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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:122

Article

Weidinger, Stephan^1,2,3  Baurecht, Hansjoerg^2,3,4  Wagenpfeil, Stefan^4,5  Henderson, John⁶  Novak, Natalija⁷  Sandilands, Aileen⁸  Chen, Huijia⁸  Rodriguez, Elke^2,3  O'Regan, Grainne M.⁹  Watson, Rosemarie⁹  Liao, Haihui⁸  Zhao, Yiwei⁸  Barker, Jonathan N. W. N.¹⁰  Allen, Michael¹⁰  Reynolds, Nick¹¹  Meggitt, Simon¹¹  Northstone, Kate¹²  Smith, George D.¹³  Strobl, Carolin¹⁴  Stahl, Caroline^1,4  Kneib, Thomas¹⁴  Klopp, Norman¹⁵  Bieber, Thomas⁶  Behrendt, Heidrun^2,3  Palmer, Colin N. A.¹⁶  Wichmann, H. -Erich¹⁵  Ring, Johannes^1,5  Illig, Thomas¹⁵  McLean, W. H. Irwin⁸  Irvine, Alan D.^9,17 

[1] Tech Univ Munich, Dept Dermatol & Allergy Biederstein, D-80802 Munich, Germany

[2] Tech Univ Munich, German Res Ctr Environm Hlth, Helmholtz Zentrum Munich, Div Environm Dermatol & Allergy, D-80802 Munich, Germany

[3] Tech Univ Munich, ZAUM Ctr Allergy & Environm, D-80802 Munich, Germany

[4] Tech Univ Munich, IMSE, D-80802 Munich, Germany

[5] Tech Univ Munich, GSISH, D-80802 Munich, Germany

[6] Univ Bristol, Dept Community Based Med, Bristol BS8 1TH, Avon, England

[7] Univ Bonn, Dept Dermatol & Allergy, D-5300 Bonn, Germany

[8] Univ Dundee, Epithelial Genet Grp, Human Genet Unit, Div Pathol & Neurosci, Dundee DD1 4HN, Scotland

[9] Our Ladys Childrens Hosp, Dept Pediat Dermatol, Dublin, Ireland

[10] Guys Hosp, St Johns Inst Dermatol, London, England

[11] Univ Newcastle, Dept Dermatol, Callaghan, NSW 2308, Australia

[12] Univ Bristol, Dept Med Sociol, Bristol BS8 1TH, Avon, England

[13] Univ Bristol, MRC, Ctr Causal Analyses Translat Epidemiol, Bristol BS8 1TH, Avon, England

[14] Univ Munich, Dept Stat, Munich, Germany

[15] German Res Ctr Environm Hlth, Helmholtz Zentrum Munich, Dept Epidemiol, Munich, Germany

[16] Univ Dundee, Biomed Res Ctr, Populat Phamacogenet Grp, Dundee DD1 4HN, Scotland

[17] Univ Dublin Trinity Coll, Dept Clin Med, Dublin 2, Ireland

关键词: eczema;    atopy;    skin barrier;    stratum corneum;    epistasis;   

DOI  :  10.1016/j.jaci.2008.05.050

来源: Elsevier

【 摘 要 】

Background: Polymorphisms in the serine protease inhibitor gene serine peptidase inhibitor Kazal type 5 (SPINK-5) 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. Objectives: 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. Conclusion: 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.

【 授权许可】

Free