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

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.

Keywords: Childhood asthma; epistasis; genetic association; skin-related genes.

Figure 1

Linkage disequilibrium (r²) among SNPs included in the gene collapsing analyses for 407 asthmatics compared to 257 allergic controls in the white discovery GCPCR populations.

Figure 2

Epistasis of SPINK5 and TSLP. (A) Discovery white GCPCR/GCC children. (B) Replication of epistasis of SPINK5 and TSLP in replication GCPCR black children.

Figure 3

Hypothesized shared pathways leading to asthma and inflammation. (A) SPINK5 overexpression increases inflammatory cytokines. (B) LEKTI deficiency increases KLK5/7/14, activating through PAR-2, and NF-κB leading to TSLP production, causing allergy and lung inflammation. (C) LEKTI deficiency increases profillagrin cleavage compromising the skin barrier and contributing to sensitization and subsequent asthma. Solid lines represent published pathways, dashed lines represent hypothesized pathways.