Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma.

Badri Padhukasahasram,Amber Dahlin,Sharon M Lutz,Michael Mcgeachie,Jessica Lasky-Su,Ann Chen Wu,Rachel S Kelly,Kelan G Tantisira,Joanne E Sordillo

doi:10.1371/journal.pone.0229241

Badri Padhukasahasram, Amber Dahlin + Show 7 more

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https://doi.org/10.1371/journal.pone.0229241

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Abstract

While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide interaction study (GWIS) of 1,321 adult and child asthmatic patients of European ancestry. We identified 107 genome-wide suggestive (P<10−05) age-by-genotype interactions, two of which also met genome-wide significance (P<5x10-08) (rs34631960 [OR 2.3±1.6–3.3] in thrombospondin type 1 domain-containing protein 4 (THSD4) and rs2328386 [OR 0.5±0.3–0.7] in human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2)) by joint analysis of GWIS results from discovery and replication populations. In addition to THSD4 and HIVEP2, age-by-genotype interactions also prioritized genes previously identified as asthma candidate genes, including DPP10, HDAC9, TBXAS1, FBXL7, and GSDMB/ORMDL3, as pharmacogenomic loci as well. This study is the first to link these genes to a pharmacogenetic trait for asthma.

Highlights

Asthma, the most common chronic illness in childhood, costs over $50 billion annually in the United States.[1,2,3] Inhaled corticosteroids (ICS) are the most effective asthma controller medications leading to significant symptom improvement for most patients; approximately a third of individuals respond minimally or not at all.[4]
The discovery genome-wide interaction study (GWIS) of 407 asthmatic cases with poor ICS response and 376 asthmatic controls with good ICS response identified 230 age-by-genotype interactions that were suggestive of genome-wide significance (P
Sixty-nine of the 107 replicated GWIS single nucleotide polymorphisms (SNPs) were localized to intergenic regions of chromosomes 2, 5, 11, and 12, while the remainder were distributed across eight unique genes in chromosomes 1 (SPRR2G and SAMD13), 6 (HIVEP2), 8 (SAMD12), (THSD4), and (RBFOX1)

Summary

Introduction

The most common chronic illness in childhood, costs over $50 billion annually in the United States.[1,2,3] Inhaled corticosteroids (ICS) are the most effective asthma controller medications leading to significant symptom improvement for most patients; approximately a third of individuals respond minimally or not at all.[4] As the genetics of childhoodonset asthma appear to be distinct from adult-onset asthma[5], different genetic mechanisms may mediate childhood-onset versus adult-onset asthma. Childhood-onset vs adult-onset asthma tends to respond better to ICS treatment.[6] In addition, national.

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