The Diamine Oxidase Gene Is Associated with Hypersensitivity Response to Non-Steroidal Anti-Inflammatory Drugs

<div><p>Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the <em>HDC</em>, <em>HNMT</em> and <em>DAO</em> genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR  = 1.7 (95% CI  = 1.3–2.1; Pc  = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc  = 0.008 and Pc  = 0.004, respectively).</p> <h3>Conclusions and implications</h3><p>The <em>DAO</em> polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response.</p> </div

<i>DAO</i> Thr16Met genotypes according to clinical presentation.

<p>Twelve patients had other symptoms (See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047571#pone-0047571-t001" target="_blank">Table 1</a>).</p

Clinical characteristics of the study subjects.

<p>Many patients reacted to two or more drugs.</p

<i>DAO rs10156191</i> plus <i>rs1049793</i> haplotypes in the two study subgroups.

<p>N: non-carrier of the risk haplotype; C: Carrier of the risk haplotype.</p

<i>HDC</i> genotypes in the study group.

<p><i>HDC</i> genotypes in the study group.</p

Genotypes of genes coding for the histamine-metabolising enzymes HNMT and DAO in the study group.

<p>Genotypes of genes coding for the histamine-metabolising enzymes HNMT and DAO in the study group.</p

<i>DAO rs10156191</i> genotypes in the two study subgroups.

<p><i>DAO rs10156191</i> genotypes in the two study subgroups.</p