Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease

Abstract

Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs) and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.

The Genetics of Drug Hypersensitivity Reactions

“…Despite growing interest in the genetics of NIUA [81][82][83][84], most available data are on NERD [85,86]. However, many studies have included limited numbers of individuals, often without replication, and largely in populations of Asian descent [85][86][87].…”

“…However, many studies have included limited numbers of individuals, often without replication, and largely in populations of Asian descent [85][86][87].…”

Genetic and Epigenetic Components of Aspirin-Exacerbated Respiratory Disease

“…Recently, we conducted the first pharmacogenomics GWAS studies of zileuton 101 and montelukast 102 responses in asthmatics and identified novel loci uniquely associated with both medications. Candidate gene studies of differential gene expression between non-AERD and AERD asthmatics also implicate multiple immune response and LT pathway genes, including the HLA allele DPB1 7,74,103 , CYSLTR1 7,103 and RGS7BP 104 . These findings implicate involvement of multiple genes within, and related to, the LT pathway in regulating differential responses to treatment in asthma and AERD.…”

Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs

“…Despite the recent increase in interest in NIUA [16,17 & ,18], most information comes from NERD [19,20]. However, many studies [19][20][21] have included limited numbers of individuals, often without replication, largely in Asian populations.…”

“…However, many studies [19][20][21] have included limited numbers of individuals, often without replication, largely in Asian populations. Overall, there is a lack of consistent genetic markers for HDRs to NSAIDs.…”