Novel genetic variants associated with inhaled corticosteroid treatment response in older adults with asthma

Abstract

Introduction: Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults.

Methods: A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases.

Results: In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10^-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome.

Conclusions: Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.

Keywords: asthma; asthma genetics.

Figure 1

Derivation of the oral corticosteroid burst ICS response phenotype in GERA. ¹Time period between the first and last ICS prescription dates; ²Subjects with days of OCS prescriptions ≥50% of ICS follow-up days were excluded, leaving subjects with OCS prescription coverage <50% of the ICS follow-up time; ³the following prespecified comorbidities were removed: cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, pulmonary embolism, primary pulmonary hypertension; ⁴Subjects with identity-by-descent estimates >0.1875. GERA, Genetic Epidemiology Research on Adult and Aging; ICS, inhaled corticosteroid; OCS, oral corticosteroid.

Figure 2

Derivation of the asthma-related exacerbation ICS response phenotype in GERA. ¹Time period between the first and last asthma ICD diagnosis code dates; ²the following prespecified comorbidities were removed: cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, pulmonary embolism, primary pulmonary hypertension; ³Subjects with identity-by-descent estimates >0.1875. GERA, Genetic Epidemiology Research on Adult and Aging; ICS, inhaled corticosteroid; OCS, oral corticosteroid.

Figure 3

Expected survival curves of rs138717703, representative of the four genome-wide significant SNPs in linkage disequilibrium (rs138717703, rs77506063, rs116023293 and rs145325916) associated with poor ICS response as measured by OCS bursts in a meta-analysis across GERA, MGB Biobank, and the Rotterdam Study.¹ (A) GERA (HR 1.73 (95% CI 1.39 to 2.16), p=7.91×10⁻⁷, MAF 0.01), (B) MGB Biobank (HR 1.48 (95% CI 0.75 to 2.90), p=2.55×10⁻¹, MAF 0.01), (C) Rotterdam Study (HR 3.34 (95% CI 1.86 to 6.03), p=5.86×10⁻⁵, MAF 0.01). ¹One subject each in GERA and MGB Biobank had the minor allele homozygous genotype (GG) for all four SNPs. The direction of effect for the homozygous minor allele genotype differed across these two cohorts due to low minor allele frequency. No subjects in the Rotterdam Study had the homozygous minor allele genotype. C, cytosine; G, guanineGERA, Genetic Epidemiology Research on Adult and Aging; ICS, inhaled corticosteroid; MGB, Mass General Brigham; OCS, oral corticosteroid; SNPs, single-nucleotide polymorphisms.