Genetic Association Between an AACC Insertion in the 3′UTR of the Stratum Corneum Chymotryptic Enzyme Gene and Atopic Dermatitis

Vasilopoulos, Yiannis; Cork, Michael J.; Murphy, Ruth; Williams, HC; Robinson, Darren; Duff, Gordon W.; Ward, Simon; Tazi-Ahnini, Rachid

doi:10.1111/j.0022-202x.2004.22708.x

Cited by 150 publications

(115 citation statements)

References 25 publications

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“…KLK7 encodes the protease SSCE, which has been suggested to be involved in the complex proteolytic processing of filaggrin. An insertion in the 3'UTR of the KLK7 gene possibly influencing SSCE activity has been reported to be associated with eczema in a UK case-control study, but this association has not been replicated so far 14,35 . SPINK5 is the gene defective in Netherton syndrome and encodes the serine proteinase inhibitor LEKTI, which has been implicated in the regulation of SSCE activity.…”

Section: Discussionmentioning

confidence: 98%

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Weidinger

Baurecht

Wagenpfeil

et al. 2008

Journal of Allergy and Clinical Immunology

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Section: Discussionmentioning

confidence: 98%

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Weidinger

Baurecht

Wagenpfeil

et al. 2008

Journal of Allergy and Clinical Immunology

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“…32 Conversely, a British case-control study described putative gain-of-function polymorphisms (AACCAACC vs AACC) in the 3′ region of KLK7,which encodes the SP SC chymotryptic enzyme or KLK7. 35 Moreover, transgenic mice forced to express human KLK7 display a severe AD-like dermatosis. 36 Yet the incidence of both these polymorphisms is quite high in unaffected healthy patients, 37-39 and it is not yet known whether either of these single nucleotide polymorphisms alters expression of its respective protein product or products.…”

Section: Inherited Barrier Abnormalities In Atopic Dermatitismentioning

confidence: 99%

Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms

Elias

Hatano

Williams

2008

Journal of Allergy and Clinical Immunology

417

364

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Until quite recently, the pathogenesis of atopic dermatitis (AD) has been attributed to primary abnormalities of the immune system. Intensive study revealed the key roles played by T H 1/T H 2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes AD. Accordingly, current therapy has been largely directed toward ameliorating T H 2-mediated inflammation and pruritus. In this review we will assess emerging evidence that inflammation in AD results from inherited and acquired insults to the barrier and the therapeutic implications of this paradigm. KeywordsAntimicrobial peptides; atopic dermatitis; barrier function; barrier repair; cytokines; filaggrin; pH; psychologic stress; Staphylococcus aureus; serine proteases; T H 2 cells Until recently, atopic dermatitis (AD) has been viewed largely as a disease of immunologic etiology. 1-5 Yet, the epidermis generates a set of protective/defensive functions (Table I) mediated by its unique differentiation end product, the stratum corneum (SC). 6,7 These functions include the permeability barrier, which retards transcutaneous evaporative water loss, allowing survival in a potentially desiccating external environment, and an antimicrobial barrier, which simultaneously encourages colonization by nonpathogenic ''normal'' flora while resisting growth of microbial pathogens. 8 Although both a defective epidermal permeability 9-13 and a propensity to secondary infection 14,15 are well-recognized features of AD, these abnormalities have been widely assumed to reflect downstream consequences of a primary immunologic abnormality (the historical inside-outside view of AD pathogenesis). We and others have long proposed that the permeability barrier abnormality inADis not merely an epiphenomenon but rather the ''driver'' of disease activity (ie, the reverse outside-inside view of disease pathogenesis) 16-19 for the following reasons: (1) the extent of the permeability barrier abnormality parallels the severity of the disease phenotype in AD 9,10,12 ; (2) both clinically uninvolved skin sites and skin cleared of inflammation for as long as 5 years continue to display significant barrier abnormalities 10,13 ; (3) emollient therapy comprises effective ancillary therapy 20 ; and most importantly, (4) specific replacement therapy, which targets the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript prominent lipid abnormalities that account for the barrier abnormality in AD (see below), corrects both the permeability barrier abnormality and comprises effective anti-inflammatory therapy for AD (see the Therapeutic implications section below). BROAD BARRIER FAILURE IN ADLike permeability barrier dysfunction, the antimicrobial barrier is also compromised in patients with AD. Colonization by Staphylococcus aureus is a common feature of AD, 21 and although colonization is highest on lesional skin, colony counts often are high on the clinically no...

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“…A significant genetic association was found between the rare AACCAACC variant of the KLK7 gene and AD in British. (141) …”

Section: (A-2)-klk ( or Scce) Genementioning

confidence: 99%

Molecular Genetic of Atopic Dermatitis : An Update

Al‐Shobaili

Ahmed

Alnomair

et al. 2016

IJHS

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Atopic dermatitis (AD) is a chronic multifactorial inflammatory skin disease. The pathogenesis of AD remains unclear, but the disease results from dysfunctions of skin barrier and immune response, where both genetic and environmental factors play a key role. Recent studies demonstrate the substantial evidences that show a strong genetic association with AD. As for example, AD patients have a positive family history and have a concordance rate in twins. Moreover, several candidate genes have now been suspected that play a central role in the genetic background of AD. In last decade advanced procedures similar to genome-wide association (GWA) and single nucleotide polymorphism (SNP) have been applied on different population and now it has been clarified that AD is significantly associated with genes of innate/adaptive immune systems, human leukocyte antigens (HLA), cytokines, chemokines, drug-metabolizing genes or various other genes. In this review, we will highlight the recent advancements in the molecular genetics of AD, especially on possible functional relevance of genetic variants discovered to date.

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Genetic Association Between an AACC Insertion in the 3′UTR of the Stratum Corneum Chymotryptic Enzyme Gene and Atopic Dermatitis

Cited by 150 publications

References 25 publications

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms

Molecular Genetic of Atopic Dermatitis : An Update

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