Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy

Asthma is a frequent disease, mainly characterized by airway inflammation, in which drug therapy is crucial in its management. The potential of pharmacogenomics testing in asthma therapy has been, to date, little explored. In this review, we discuss pharmacogenetic factors affecting asthma treatment, both related to drugs used as controller medications for regular maintenance, such as inhaled corticosteroids, anti-leukotriene agents, long-acting beta-agonists, and the new biologic agents used to treat severe persistent asthma. In addition, we discuss current pharmacogenomics knowledge for rescue medications provided to all patients for as-needed relief, such as short-acting beta-agonists. Evidence for genetic variations as a factor related to drugs response has been provided for the following genes and groups of drugs: Inhaled corticosteroids: FCER2; anti-leukotriene agents: ABCC1, and LTC4S; beta-agonists: ADRB2. However, the following genes require further studies confirming or rejecting association with the response to asthma therapy: ADCY9, ALOX5, ARG1, ARG2, CRHR1, CRHR2, CYP3A4, CYP3A5, CYSLTR1, CYSLTR2, GLCCI1, IL4RA, LTA4H, ORMDL3, SLCO2B1, SPATS2L, STIP1, T, TBX21, THRA, THRB, and VEGFA. Although only a minority of these genes are, at present, listed as associated with drugs used in asthma therapy, in the Clinical Pharmacogenomics Implementation Consortium gene-drug pair list, this review reveals that sufficient evidence to start testing the potential of clinical pharmacogenomics in asthma therapy already exists. This evidence supports the inclusion in pilot pharmacogenetics tests of at least four genes. Hopefully these tests, if proven useful, will increase the efficiency and the safety of asthma therapy

A nonsynonymous FCER1B SNP is associated with risk of developing allergic rhinitis and with IgE levels

Allergic rhinitis is associated with elevated serum IgE levels. IgE response is mediated by the highaffinity IgE receptor (FcεRI), which is polymorphic. Studies analyzing the association between allergic rhinitis and FcεRI variants have been conducted with controversial results. The objective of this study is to analyze, in 1,041 individuals, the putative clinical association of allergic rhinitis with common polymorphisms in FcεRI subunits genes. These SNPs included FECR1A rs2494262, rs2427837 and rs2251746; FECR1B rs1441586, rs569108 and rs512555; FCER1G rs11587213, rs2070901 and rs11421. Statistically significant differences were observed for the FCER1B rs569108 and rs512555 polymorphisms frequencies when comparing patients with allergic rhinitis without asthma and controls. The OR (95% CI) value for the 237Gly allele (rs569108) is equal to 0.26 (0.08–0.86, P = 0.017) and for the G allele (rs512555) it is equal to 0.27 (0.08–0.88, P = 0.020). These two SNPs are linked (D’ = 1.0, LOD = 56.05). Also observed was a statistically significant trend towards lower IgE values among allergic rhinitis patients with variant alleles for both SNPs. In conclusion, in patients with allergic rhinitis without asthma, the FCER1B rs569108 and rs512555 polymorphisms are associated with increased risk of developing allergic rhinitis and with lower IgE levels.Trabajo financiado por: Instituto de Salud Carlos III. Fondo de Investigación Sanitaria. Becas PI12/00241, PI12/00324 y RETICS RD12/0013/0002 Junta de Extremadura y Fondos FEDER. Ayuda GR15026peerReviewe

Polimorfismo Nat2 y patología humana

El polimorfismo acetilador fue descubierto hace más de 40 años. Se sabe que la enzima NAT2 es polimórfica y metaboliza a numerosos fármacos y otros xenobióticos. El porcentaje de metabolizadores lentos varia dependiendo de la localización geográfica y de la raza. Este polimorfismo se ha relacionado con la posibilidad de sufrir con mas facilidad determinadas enfermedades. Estudios previos realizados a nivel de fenotipo concluían que entre los diabéticos aparecían mas acetiladores rápidos que en la población general. Nuestro estudio ha analizado a una población de pacientes con diabetes mellitus no insulin-dependiente (DMNID). Se han estudiado las mutaciones del gen NAT2 presente en dicha población y se han comparado con las halladas en población sana utilizada como control. No se ha encontrado ninguna diferencia en las variantes alélicas halladas en ambas poblaciones. Así pues, nuestros resultados no confirman aquellos de estudios previos realizados a nivel de fenotipo. Los resultados de otros estudios en los que el fenotipo acetilador rápido parecía estar asociado a la DMNID podria ser debidos a la propia diabetes y/o a los fármacos administrados

Polimorfismo Nat2 y patología humana

El polimorfismo acetilador fue descubierto hace más de 40 años. Se sabe que la enzima NAT2 es polimórfica y metaboliza a numerosos fármacos y otros xenobióticos. El porcentaje de metabolizadores lentos varia dependiendo de la localización geográfica y de la raza. Este polimorfismo se ha relacionado con la posibilidad de sufrir con mas facilidad determinadas enfermedades. Estudios previos realizados a nivel de fenotipo concluían que entre los diabéticos aparecían mas acetiladores rápidos que en la población general. Nuestro estudio ha analizado a una población de pacientes con diabetes mellitus no insulin-dependiente (DMNID). Se han estudiado las mutaciones del gen NAT2 presente en dicha población y se han comparado con las halladas en población sana utilizada como control. No se ha encontrado ninguna diferencia en las variantes alélicas halladas en ambas poblaciones. Así pues, nuestros resultados no confirman aquellos de estudios previos realizados a nivel de fenotipo. Los resultados de otros estudios en los que el fenotipo acetilador rápido parecía estar asociado a la DMNID podria ser debidos a la propia diabetes y/o a los fármacos administrados

Nonsynonymous FCER1B SNP is Associated with Risk of Developing Allergic Rhinitis and with IgE Levels.

