Genetic variation in small proline rich protein 2B as a predictor for asthma among children with eczema

Epstein, Tolly; LeMasters, Grace K.; Bernstein, David I.; Ericksen, Mark B.; Martin, Lisa J.; Ryan, Patrick; Myers, Jocelyn M. Biagini; Kovacic, Melinda S. Butsch; Lindsey, Mark; He, Hua; Reponen, Tiina; Villareal, Manuel; Lockey, James E.; Bernstein, Cheryl; Hershey, Gurjit K. Khurana

doi:10.1016/j.anai.2012.01.004

Cited by 11 publications

(13 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All dependent and independent variables were dichotomized prior to analysis based on prior studies of this cohort. 10,19,20 Low socioeconomic status was defined as a household income of < $20k per year. Parental report of asthma was defined as either biologic parent ever having been diagnosed with asthma.…”

Section: Methodsmentioning

confidence: 99%

“…Eczema was defined as physician diagnosed eczema based on physical exam findings consistent with probable or definitive eczema from birth to three years. 20 All covariates with p<0.05 in the univariate analysis were included in the multivariate logistic regression model. Separate multivariate models were developed for the ucAPI and all three persistent wheezing phenotypes.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Optimum Predictors of Childhood Asthma: Persistent Wheeze or the Asthma Predictive Index?

Amin

Levin

Epstein

et al. 2014

The Journal of Allergy and Clinical Immunology: In Practice

Self Cite

View full text Add to dashboard Cite

Background The Asthma Predictive Index (API) and persistent wheezing phenotypes are associated with childhood asthma, but previous studies have not assessed their ability to predict objectively confirmed asthma. Objective To determine whether the University of Cincinnati API (ucAPI) and/or persistent wheezing at age three can accurately predict objectively confirmed asthma at age seven. Methods Data from the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), a high risk prospective birth cohort, was used. Asthma was defined as: parent-reported or physician-diagnosed asthma objectively confirmed by a change in FEV1 of ≥ 12% post bronchodilator or a positive methacholine challenge (PC20 ≤ 4 mg/ml); or prior treatment with daily asthma controller medication(s). Multivariate logistic regression was used to investigate the relationship between confirmed asthma at age seven and a positive ucAPI (adapted and modified from prior published API definitions) and persistent wheezing at age three. Results At age seven, 103 of 589 (17.5%) children satisfied the criteria for asthma. Confirmed asthma at age seven was significantly associated with a positive ucAPI (adjusted [a]OR=13.3; 95% CI [7.0–25.2]; p<0.01) and the persistent wheezing phenotype (aOR = 9.8 [4.9–19.5]; p <0.01) at age three. Allergic persistent wheezing was associated with a significantly higher risk of asthma (aOR = 10.4 [4.1–26.0]; p<0.01) than non-allergic persistent wheezing (aOR = 5.4 [2.04–14.06]; p <0.01). Conclusions Both a positive ucAPI and persistent wheeze at age 3 years were associated with objectively confirmed asthma at age seven; however the highest risk was associated with ucAPI. These results demonstrate that the ucAPI as a clinically useful tool for predicting future asthma in school-age children.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Optimum Predictors of Childhood Asthma: Persistent Wheeze or the Asthma Predictive Index?

Amin

Levin

Epstein

et al. 2014

The Journal of Allergy and Clinical Immunology: In Practice

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several types of mutations in SPRR3, including an extra 24 base pair defect in the central domain, as well as additional in-frame deletions and insertions 64 have been associated not only with AD 65 , but also with asthma 66 . These mutations result in expression of SPRR3 at higher than normal levels in AD 64, 65 , likely impacting barrier function through production of a CE scaffold that impairs the supramolecular organization of lamellar body-derived lipids into normal bilayer structures (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis

Elias

Wakefield

2014

Journal of Allergy and Clinical Immunology

186

194

View full text Add to dashboard Cite

We review here how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in AD. Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (i.e., hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (e.g., SPRR3); mattrin, encoded by Tmem79, which regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor, LEKTI1; and the fatty acid transporter, FATP4, have all been linked to AD. Yet, these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function; e.g., psychological stress, a low ambient humidity, or high pH surfactants, often are required to trigger disease. Th2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion and/or extracellular lamellar membrane organization, as well as in antimicrobial defense. Finally, we briefly review therapeutic options that address this new pathogenic paradigm.

show abstract

“…Genotypes were assigned using BeadStudio's genotyping module (BeadStudio v3.2, San Diego, CA). Genotyping of FLG R501X truncation and 2282del4 deletion was performed by PCR and restriction fragment length polymorphism in both CCAAPS and the GCPCR as previously described 36, 37 . Genotyping of the CCAAPS population for SPINK5 (29 SNPs) and TSLP (10 SNPs) was performed on banked saliva samples using a second custom Illumina Golden Gate assay.…”

Section: Methodsmentioning

confidence: 99%

Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma

Myers

Martin

Kovacic

et al. 2014

Journal of Allergy and Clinical Immunology

Self Cite

View full text Add to dashboard Cite

Background Epithelial genes have previously been associated with asthma, but only explain a small fraction of heritability. In part, this may be due to epistasis that is often not considered. Objective To determine independent and epistatic associations between FLG, SPINK5 and TSLP gene variants and childhood asthma. Methods Using a candidate gene approach, we genotyped 29 variants in FLG, SPINK5 and TSLP in asthmatic, allergic, and non-allergic-non-asthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository (GCPCR). Associations with asthma were also assessed in six replication populations. Results We observed independent associations of variants in SPINK5 (p=0.003) and TSLP (p=0.006) with childhood asthma; a SPINK5 SNP was replicated. In subjects with one or more SPINK5 risk alleles, the absence of the TSLP protective minor alleles was associated with a significant increase in asthma (67% vs. 53%, p=0.0017). In contrast, the presence or absence of TSLP minor alleles did not affect asthma risk in subjects without the SPINK5 risk alleles. The SPINK5 and TSLP epistasis was replicated in a black population (p=0.036) that did not display independent association with variants in these genes. Conclusions Our results support epistasis between SPINK5 and TSLP which contributes to childhood asthma. These findings emphasize the importance of utilizing biology to inform analyses to identify genetic susceptibility to complex diseases. The results from our study have clinical relevance and support that the therapeutic effects of anti-TSLP therapy in asthmatics may be dependent on SPINK5 genotype.

show abstract

Genetic variation in small proline rich protein 2B as a predictor for asthma among children with eczema

Abstract: Background-Small proline rich protein 2B (SPRR2B) is a skin and lung epithelial protein associated with allergic inflammation in mice that has not been evaluated in human atopic diseases.

Cited by 11 publications

References 39 publications

Optimum Predictors of Childhood Asthma: Persistent Wheeze or the Asthma Predictive Index?

Optimum Predictors of Childhood Asthma: Persistent Wheeze or the Asthma Predictive Index?

Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis

Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma

Contact Info

Product

Resources

About