F. Lorente

Epigenetic changes in B lymphocytes associated with house dust mite allergic asthma.

Although there is no doubt about the influence of the genetic background in the onset of the allergic diseases, Epigenome-Wide Association Studies are needed to elucidate the possible relationship between allergic diseases and epigenomic dysregulation. In this study we aimed to analyze the epigenetic patterns, in terms of DNA methylation, of three well-characterized populations of house dust mite allergic subjects, aspirin-intolerant asthmatics and controls. As a first, genome-wide phase, we used the HELP assay to study the methylation patterns in CD19+ B lymphocytes in these populations, and found that there are reproducible epigenetic differences at limited numbers of loci distinguishing the groups, corroborated by bisulphite MassArray in a second validation phase of an expanded 40 subject group. These validated epigenetic changes occur at loci characterized as important for the immune response. One such locus is a new candidate gene, CYP26A1, which shows differential methylation patterns and expression levels between groups. Our results suggest that epigenomic dysregulation may contribute to the susceptibility to allergic diseases, showing for the first time differences in DNA methylation between allergic and non-allergic healthy subjects, both globally and at specific loci. These observations indicate that the epigenome may offer new pathophysiological insights and therapeutic targets in atopic diseases.

Interleukin-4 (IL4) and Interleukin-4 receptor (IL4RA) polymorphisms in asthma: a case control study

BackgroundIL4/IL4RA pathway plays an important role in atopy and asthma. Different polymorphisms in IL4 and IL4RA genes have been described. Particularly, -33C>TIL4 and 576Q>RIL4RA SNPs have been independently associated to atopy and asthma. The purpose of this study was to analyse these polymorphisms in a population of patients with a well-characterized asthma phenotype.MethodsA total of 212 unrelated Caucasian individuals, 133 patients with asthma and 79 healthy subjects without symptoms or history of asthma or atopy and with negative skin prick tests were recruited. Lung function was measured by spirometry and asthma was specialist physician-diagnosed according to the ATS (American Thoracic Society) criteria and classified following the GINA (Global Initiative for Asthma) guidelines. Skin prick tests were performed according to EAACI recommendations. -33C>TIL4 was studied with TaqMan assay and 576Q>RIL4RA by PCR-RFLP technique. Hardy-Weinberg equilibrium was analysed in all groups. Dichotomous variables were analysed using χ2, Fisher exact test, Monte Carlo simulation test and odds ratio test. To model the effects of multiple covariates logistic regression was used.ResultsNo statistically significant differences between the group of patients with asthma and the controls were found when the allele and genotype distribution of -33C>TIL4 and 576Q>RIL4RA polymorphisms were compared. However, the T allele of the -33C>TIL4 SNP was more frequent in patients with persistent asthma. Multivariate analysis adjusted for age and sex confirmed that carriers of allele T had an increased risk of persistent asthma (OR:2.77, 95%CI:1.18–6.49; p = 0.019). Analysis of combination of polymorphisms showed that patients carrying both the T allele of -33C>TIL4 and the A allele of 576Q>RIL4RA had an increased risk of asthma. This association was particularly observed in persistent asthma [Fishers p value = 0.0021, Monte Carlo p value (after 104 simulations) = 0.0016, OR:3.39; 95% CI:1.50–7.66].ConclusionOur results show a trend of association between the genetic combination of the T allele of -33C>TIL4 and the A allele of 576Q>RIL4RA with asthma. This genetic variant was more frequently observed in patients with persistent asthma. As long as this study was performed in a small population, further studies in other populations are needed to confirm these results.

PTGDR gene in asthma: a functional, genetic, and epigenetic study.

To cite this article: Isidoro‐García M, Sanz C, García‐Solaesa V, Pascual M, Pescador DB, Lorente F, Dávila I. PTGDR gene in asthma: a functional, genetic, and epigenetic study. Allergy 2011; 66: 1553–1562.

Hypersensitivity reactions to cephalosporins

At present, cephalosporins represent one of the most prescribed classes of antibiotics. Although allergic reactions have been estimated to be infrequent, the number of reactions to cephalosporins is increasing due to their wide use. Cross-reactivity with penicillins has mainly been evaluated in patients with penicillin allergy. It is higher between first- and second-generation cephalosporins with the same or similar side chain than between cephalosporins with different side chains. Unlike penicillins, cephalosporin haptens or determinants have not been defined, and therefore the diagnosis is complicated. Nevertheless, skin tests with cephalosporins are useful in the evaluation of several allergic reactions. Although more studies are necessary, a negative result in skin testing to penicillin and cephalosporins with different side chains seems to be a good predictor of tolerance, and could be used in select cases.

Promoter genetic variants of prostanoid DP receptor (PTGDR) gene in patients with asthma

Background:  PTGDR gene has been identified as an asthma‐susceptibility gene. Recently, functional genetic variants have been associated with asthma. The objective of this work was to study −549T>C, −441C>T and −197T>C PTGDR promoter polymorphisms in a Spanish population.

927T>C polymorphism of the cysteinyl-leukotriene type-1 receptor (CYSLTR1) gene in children with asthma and atopic dermatitis.

