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

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

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

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

Variants of CEP68 Gene Are Associated with Acute Urticaria/Angioedema Induced by Multiple Non-Steroidal Anti-Inflammatory Drugs

<div><p>Non-steroidal anti-inflammatory drugs (NSAIDs) are the most consumed drugs worldwide because of their efficacy and utility in the treatment of pain and inflammatory diseases. However, they are also responsible for an important number of adverse effects including hypersensitivity reactions. The most important group of these reactions is triggered by non-immunological, pharmacological mechanisms catalogued under the denomination of cross-intolerance (CRI), with acute urticaria/angioedema induced by multiple NSAIDs (MNSAID-UA) the most frequently associated clinical entity. A recent genome-wide association study identified the gene encoding the centrosomal protein of 68 KDa (<i>CEP68</i>) as the major locus associated with aspirin intolerance susceptibility in asthmatics. In this study, we aimed to assess the role of this locus in susceptibility to CRI to NSAIDs by examining 53 common gene variants in a total of 635 patients that were classified as MNSAID-UA (n = 399), airway exacerbations (n = 110) or blended pattern (n = 126), and 425 controls. We found in the MNSAID-UA group a number of variants (17) associated (lowest <i>p</i>-value = 1.13×10⁻⁶), including the non-synonymous Gly74Ser variant (rs7572857) previously associated with aspirin intolerance susceptibility in asthmatics. Although not being significant in the context of multiple testing, eight of these variants were also associated with exacerbated respiratory disease or blended reactions. Our results suggest that <i>CEP68</i> gene variants may play an important role in MNSAID-UA susceptibility and, despite the different regulatory mechanisms involved depending on the specific affected organ, in the development of hypersensitivity reactions to NSAIDs.</p></div

Association results and the predicted function for the 17 <i>CEP68</i> SNPs surviving the correction for multiple comparisons.

<p><b>Abbreviations</b>: <b>miRNABS</b>, micro RNA binding site; <b>nsSNP</b>, non-synonymous single nucleotipe polymorphism; <b>TFBS</b>, transcription factor binding site.</p><p>* According to NCBI build 37.</p

Demographic and clinical data of patients and controls.

<p><b>Abbreviations</b>: <b>AERD</b>, aspirin-exacerbated respiratory disease; <b>CI</b>, confidence intervals; <b>MNSAID-UA</b>, multiple NSAIDs-induced urticaria/angioedema; <b>NSAIDs</b>, non-steroidal anti-inflammatory drugs; <b>SD</b>, standard deviation.</p