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

• Published in: Journal of allergy and clinical immunology 2014-10, Vol.134 (4), p.891-899.e3
• Main Authors: Biagini Myers, Jocelyn M., PhD, Martin, Lisa J., PhD, Kovacic, Melinda Butsch, MPH, PhD, Mersha, Tesfaye B., PhD, He, Hua, MS, Pilipenko, Valentina, PhD, Lindsey, Mark A., BS, Ericksen, Mark B., MS, Bernstein, David I., MD, LeMasters, Grace K., PhD, Lockey, James E., MD, Khurana Hershey, Gurjit K., MD, PhD
• Format: Article
• Language: English
• Subjects: Adolescent; African Continental Ancestry Group; Allergies; Allergy and Immunology; Asthma; Asthma - genetics; Biological and medical sciences; Case-Control Studies; Child; Child, Preschool; Childhood asthma; Chronic obstructive pulmonary disease, asthma; Cytokines - genetics; epistasis; Epistasis, Genetic; European Continental Ancestry Group; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Frequency; Genes; genetic association; Genetic Predisposition to Disease; Genotype; Humans; Immunopathology; Intermediate Filament Proteins - genetics; Male; Medical sciences; Pneumology; Polymorphism, Genetic; Proteinase Inhibitory Proteins, Secretory - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Serine Peptidase Inhibitor Kazal-Type 5; skin-related genes; Studies
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2014.03.037

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.