Journal Article; Research Support, Non-U.S. Gov't;Allergic rhinitis is associated with elevated serum IgE levels. IgE response is mediated by the high-affinity IgE receptor (FcεRI), which is polymorphic. Studies analyzing the association between allergic rhinitis and FcεRI variants have been conducted with controversial results. The objective of this study is to analyze, in 1,041 individuals, the putative clinical association of allergic rhinitis with common polymorphisms in FcεRI subunits genes. These SNPs included FECR1A rs2494262, rs2427837 and rs2251746; FECR1B rs1441586, rs569108 and rs512555; FCER1G rs11587213, rs2070901 and rs11421. Statistically significant differences were observed for the FCER1B rs569108 and rs512555 polymorphisms frequencies when comparing patients with allergic rhinitis without asthma and controls. The OR (95% CI) value for the 237Gly allele (rs569108) is equal to 0.26 (0.08-0.86, P = 0.017) and for the G allele (rs512555) it is equal to 0.27 (0.08-0.88, P = 0.020). These two SNPs are linked (D' = 1.0, LOD = 56.05). Also observed was a statistically significant trend towards lower IgE values among allergic rhinitis patients with variant alleles for both SNPs. In conclusion, in patients with allergic rhinitis without asthma, the FCER1B rs569108 and rs512555 polymorphisms are associated with increased risk of developing allergic rhinitis and with lower IgE levels.This study was financed by grants PI12/00241, PI12/00324 and RETICS RD12/0013/0002 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, and GR15026 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union.Ye

Identification of Novel Biomarkers for Drug Hypersensitivity After Sequencing of the Promoter Area in 16 Genes of the Vitamin D Pathway and the High-Affinity IgE Receptor.

The prevalence of allergic diseases and drug hypersensitivity reactions (DHRs) during recent years is increasing. Both, allergic diseases and DHRs seem to be related to an interplay between environmental factors and genetic susceptibility. In recent years, a large effort in the elucidation of the genetic mechanisms involved in these disorders has been made, mostly based on case-control studies, and typically focusing on isolated SNPs. These studies provide a limited amount of information, which now can be greatly expanded by the complete coverage that Next Generation Sequencing techniques offer. In this study, we analyzed the promoters of sixteen genes related to the Vitamin D pathway and the high-affinity IgE receptor, including FCER1A, MS4A2, FCER1G, VDR, GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, RXRA, RXRB, RXRG, IL4, IL4R, IL13, and IL13RA1. The study group was composed of patients with allergic rhinitis plus asthma (AR+A), patients with hypersensitivity to beta-lactams (BLs), to NSAIDs including selective hypersensitivity (SH) and cross-reactivity (CR), and healthy controls without antecedents of atopy or adverse drug reactions. We identified 148 gene variations, 43 of which were novel. Multinomial analyses revealed that three SNPs corresponding to the genes FCER1G (rs36233990 and rs2070901), and GC (rs3733359), displayed significant associations and, therefore, were selected for a combined dataset study in a cohort of 2,476 individuals. The strongest association was found with the promoter FCER1G rs36233990 SNP that alters a transcription factor binding site. This SNP was over-represented among AR+A patients and among patients with IgE-mediated diseases, as compared with control individuals or with the rest of patients in this study. Classification models based on the above-mentioned SNPs were able to predict correct clinical group allocations in patients with DHRs, and patients with IgE-mediated DHRs. Our findings reveal gene promoter SNPs that are significant predictors of drug hypersensitivity, thus reinforcing the hypothesis of a genetic predisposition for these diseases

Asthma and allergic rhinitis associate with the rs2229542 variant that induces a p.Lys90Glu mutation and compromises AKR1B1 protein levels.

Asthma and rhinitis are two of the main clinical manifestations of allergy, in which increased reactive oxygen or electrophilic species can play a pathogenic role. Aldose reductase (AKR1B1) is involved in aldehyde detoxification and redox balance. Recent evidence from animal models points to a role of AKR1B1 in asthma and rhinitis, but its involvement in human allergy has not been addressed. Here, the putative association of allergic rhinitis and asthma with AKR1B1 variants has been explored by analysis of single-strand variants on the AKR1B1 gene sequence in 526 healthy subjects and 515 patients with allergic rhinitis, 366 of whom also had asthma. We found that the rs2229542 variant, introducing the p.Lys90Glu mutation, was significantly more frequent in allergic patients than in healthy subjects. Additionally, in cells transfected with expression vectors carrying the wild-type or the p.Lys90Glu variant of AKR1B1, the mutant consistently attained lower protein levels than the wild-type and showed a compromised thermal stability. Taken together, our results show that the rs2229542 variant associates with asthma and rhinitis, and hampers AKR1B1 protein levels and stability. This unveils a connection between the genetic variability of aldose reductase and allergic processes