title: Association screening in the Epidermal Differentiation Complex (EDC) identifies an SPRR3 repeat number variant as a risk factor for eczema.
abstract: The genetically determined impairment of the skin barrier is a primary cause of eczema. As numerous genes essential for an intact epidermis reside within the epidermal differentiation complex (EDC), we screened the National Center for Biotechnology Information (NCBI) database for putatively functional polymorphisms in the EDC genes and tested them for association with eczema. We identified 20 polymorphisms with predicted major impact on protein function. Of these, 4 were validated in 94 eczema patients: a nonsense mutation in FLG2 (rs12568784), a stop codon mutation in LCE1D (rs41268500), a 24-bp deletion in SPRR3 (rs28989168), and a frameshift mutation in S100A3 (rs11390146). The minor allele frequencies were 15.1, 6.1, 47.2, and 0.4%, respectively. Association testing of the validated polymorphisms in 555 eczema patients and 375 controls identified a significant effect of rs28989168 (SPRR3) on eczema. The association was replicated in another 1,314 cases and 1,322 controls, yielding an overall odds ratio of 1.30 (95% confidence interval 1.12-1.51; P=0.00067) for a dominant mode of inheritance. Small proline-rich proteins (SPRRs) are crossbridging proteins in the cornified cell envelope (CE), which provides the main barrier function of stratified squamous epithelia. The SPRR3 variant associated with eczema carried an extra 24-bp repeat in the central domain, which may alter the physical properties of the CE.
authors.affiliation: Pediatric Pneumology and Immunology and Experimental and Clinical Research Center, Charité, Berlin, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Marenholz
authors.forename: Vladimir A Gimenez
authors.initials: VA
authors.lastname: Rivera
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.forename: Anja
authors.initials: A
authors.lastname: Bauerfeind
authors.forename: Min-Ae
authors.initials: MA
authors.lastname: Lee-Kirsch
authors.forename: Andrzej
authors.initials: A
authors.lastname: Ciechanowicz
authors.forename: Michael
authors.initials: M
authors.lastname: Kurek
authors.forename: Tereza
authors.initials: T
authors.lastname: Piskackova
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Lee
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D018389:Codon, Nonsense; D018388:Codon, Terminator / Q000235:genetics; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics*; D042622:DNA Repeat Expansion / Q000235:genetics*; D030541:Databases, Genetic; D004485:Eczema / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D004817:Epidermis / Q000473:pathology / Q000502:physiology*; D000091344:Filaggrin Proteins; D016368:Frameshift Mutation; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D055233:Cornified Envelope Proline-Rich Proteins; C000717250:FLG2 protein, human; D000091344:Filaggrin Proteins; C112254:SPRR3 protein, human