Polymorphisms in SPINK5 are not associated with asthma in a Dutch population

doi:10.1016/j.jaci.2004.12.013

Journal of Allergy and Clinical Immunology

Volume 115, Issue 3, March 2005, Pages 486-492

https://doi.org/10.1016/j.jaci.2004.12.013 Get rights and content

Background

Asthma and allergic phenotypes are complex genetic diseases with known linkage to chromosome 5q. This region has many candidate genes, including serine protease inhibitor Kazal type 5 (SPINK5), which has been associated with asthma and atopic dermatitis in family-based studies of children with atopic dermatitis.

Objective

We sought to investigate whether single nucleotide polymorphisms in SPINK5 are associated with asthma, atopic phenotypes, and atopic dermatitis.

Methods

We investigated whether single nucleotide polymorphisms in SPINK5 (ie, −785 A/G, Asn368Ser, and Lys420Glu) are associated with asthma, atopic phenotypes, and atopic dermatitis in 200 families ascertained by a proband with asthma (nonaffected spouses served as a matched control population) and an independent set of 252 trios with asthma.

Results

We found no association with asthma, atopic phenotypes, and atopic dermatitis after correction for multiple testing.

Conclusion

The negative results in this study suggest that SPINK5 is not associated with asthma or atopic phenotypes in individuals ascertained by a proband with asthma. This is consistent with the finding that SPINK5 is not expressed in the lung. Because our patients were ascertained for asthma, a role of SPINK5 in atopic dermatitis cannot be excluded.

Section snippets

Study populations

Between 1963 and 1975, patients with symptomatic asthma were referred to Beatrixoord, a local asthma center in the northern part of the Netherlands, for clinical evaluation and optimization of asthma treatment. Two hundred of these asthmatic patients participated between 1991 and 1999 in a family study on the genetics of asthma, together with their spouses, children, children's spouses, available grandchildren and their spouses, and available great-grandchildren. All individuals have been

Results

A total of 200 asthmatic probands and their spouses from the families and 252 probands from the trios were evaluated. Classical trios consisting of proband and both parents were analyzed (69.4% [n = 175]). The clinical characteristics of both the cases and control subjects of the families and the trios are outlined in Table II. The Frisian asthmatic patients were younger than the probands from the families. In addition, FEV₁ was higher in the Frisian patients.

Allele frequencies of the SNPs (ie,

Discussion

This study suggests that the polymorphisms of the SPINK5 gene we genotyped do not contribute to susceptibility to asthma and atopic phenotypes in the Dutch population. In 2 independent populations, both ascertained by a proband with asthma, we found one significant association between the A allele of the −785 SNP and specific IgE to Der p 1 (P = .04). However, because 3 SNPs and 7 phenotypes had been analyzed, we performed a multiple testing correction. Correcting for 21 tests would, however, be

