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

Amo, Gemma; García-Menaya, Jesús Miguel; Campo, Paloma; Cordobés, Concepción; Plaza-Serón, María del Carmen; Ayuso, Pedro; Esguevillas, Gara; Blanca, Miguel; Agúndez, José A. G.; García‐Martín, Elena

doi:10.1038/srep19724

Cited by 18 publications

(33 citation statements)

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“…Fcer1g , Nnmt and Cuedc1 were three top candidate genes with the highest fold changes in the microarray analysis. Fcer1g encodes the gamma chain of the high-affinity IgE receptor that is involved in allergic reactions 20 . Nnmt encodes Nicotinamide N-methyltransferase that is involved in homocysteine synthesis 21 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2

Chen

Wang

et al. 2016

Sci Rep

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The homozygous p.V37I variant in GJB2 is prevalent in East and Southeast Asians and may lead to mild-to-moderate hearing loss with reduced penetrance. To investigate the pathogenic mechanism underlying this variant, we generated a knock-in mouse model of homozygous p.V37I by an embryonic stem cell gene targeting method. Auditory brainstem response test showed that the knock-in mice developed progressive, mild-to-moderate hearing loss over the first 4–9 months. Overall no significant developmental and morphological abnormality was observed in the knock-in mouse cochlea, while confocal immunostaining and electron microscopic scanning revealed minor loss of the outer hair cells. Gene expression microarray analysis identified 105 up-regulated and 43 down-regulated genes in P5 knock-in mouse cochleae (P < 0.05 adjusted by the Benjamini & Hochberg method), among which four top candidate genes with the highest fold-changes or implication to deafness Fcer1g, Nnmt and Lars2 and Cuedc1 were verified by quantitative real-time PCR. Our study demonstrated that the homozygous p.V37I knock-in mouse modeled the hearing phenotype of the human patients and can serve as a useful animal model for further studies. The differentially expressed genes identified in this study may shed new insights into the understanding of the pathogenic mechanism and the phenotypic modification of homozygous p.V37I.

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Section: Discussionmentioning

confidence: 99%

Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2

Chen

Wang

et al. 2016

Sci Rep

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“…The cohort of patients considered has been included in a previous study (Amo et al., ) where the general parameters regarding clinical characterization have been described. Briefly, there were no statistically significant differences between patients and control subjects regarding gender or age, whereas the percentage of smokers was lower in rhinitis plus asthma patients than in control subjects (Chi‐Square test P = 0.002) (Amo et al., ).…”

Section: Resultsmentioning

confidence: 99%

“…A cohort of 1041 Caucasian individuals, including 526 healthy subjects and 515 allergic rhinitis patients, whose clinical features have been summarized previously (Amo et al., ), was studied. Patients were recruited from the Allergy Department, Infanta Cristina Hospital (Badajoz, Spain) and from the UGC Allergy, Regional Hospital (Málaga, Spain) (265 and 250 patients, respectively) and most of them have been included in previous studies (Gervasini et al., ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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.

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“…Two major clinical phenotypes have been described: Selective NSAID hypersensitivity, which is drug-specific and an IgE-mediated mechanism, and cross-intolerance in which chemically non-related NSAIDs induce the reaction (Kowalski et al, 2013 ). Because selective hypersensitivity is an IgE-mediated mechanism, we analyzed genetic variations at the high-affinity IgE receptor, which has been shown to be related with allergic disorders (MacGlashan et al, 1998 , 1999 ; Saini et al, 1999 ; Weidinger et al, 2008 ; Zhang et al, 2010 ; Li et al, 2014 ; Amo et al, 2016 ). 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 NSAID hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA was obtained from peripheral leukocytes and purified in accordance with standard procedures. The SNPs analyzed were selected according to allele frequencies (over 0.01) in the study population, and either functional or clinical relevance, in line with published evidence (Preuss et al, 1998 ; García-Martín et al, 2006 , 2007a , 2009 ; Ayuso et al, 2007 ; Maintz et al, 2011 ; Amo et al, 2016 ), and the public 1000 genomes database release of 17 Nov. 2015. Genotyping was performed by TaqMan assays (Life Technologies, Alcobendas, Madrid, Spain).…”

Section: Methodsmentioning

confidence: 99%

FCERI and Histamine Metabolism Gene Variability in Selective Responders to NSAIDS

et al. 2016

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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).

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

Cited by 18 publications

References 40 publications

Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2

Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2

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

FCERI and Histamine Metabolism Gene Variability in Selective Responders to NSAIDS

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