title: 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.
abstract: BACKGROUND
  Polymorphisms in the serine protease inhibitor gene serine peptidase inhibitor Kazal type 5 (SPINK5) and the serine protease kallikrein-related peptidase 7 gene (KLK7) appear to confer risk to eczema in some cohorts, but these findings have not been widely replicated. These genes encode proteins thought to be involved in the regulation of posttranslation processing of filaggrin (FLG), the strongest identified genetic risk factor for eczema to date.
  
  
  OBJECTIVE
  We sought to clarify the individual risk of eczema conferred by the SPINK5 polymorphism rs2303067 (Glu420Lys) and a previously described insertion in the 3' untranslated region of KLK7 and to examine potential epistatic effects between these variants and FLG mutations.
  
  
  METHODS
  Initially, we examined the effects of these polymorphisms and FLG in 486 unrelated patients from a German family-based study, an additional 287 German patients, and 418 unrelated Irish/English patients with eczema (n for 3 genes studied = 1191 vs 4544 control subjects). We then additionally studied the SPINK5 polymorphism and FLG mutations in 1583 patients with eczema from the Avon Longitudinal Study of Parents and Children cohort (sample size for 2 genes studied = 2774 vs 10,607 control subjects).
  
  
  RESULTS
  No association was seen with the SPINK5 or KLK7 variants in the case-control analysis; however, a weaker effect was observed for the SPINK5 variant with maternal transmission in the family-based study. No interactions were seen between the polymorphisms in KLK7, SPINK5, and FLG.
  
  
  CONCLUSIONS
  The SPINK5 420LysSer mutation confers a risk of eczema when maternally inherited but is not a major eczema risk factor. The KLK7 insertion appears to confer no risk of eczema. We found no interaction between the SPINK5 risk allele or the putative KLK7 risk allele and FLG mutations.
authors.affiliation: Department of Dermatology and Allergy Biederstein, Technical University Munich, Munich, Germany. weidinger@lrz.tum.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Weidinger
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Baurecht
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagenpfeil
authors.forename: John
authors.initials: J
authors.lastname: Henderson
authors.forename: Natalija
authors.initials: N
authors.lastname: Novak
authors.forename: Aileen
authors.initials: A
authors.lastname: Sandilands
authors.forename: Huijia
authors.initials: H
authors.lastname: Chen
authors.forename: Elke
authors.initials: E
authors.lastname: Rodriguez
authors.forename: Grainne M
authors.initials: GM
authors.lastname: O'Regan
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Watson
authors.forename: Haihui
authors.initials: H
authors.lastname: Liao
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jonathan N W N
authors.initials: JN
authors.lastname: Barker
authors.forename: Michael
authors.initials: M
authors.lastname: Allen
authors.forename: Nick
authors.initials: N
authors.lastname: Reynolds
authors.forename: Simon
authors.initials: S
authors.lastname: Meggitt
authors.forename: Kate
authors.initials: K
authors.lastname: Northstone
authors.forename: George D
authors.initials: GD
authors.lastname: Smith
authors.forename: Carolin
authors.initials: C
authors.lastname: Strobl
authors.forename: Caroline
authors.initials: C
authors.lastname: Stahl
authors.forename: Thomas
authors.initials: T
authors.lastname: Kneib
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Thomas
authors.initials: T
authors.lastname: Bieber
authors.forename: Heidrun
authors.initials: H
authors.lastname: Behrendt
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Johannes
authors.initials: J
authors.lastname: Ring
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D004485:Eczema / Q000235:genetics*; D005260:Female; D000091344:Filaggrin Proteins; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D007610:Kallikreins / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; C082472:KLK7 protein, human; D007610:Kallikreins