pathogenesis of AI. In contrast, no expression of NCT, as well as APH-la, might not act independently in causing the disease.(2)γ-secretase appears to be able to subtly affect hair follicle and sweat glands in the pathogenesis of AI. BackgroundsAcne vulgaris is a chronic disorder of the pilosebaceous apparatus.The cause of the disease is unknown, but suggested contributory factors include hormone, an increase sebum secretion, Propionibacterium acnes, abnormal keratinocyte function and inflammation.Upon the activation of pattern recognition receptors, a rapid signaling cascade is initiated in the cytoplasm of the keratinocytes, leading to the increased expression of downstream target genes, which include genes encoding the cytokines TNF-α and interleukin-1(IL-1). The TNFA gene encoding the TNF-α cytokine is located on the short arm of chromosome6(6p21.3) in the major histocompatibility class Ⅲ region, which is characteristic of a high degree of genetic polymorphism. Different types of polymorphisms exist in the TNFA promoter, including SNPs and microsatellites, whereas the coding region is highly conserved The cytokine TNF-α is a key molecule in various biologic processes,and its misregulation may have deleterious effects on the host organism. The SNPs in the promoter region can play a role in the allele-specific regulation of gene expression and are often reported to act as protective or disease-predisposing factors in the development of inflammatory and infectious diseases and certain types of cancers.ObjectiveFor the past few years, gene polymorphisms of acne vulgaris were frequently investigated. However, since the currently published studies only referred to a modest sample size and unified ethnicity, which might not achieve a reliable conclusion, proposing that a meta-analysis is needed to pool and analyze the current data. To date, there have been6articles concerning the role of TNFA promoter SNPs in the pathogenesis of acne vulgaris. The TNFA-308G>A polymorphism was common in all of them, but the conclusions were different. The aim of this meta-analysis is to make precise estimate regarding associations between TNFA-308polymorphisms and acne vulgaris.MethodsBased on an extensive literature search to identify all case-control studies of relevant subjects, we conducted a meta-analysis to assess the association between TNFA-308G/A polymorphisms and susceptibility to acne vulgaris. We also performed subgroup analyses targeting ethnicity.ResultsAmong studies investigating such association6were identified to be eligible, including801patients and909controls. No significant association was observed in all genotypes in overall populations, but analysis with stratification by ethnicity indicated that the TNFA-308A allele in comparison with the G allele, was associated with an increased risk of acne vulgaris in Caucasian and Mongoloid Mixed (Trukese) individuals (OR=4.14,95%CI=2.25-7.61) and Mongoloid individuals (OR=2.61,95%CI=1.57-4.33). Similar results were obtained when the AA+AG genotype was compared with the GG genotype (OR=4.70,95%CI=2.43-9.09) in Caucasian and Mongoloid Mixed (Trukese) individuals and Mongoloid individuals (OR=2.55,95%CI=1.44-4.51) except Caucasian individuals.ConclusionThe results of this meta-analysis indicate that the TNFA-308A allele may be an important risk factor for acne vulgaris in Caucasian and Mongoloid Mixed (Trukese) individuals and Mongoloid individuals, but it is not likely to confer susceptibility to acne vulgaris in Caucasian individuals.