Variants of CEP68 gene are associated with acute urticaria/angioedema induced by multiple non-steroidal anti-inflammatory drugs

PLoS One. 2014 Mar 11;9(3):e90966. doi: 10.1371/journal.pone.0090966. eCollection 2014.

Abstract

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 (CEP68) 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 p-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 CEP68 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Angioedema / chemically induced*
  • Angioedema / genetics*
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Case-Control Studies
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Humans
  • Microtubule-Associated Proteins / genetics*
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Single Nucleotide

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • CEP68 protein, human
  • Microtubule-Associated Proteins

Grants and funding

This study was supported by grants from Carlos III Institute of the Spanish Health Ministry network Red de Investigación de Reacciones Adversas a Alérgenos y Fármacos (RIRAAF, RD12/0013/0001), PI071220, PI10/01598, PS09/02419, PI11/00623, which were co-financed by the European Regional Development Funds, “A way of making Europe” from the European Union; and from the Health Government of Andalucía, PI-0279-2012. Dr. Cornejo-García is a postdoctoral researcher of the Juan de la Cierva Program (Spanish Ministry of Science and Innovation). Dr. Flores was supported by a specific agreement Carlos III Institute and Canary Islands Government (EMER07/001). M. Acosta-Herrera was supported by a fellowship from Carlos III Institute (FI11/00074). Carlos III website: http://www.isciii.es. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.