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However, the mutation C-T at locus +1312 was not associated with either resistant or susceptible stock (p > 0.05). In the previous studies, the polymorphism of kazal-type serine protease inhibitor was reported to associate with various diseases like asthma, alcoholic pancreatitis, and atopic dermatitis in human [28–33]. In oyster, the polymorphism of SPI and its association with Dermo disease were also recorded [34].
Serine protease inhibitors (SPIs) play a crucial role in regulation of both host and bacterial serine protease. They are classified into several protein families, where Kazal-type inhibitors are one of families with multi-domain. In the present study, the polymorphism of AiSPI from Bay scallop Argopecten irradians was found to be associated with disease resistance of bay scallop against Listonella anguillarum. Nine single nucleotide polymorphisms (SNPs) were identified in the exon region of AiSPI, where five SNPs were non-synonymous mutation. Three of these mutations were located in “kazal-like 3”domain, two SNP loci positioned at +536, +1312 were selected for further association studies. For the locus +536, the genotype frequency of A/G in the resistant stock (12.8%) was significantly lower (p < 0.05) than that in the susceptible stock (35.1%), while, the genotype A/A in the resistant stock (87.2%) was significantly higher in comparison with susceptible stock (64.9%) (p < 0.05). The G allele frequencies were 6.4% and 17.6% in resistant stock and susceptible stock, respectively, and χ²-test revealed a significant difference in the frequency distribution between the two stocks (p < 0.05). But there was no significant association between the mutation C-T at locus +1312 with either resistant or susceptible group (p > 0.05). The genotype frequencies of T/T, T/C, C/C at locus +1312 were 94.6%, 2.7% and 2.7% respectively in the susceptible stock, while 100%, 0% and 0% respectively in the resistant stock. The amino acid change for the mutation at locus +536 A-G was from asparagine to serine, and the predicted homology model of this amino acid variation could affect its function as well as the structural integrity of the domain. In vitro elastase inhibition assay of the protein variants at locus +536 was conducted to explicate the effect of SNP. The increasing concentration of protein (0 mmol/L– 2.93 mmol/L) was incubated with 80 nmol/L elastase where the residual enzyme activity values for rAiSPI (N) with A variant and rAiSPI (S) with G variant were started to reduce from 0.40 to 0.215 and 0.435 to 0.356, respectively. The elastase inhibition ability of rAiSPI (N) variant was significantly higher than that of rAiSPI (S) (p < 0.01). The results suggested that the mutation at locus +536A/A significantly associated with disease resistance of bay scallop would shed light for selective breeding program.
Inhibition of transcription factor specificity protein 1 alters the gene expression profile of keratinocytes leading to upregulation of kallikrein-related peptidases and thymic stromal lymphopoietin
2011, Journal of Investigative Dermatology
Citation Excerpt :
Briot et al. (2009) have recently demonstrated that hyperactivity of KLK5 in lymphoepithelial Kazal-type 5 serine protease inhibitor-deficient keratinocytes of patients with NS has a key role in causing atopic skin lesions, thus highlighting the clinical significance of enhanced epidermal serine protease activity in the pathogenesis of NS. The reports of SPINK5 mutations in NS have attracted several groups to investigate the association of SPINK5 gene variants in AD (Walley et al., 2001; Kato et al., 2003; Nishio et al., 2003; Kabesch et al., 2004; Moffatt, 2004; Folster-Holst et al., 2005; Jongepier et al., 2005; Hubiche et al., 2007). However, their results were contradictory, suggesting that SPINK5 genetic variants only partially account for genetic predisposition to AD.
Transcription factor specificity protein 1 (Sp1) is involved in diverse cellular functions. We recently found that Sp1 was significantly decreased in skin biopsy samples obtained from patients with atopic dermatitis (AD) and had an even greater reduction in AD patients with a history of eczema herpeticum. In the current study, we sought to better understand the role of Sp1 in skin biological processes by using a small-interfering RNA (siRNA) technique to knock down Sp1 gene expression in normal human keratinocytes (NHKs) and investigated the genome-wide gene expression profiling of Sp1-silenced NHKs. The gene arrays revealed that 53 genes had greater than 3-fold changes in the expression in Sp1-silenced NHKs as compared with scrambled siRNA-silenced cells. Strikingly, six kallikrein (KLK)-related peptidase genes, namely KLK5, KLK6, KLK7, KLK8, KLK10, and KLK12, were upregulated in NHKs following Sp1 silencing. Functionally, protease activity was significantly enhanced in Sp1-silenced keratinocytes as compared with scrambled siRNA-silenced keratinocytes. Moreover, thymic stromal lymphopoietin (TSLP), an epithelial-derived T_H2-promoting cytokine, was induced in Sp1-silenced keratinocytes because of elevated KLK activity. These results indicate that Sp1 expression deficiency leads to abnormally increased KLK protease activity in keratinocytes and may contribute to T_H2 immune responses in the skin by inducing TSLP.
Genetics of asthma and copd
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This chapter sets out the current knowledge focusing on the heritability of asthma and chronic obstructive pulmonary disease (COPD) and the genes found by positional cloning and association studies. It also focuses on particular genes to provide insight into the current knowledge on genetic approaches to understanding diseases like asthma and COPD. It has been known for centuries that asthma clusters in families (familial aggregation). For COPD, a role for genetic factors has been less obvious, because cigarette smoking is such a major environmental risk factor. A large number of single-nucleotide polymorphisms (SNPs) in the promoters and coding regions of a wide range of candidate genes have been examined for genetic association in asthma. There are now over 500 studies that have examined polymorphisms in over 200 genes for association with atopy and allergic disease phenotypes. These studies have provided us with increasing insight into genetic susceptibility to asthma, the role of gene–environment interaction and the role of genetic variation in inter-individual response to treatment. Both in asthma and in COPD the heterogeneity of the diseases with complex hereditary traits and many (sub) phenotypes are obstacles to find the right genetic information easily. Although a rapidly increasing number of genes are being implicated in asthma and COPD pathogenesis, the functional variants in these genes have not been definitively identified; this is a major area requiring investigation.
Positionally cloned genes and age-specific effects in asthma and atopy: An international population-based cohort study (ECRHS)
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Several genes identified by positional cloning have been associated with asthma and atopy, but few findings have been replicated. Age at onset of asthma has been associated with different phenotypic characteristics, and with variants at chromosome 17q21 identified through genome-wide association. This study examined the associations and age-specific effects on asthma, atopy and bronchial hyper-responsiveness (BHR) of five candidate genes previously identified by positional cloning (ADAM33, PHF11, NPSR1, DPP10, SPINK5).
51 polymorphisms from 2474 participants from 13 countries who took part in the European Community Respiratory Health Survey (1990–2000) were studied. Asthma and age at onset of asthma were assessed by questionnaire data, BHR by methacholine challenge and atopy by specific immunoglobulin E to four common allergens.
Significant associations with asthma, atopy and particularly for asthma with atopy were observed for a large region of 47 kb in the NPSR1 gene, even after Bonferroni correction for multiple comparisons (p<0.001). The associations with NPSR1 were stronger in those reporting a first attack of asthma before the age of 15, with statistically significant interactions with age of onset found for three SNPs. The evidence for ADAM33 and BHR and for an age-specific effect of two SNPs in DPP10 and asthma was weaker.
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: Supported by grants of the Netherlands Asthma Foundation (AF 95.09 and AF 98.48).

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Mechanisms of asthma and allergic inflammationPolymorphisms in SPINK5 are not associated with asthma in a Dutch population

Background

Objective

Methods

Results

Conclusion

Section snippets

Study populations

Results

Discussion

J Allergy Clin Immunol

Am J Hum Genet

Chest

J Allergy Clin Immunol

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

J Dermatol Sci

J Invest Dermatol

Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population

Am J Respir Cell Mol Biol

Mutations in the gene encoding for the beta-2-adrenergic receptor in normal and asthmatic subjects

Am J Respir Cell Mol Biol

Association of a promoter polymorphism of the CD14 gene and atopy

Am J Respir Crit Care Med

Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome

Nat Genet

Mechanisms of asthma and allergic inflammation
Polymorphisms in SPINK5 are not associated with asthma in a Dutch population