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

Abstract

IntroductionOlder 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.MethodsA 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.ResultsIn 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six nearPTCHD4validated 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 × 10−5were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci forCPED1,CRADDandDSTfor the OCS burst outcome andGM2A,SNW1,CACNA1C,DPH1, andRPS10for the asthma-related exacerbation outcome.ConclusionsMultiple 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, includingPTCHD4.