Abstract
The high-affinity IgE receptor (Fcε RI) is a heterotetramer of three subunits: Fcε RIα, Fcε RIβ, and Fcε RIγ (αβγ2) encoded by three genes designated as FCER1A, FCER1B (MS4A2), and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity. From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA), propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone, or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPs FCER1A rs2494262, rs2427837, and rs2251746; FCER1B rs1441586, rs569108, and rs512555; FCER1G rs11587213, rs2070901, and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742, and rs1049793 in the HDC, HNMT, and DAO genes. No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug, or clinical presentation) were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG) were strongly related (P < 0.001 and P = 0.005, respectively) with selective hypersensitivity to ibuprofen. With regard to patients with selective hypersensitivity to ASA, men were more prone to develop such a reaction than women (P = 0.011), and the detrimental DAO SNP rs10156191 in homozygosity increased the risk of developing such hypersensitivity (P = 0.039).
Highlights
Type B drug-induced hypersensitivity reactions (DHR) occur only in susceptible individuals with a frequency of 5–10% of all adverse drug reactions (Khan and Solensky, 2010)
It is to be noted that, despite the large body of published evidence supporting association of FCER1 SNPs with allergic diseases, this is the first study to analyze the putative role of FCER1 SNPs in selective nonsteroidal anti-inflammatory drugs (NSAIDs) hypersensitivity
We previously identified genetic factors related to cross intolerance (Agúndez et al, 2012) and, of these, one non-synonymous DAO gene variation, designated as rs10156191, was overrepresented among cross-intolerant patients, providing the basis for a detailed study on the role of genetic variations in histamine metabolism in patients with selective hypersensitivity to NSAIDs
Summary
Type B drug-induced hypersensitivity reactions (DHR) occur only in susceptible individuals with a frequency of 5–10% of all adverse drug reactions (Khan and Solensky, 2010). These reactions are severe and occasionally may be lifethreatening. Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequent causes of DHR together with antibiotics (CornejoGarcia et al, 2009; Doña et al, 2011, 2012; Kowalski et al, 2011). Hypersensitivity reactions to a single NSAID (selective reactions) are the result of an immunological mechanism, which is either IgE-mediated in acute reactions or T cell-mediated in delayed reactions. Histamine release from mast cells after IgE receptor activation plays a relevant role in allergic inflammation and in the development of clinical symptoms (Mita et al, 2001; Kowalski et al, 2011)
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