Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

Abstract

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

Gene‐environment interactions in childhood asthma revisited; expanding the interaction concept

“…Moreover, age has been proposed to be an important modifier of the association of genetic variants with other asthma‐related traits apart from susceptibility, such as treatment response. Indeed, two recent GWIS explored interactions with age in the response to the most commonly used asthma medications (short‐acting beta‐2 agonists [SABA] and ICS) in European populations 85,86 (Table 1). Interestingly, age‐related modifications of genetic associations at several loci previously linked to asthma pathophysiology were revealed in asthma exacerbations despite ICS and bronchodilator response in pediatric and adult asthma patients (Table 3).…”

A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts

“…In addition, our validation cohorts were fundamentally different from the discovery cohorts in that they were paediatric studies of asthma and did not include participants with AA. Associations observed in adults might not be present in children, especially given the possible presence of age-by-genotype interaction that has been previously reported [ 42 ]. Heterogeneity across studies included in the meta-analysis and in the paediatric cohorts may have limited our ability to detect genome-wide associations.…”

Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis

“…As genetic factors constitute a well-established regulatory mechanism of gene expression, 12 we investigated whether different CREM genotype distributions account for the higher CREM expression found in RA. We first retrieved all CREM variants studied in the literature (Table 1), [23][24][25][26][27][28][29][30][31] two of which (rs11592989 and rs12770114) are monomorphic in CHB (Table 1). Of the remaining variants, 30 were in linkage disequilibrium with either rs12765063, rs17499247, or rs1213386 (Table 1).…”