Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma - 02/10/14
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Abstract |
Background |
Epithelial genes have previously been associated with asthma but only explain a small fraction of heritability. In part, this might be due to epistasis, which is often not considered.
Objective |
We sought to determine independent and epistatic associations between filaggrin (FLG), serine protease inhibitor Kazal-type 5 (SPINK5), and thymic stromal lymphopoietin (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 nonallergic nonasthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository. Associations with asthma were also assessed in 6 replication populations.
Results |
We observed independent associations of variants in SPINK5 (P = .003) and TSLP (P = .006) with childhood asthma; a SPINK5 single nucleotide polymorphism was replicated. In subjects with 1 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 = .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 = .036) who 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 using 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 asthmatic patients might be dependent on SPINK5 genotype.
Le texte complet de cet article est disponible en PDF.Key words : Childhood asthma, genetic association, epistasis, skin-related genes
Abbreviations used : AD, AIM, CAMP, CARE, CCAAPS, CCC, dbGaP, FLG, GCC, GCPCR, GWAS, KLK, LD, LEKTI, OR, PC, SNP, SPT, TSLP
Plan
Supported by National Institutes of Health grants U19AI070235 (to G.K.K.H.), R01ES011170 (to G.K.L.), and R21ES016830 (to M.B.K.). Supported in part by the Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort. |
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Disclosure of potential conflict of interest: The institutions of J. M. Biagini Myers, L. J. Martin, M. Butsch Kovacic, T. B. Mersha, H. He, V. Pilipenko, M. A. Lindsey, M. B. Ericksen, D. I. Bernstein, G. K. LeMasters, J. E. Lockey and G. K. Khurana Hershey have received funding from the National Institutes of Health (NIH). G. K. LeMasters also has grants pending from the NIH. G. K. Khurana Hershey has also received consultancy fees from the KAO. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 134 - N° 4
P. 891 - octobre 2014 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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