KIF3A genetic variation is associated with pediatric asthma in the presence of eczema independent of allergic rhinitis

Johansson, Erika; Myers, Jocelyn M. Biagini; Martin, Lisa J.; He, Hua; Pilipenko, Valentina; Mersha, Tesfaye B.; Weirauch, Matthew T.; Salomonis, Nathan; Ryan, Patrick; LeMasters, Grace K.; Bernstein, David I.; Lockey, James E.; Hershey, Gurjit K. Khurana

doi:10.1016/j.jaci.2017.02.003

Cited by 18 publications

(26 citation statements)

References 9 publications

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“…This model proposes that compromised epithelial barriers promote sensitization to food and airway allergens and to wheezing illnesses in early life 35, 50 . In fact, childhood onset specific loci identified here have been associated with atopic dermatitis or food allergies, such as FLG on 1q21·3 with the atopic march 45 , atopic dermatitis 31–33 and food allergies 28–30 , KIF3A on 5q31.1 and AP5B1 / OVOL1 on 11q13.1 with the the atopic march 45 and atopic dermatitis 51 , SERPINB7 on 18q21.33 with food allergies 43 , and CRNN (cornulin) on 1q21·3 with atopic dermatitis concomitant with asthma and reduced expression in atopic dermatitis-affected skin 52 . Variants at those loci were all associated with earlier age of asthma onset.…”

Section: Discussionmentioning

confidence: 78%

Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

Pividori

Schoettler

Nicolae

et al. 2018

Preprint

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14 15 16 We detected 61 independent asthma loci: 23 were childhood onset specific, one was 33 adult onset specific, and 37 were shared. Nineteen loci were associated with age of 34 asthma onset. Genes at the childhood onset loci were most highly expressed in skin, 35 blood and small intestine; genes at the adult onset loci were most highly expressed in 36 lung, blood, small intestine and spleen. PrediXcan identified 113 unique candidate 37 genes at 22 of the 61 GWAS loci. 38 Interpretation 39Genetic risk factors for adult onset asthma are largely a subset of the genetic risk for 40 childhood onset asthma but with overall smaller effects, suggesting a greater role for 41 non-genetic risk factors in adult onset asthma. In contrast, the onset of disease in 42 childhood is associated with additional genes with relatively large effect sizes, and SNP-43 based heritability estimates that are over 3-times larger than for adult onset disease. 44Combined with gene expression and tissue enrichment patterns, we suggest that the 45 establishment of disease in children is driven more by dysregulated allergy and 46 epithelial barrier function genes whereas the etiology of adult onset asthma is more 47 lung-centered and environmentally determined, but with immune mediated mechanisms 48 driving disease progression in both children and adults. 49 50

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Section: Discussionmentioning

confidence: 78%

Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

Pividori

Schoettler

Nicolae

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…An important observation is that asthma risk in both of the high‐risk groups was modified by genetic variation in KIF3A , which has been reported by numerous GWAS and genetic association studies to be associated with eczema, asthma, and the atopic march . The KIF3A rs12186803 risk allele differentially interacted with the distinct sensitization pattern in each high‐risk group to modify asthma risk.…”

Section: Discussionmentioning

confidence: 93%

“…In a previous study, genotyping for single nucleotide polymorphisms (SNPs) in KIF3A had been done for 504 CCAAPS children . In that study, rs12186803 was the most strongly associated with the asthma+eczema phenotype.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we focused our analyses on this SNP. In this study, the risk allele was defined as the rs12186803 variant associated with higher risk of asthma in previous studies (the A allele) …”

Section: Methodsmentioning

confidence: 99%

“…KIF3A is a component of both primary and motile cilia, has been consistently associated with asthma and eczema . More recently, a KIF3A genotype has been associated with eczema and asthma co‐morbidity and with the atopic march in a genome‐wide association study . In animal models, deletion of Kif3a in epidermal cells results in disrupted keratinocyte differentiation, suggesting a role for KIF3A in skin barrier function.…”

Section: Introductionmentioning

confidence: 99%

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Identification of two early life eczema and non‐eczema phenotypes with high risk for asthma development

Johansson

Myers

Martin

et al. 2019

Clin Experimental Allergy

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Background:The "atopic march" has been considered a linear progression starting with eczema and culminating with development of asthma. Not all asthma cases, however, are preceded by eczema, and not all children with eczema go on to develop asthma.Objective: The aim of this study was to explore the impact of allergic sensitization patterns on the association between early eczema and later childhood asthma. Given the numerous reported associations of the ciliary gene KIF3A with the atopic march, we also examined the impact of KIF3A risk allele rs12186803 on our analyses. Methods: We studied 505 participants in the Cincinnati Childhood Allergy and AirPollution Study (CCAAPS), a prospective birth cohort, with longitudinal eczema and asthma outcomes as well as prospective data regarding timing of sensitization to foods and aeroallergens. KIF3A genotypes were available on all children.Results: Two high-risk groups were identified: one with and one without early eczema. The high-risk group with early eczema was more likely to be sensitized to food allergens, while the group without early eczema was more likely to be polysensitized to aeroallergens. The KIF3A rs12186803 risk allele interacted with food sensitization to increase asthma risk in children with eczema (P = 0.02). In children without eczema, asthma was associated with the interaction between rs12186803 and aeroallergen sensitization (P = 0.007). Conclusions & ClinicalRelevance: KIF3A interacted differentially with sensitization pattern to increase the risk of asthma in two high-risk groups of children with and without early eczema. Given the reported role of KIF3A in epithelial cell functioning, the results add evidence to the hypothesis that an impaired epithelial barrier is a key aspect in the development of allergic disease. K E Y W O R D S asthma, atopic dermatitis, Eczema, KIF3A, phenotype S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Johansson E, Biagini Myers JM, Martin LJ, et al. Identification of two early life eczema and noneczema phenotypes with high risk for asthma development.

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Resolving Clinical Phenotypes into Endotypes in Allergy: Molecular and Omics Approaches

Mersha

Afanador

Johansson

et al. 2020

Clinic Rev Allerg Immunol

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KIF3A genetic variation is associated with pediatric asthma in the presence of eczema independent of allergic rhinitis

Cited by 18 publications

References 9 publications

Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

Shared and Distinct Genetic Risk Factors for Childhood Onset and Adult Onset Asthma: Genome- and Transcriptome-wide Studies

Identification of two early life eczema and non‐eczema phenotypes with high risk for asthma development

Resolving Clinical Phenotypes into Endotypes in Allergy: Molecular and Omics Approaches

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