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

Stephan Weidinger; Hansjoerg Baurecht; Stefan Wagenpfeil; John Henderson; Natalija Novak; Aileen Sandilands; Huijia Chen; Elke Rodriguez; Grainne M. O'Regan; Rosemarie Watson; Haihui Liao; Yiwei Zhao; Jonathan N. W. N. Barker; Michael  Allen; Nick Reynolds; Simon Meggitt; Kate Northstone; George D. Smith; Carolin Strobl; Caroline Stahl; Thomas Kneib; Norman Klopp; Thomas Bieber; Heidrun Behrendt; Colin N. A. Palmer; H. -Erich Wichmann; Johannes Ring; Thomas Illig; W. H. Irwin McLean; Alan D. Irvine

doi:10.1016/j.jaci.2008.05.050

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

Stephan Weidinger, Hansjoerg Baurecht, Stefan Wagenpfeil, John Henderson, Natalija Novak, Aileen Sandilands, Huijia Chen, Elke Rodriguez, Grainne M. O'Regan, Rosemarie Watson, Haihui Liao, Yiwei Zhao, Jonathan N. W. N. Barker, Michael Allen, Nick Reynolds, Simon Meggitt, Kate Northstone, George D. Smith, Carolin Strobl, Caroline StahlThomas Kneib, Norman Klopp, Thomas Bieber, Heidrun Behrendt, Colin N. A. Palmer, H. -Erich Wichmann, Johannes Ring, Thomas Illig, W. H. Irwin McLean, Alan D. Irvine

Research output: Contribution to journal › Article › peer-review

71 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	560-568
Number of pages	9
Journal	Journal of Allergy and Clinical Immunology
Volume	122
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2008.05.050
Publication status	Published - Sept 2008

Keywords

eczema
atopy
skin barrier
stratum corneum
epistasis
CAUSE ICHTHYOSIS VULGARIS
OF-FUNCTION MUTATIONS
ATOPIC-DERMATITIS
NETHERTON-SYNDROME
FUNCTION VARIANTS
NORTHERN GERMANY
RARE MUTATIONS
SKIN BARRIER
EARLY-ONSET
ASSOCIATION

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Weidinger, S., Baurecht, H., Wagenpfeil, S., Henderson, J., Novak, N., Sandilands, A., Chen, H., Rodriguez, E., O'Regan, G. M., Watson, R., Liao, H., Zhao, Y., Barker, J. N. W. N., Allen, M., Reynolds, N., Meggitt, S., Northstone, K., Smith, G. D., Strobl, C., ... Irvine, A. D. (2008). 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, 122(3), 560-568. https://doi.org/10.1016/j.jaci.2008.05.050

Weidinger, Stephan ; Baurecht, Hansjoerg ; Wagenpfeil, Stefan et al. / 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. In: Journal of Allergy and Clinical Immunology. 2008 ; Vol. 122, No. 3. pp. 560-568.

@article{c6b27b16a1be4df8af8b583b1556b52f,

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 (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.",

keywords = "eczema, atopy, skin barrier, stratum corneum, epistasis, CAUSE ICHTHYOSIS VULGARIS, OF-FUNCTION MUTATIONS, ATOPIC-DERMATITIS, NETHERTON-SYNDROME, FUNCTION VARIANTS, NORTHERN GERMANY, RARE MUTATIONS, SKIN BARRIER, EARLY-ONSET, ASSOCIATION",

author = "Stephan Weidinger and Hansjoerg Baurecht and Stefan Wagenpfeil and John Henderson and Natalija Novak and Aileen Sandilands and Huijia Chen and Elke Rodriguez and O'Regan, {Grainne M.} and Rosemarie Watson and Haihui Liao and Yiwei Zhao and Barker, {Jonathan N. W. N.} and Michael Allen and Nick Reynolds and Simon Meggitt and Kate Northstone and Smith, {George D.} and Carolin Strobl and Caroline Stahl and Thomas Kneib and Norman Klopp and Thomas Bieber and Heidrun Behrendt and Palmer, {Colin N. A.} and Wichmann, {H. -Erich} and Johannes Ring and Thomas Illig and McLean, {W. H. Irwin} and Irvine, {Alan D.}",

year = "2008",

month = sep,

doi = "10.1016/j.jaci.2008.05.050",

language = "English",

volume = "122",

pages = "560--568",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier",

number = "3",

}

Weidinger, S, Baurecht, H, Wagenpfeil, S, Henderson, J, Novak, N, Sandilands, A, Chen, H, Rodriguez, E, O'Regan, GM, Watson, R, Liao, H, Zhao, Y, Barker, JNWN, Allen, M, Reynolds, N, Meggitt, S, Northstone, K, Smith, GD, Strobl, C, Stahl, C, Kneib, T, Klopp, N, Bieber, T, Behrendt, H, Palmer, CNA, Wichmann, H-E, Ring, J, Illig, T, McLean, WHI & Irvine, AD 2008, '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, vol. 122, no. 3, pp. 560-568. https://doi.org/10.1016/j.jaci.2008.05.050

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, Stephan; Baurecht, Hansjoerg; Wagenpfeil, Stefan et al.
In: Journal of Allergy and Clinical Immunology, Vol. 122, No. 3, 09.2008, p. 560-568.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Weidinger, Stephan

AU - Baurecht, Hansjoerg

AU - Wagenpfeil, Stefan

AU - Henderson, John

AU - Novak, Natalija

AU - Sandilands, Aileen

AU - Chen, Huijia

AU - Rodriguez, Elke

AU - O'Regan, Grainne M.

AU - Watson, Rosemarie

AU - Liao, Haihui

AU - Zhao, Yiwei

AU - Barker, Jonathan N. W. N.

AU - Allen, Michael

AU - Reynolds, Nick

AU - Meggitt, Simon

AU - Northstone, Kate

AU - Smith, George D.

AU - Strobl, Carolin

AU - Stahl, Caroline

AU - Kneib, Thomas

AU - Klopp, Norman

AU - Bieber, Thomas

AU - Behrendt, Heidrun

AU - Palmer, Colin N. A.

AU - Wichmann, H. -Erich

AU - Ring, Johannes

AU - Illig, Thomas

AU - McLean, W. H. Irwin

AU - Irvine, Alan D.

PY - 2008/9

Y1 - 2008/9

N2 - 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.

AB - 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.

KW - eczema

KW - atopy

KW - skin barrier

KW - stratum corneum

KW - epistasis

KW - CAUSE ICHTHYOSIS VULGARIS

KW - OF-FUNCTION MUTATIONS

KW - ATOPIC-DERMATITIS

KW - NETHERTON-SYNDROME

KW - FUNCTION VARIANTS

KW - NORTHERN GERMANY

KW - RARE MUTATIONS

KW - SKIN BARRIER

KW - EARLY-ONSET

KW - ASSOCIATION

U2 - 10.1016/j.jaci.2008.05.050

DO - 10.1016/j.jaci.2008.05.050

M3 - Article

SN - 0091-6749

VL - 122

SP - 560

EP - 568

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 3

ER -

Weidinger S, Baurecht H, Wagenpfeil S, Henderson J, Novak N, Sandilands A et al. 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. 2008 Sept;122(3):560-568. doi: 10.1016/j.jaci.2008.05.050