Asthma and atopic dermatitis share several common features and Cysteinyl‐leukotrienes are mediators that participate in the pathogenesis of both diseases. Recently, a new polymorphism (927T>C) has been identified in cysteinyl‐leukotriene type‐1 receptor (CYSLTR1) gene. This gene is found on the X chromosome. The aim of this study was to analyze this SNP in a population of children with asthma and atopic dermatitis. In this study, 166 individuals, 79 adult controls (CTR) and 87 children with asthma (AA) were included. Forty‐one patients with asthma presented atopic dermatitis (AA‐AD). Adults were chosen as controls to confirm lack of development of asthma and allergy during childhood. Standardized history, physical examination, skin prick tests, and lung function measurements were performed in all patients. The 927T>C CYSLTR1 SNP was analyzed by direct sequencing after PCR amplification. In males (53 individuals), the C allele was significantly more common among AA‐AD patients (47%) than in CTR (8%) (Fishers p < 0.005; Monte Carlo p < 0.008; OR:9.78; 95%CI: 1.73–55.30). When comparing AA‐AD vs. AA‐NAD (patients with asthma but not atopic dermatitis), significant differences were observed, (47% vs. 15%, Fishers p = 0.014; Monte Carlo p = 0.022; OR: 4.97; 95%CI: 1.29–19.13). No differences in allele distribution were observed between these disease sub‐groups in females. The 927T>C is a silent SNP; however, it could affect transcription or translation or may be linked to an unidentified, functional polymorphism and thus may pre‐dispose male children to asthma and atopic dermatitis in our population. Further studies are needed to confirm these findings.

Prevalence of latex sensitization and allergy in Portuguese children

The prevalence of latex allergy has been increasing not only in risk groups but also in the general population, where it is accepted to average 1%. In children, latex sensitization prevalence studies are scarce and involve different population sampling and allergy testing methods, which makes it difficult to compare across studies. Nevertheless, existing studies point towards a low prevalence of latex allergy in children, which still needs to be confirmed in the Portuguese population. Aiming at studying the prevalence of latex sensitization and allergy in a sample of Portuguese children, we studied 182 children from two different hospital outpatient clinics. A standardized questionnaire focusing on atopic background, previous history and allergic signs or symptoms on exposure to latex or fruits was given to all children and parents. Skin prick testing was performed with a battery of common aeroallergens as well as latex. Serum total IgE, Phadiatop, F × 5E and latex‐specific IgE were determined in all children. Specific IgE to latex‐crossreacting fruits was determined in latex‐sensitized children. Based upon the questionnaire, the prevalence of latex allergy would be 0.5%. The prevalence of latex sensitization would be 3.8%, when based solely upon skin prick testing, and 12.1% (≥0.35 IU/ml) or 6.6% (≥0.70 IU/ml) when based singly upon determination of latex‐specific IgE. When positive results for either test were considered, the prevalence of latex sensitization was 14.3%. All latex‐sensitized children were atopic. Sensitivity to latex‐crossreacting foodstuffs was demonstrated in 61.5% of latex‐sensitized children (16/26). This study shows that the prevalence of latex allergy and sensitization in Portuguese atopic and non‐atopic children, as analysed using various diagnostic methods, is similar to that observed in other countries. In addition, the assessment of latex allergy and sensitization should always include skin prick testing and determination of serum IgE.

A new PTGDR promoter polymorphism in a population of children with asthma

Recently, functional genetic variants of the PTGDR gene have been associated with asthma. The objective of this work was to study polymorphisms of the promoter region of PTGDR and their haplotype and diplotype combinations in a Spanish population of children with asthma. In this study, 200 Caucasian individuals were included. Asthma was specialist–physician diagnosed according to the ATS criteria. The polymorphisms were analyzed by direct sequencing. In the study, the new polymorphism (‐613C > T) in the promoter region of PTGDR was analyzed. The CT genotype was more common in controls (17%) than in patients with asthma (1%) (p‐value = 0.0003; OR, 0.057; 95% CI, 0.007–0.441). The CCCT CCCC diplotype (promoter positions ‐613, ‐549, ‐441, and ‐197) was more frequent in the group of patients with asthma [Fisher’s p‐value = 0.012; OR, 10.24; 95% CI (1.25–83.68)]; this diplotype is unambiguous. To our knowledge, this is the first study of ‐613C > T PTGDR polymorphism in patients. This analysis provides more complete information on influence of diplotype combinations of PTGDR polymorphisms in asthma.

Analysis of 927T > C CYSLTR1 and -444A > C LTC4S polymorphisms in children with asthma

INTRODUCTION The cysteinyl leukotrienes (Cys-LTs) are potent inflammatory mediators in asthma. It has been suggested that the different response of patients to Cys-LTs inhibitors could be due to the presence of polymorphisms in the genes implicated in this pathway. METHODS In this study, polymorphisms 927T > C CYSLTR1 and -444A > C LTC4S were analysed in a Spanish population of 188 individuals (109 asthmatic children and 79 controls). Standardised history, skin prick tests and lung function measurements were performed in all patients. Genotypes were determined by sequencing after PCR amplification. RESULTS Differences were observed in 927T > C CYSLTR1, regarding the severity of asthma in males. A greater presence of allele C in the population with persistent asthma versus the control group (Fishers p-value = 0.001; Monte Carlo p-value = 0.003; OR: 12.35; 95 %CI: 2.18-70.00) was observed. Differences were also detected in the combined study of both polymorphisms, among controls and asthmatic patients (Monte Carlo p-value = 0.0002). In the group of males with asthma, an increase of AC variant (-444A LTC4S and 927C CYSLTR1) and a reduction in the AT genetic combination were detected. CONCLUSIONS The combined study of polymorphisms in genes of the leukotriene pathway could explain the differences observed in the studies reported on polymorphism -444A < C LTC4S individually analysed.

Usefulness of intradermal test and patch test in the diagnosis of nonimmediate reactions to metamizol

Background:  Metamizole is a pyrazolone derivative, and its most common reactions are IgE‐mediated reaction and idiosyncratic reactions. Non‐immediate reactions are poorly described and there are very few reports on non‐immediate reactions to pyrazolones.