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Towards prevention

Effects of diet on the childhood gut microbiome and its implications for atopic dermatitis

Recently, our research team found a strong and significant association between loss-of-function (LOF) mutations in filaggrin (FLG), a gene that encodes a skin barrier protein, in European and Canadian individuals with peanut allergy (PA).1Brown S.J. Asai Y. Cordell H.J. Campbell L.E. Zhao Y. Liao H. et al.Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol. 2011; 127: 661-667Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar These mutations result in a barrier defect and have been associated with atopic dermatitis, asthma, and allergic rhinitis.2Irvine A.D. McLean W.H. Leung D.Y. Filaggrin mutations associated with skin and allergic diseases.N Engl J Med. 2011; 365: 1315-1327Crossref PubMed Scopus (812) Google Scholar This finding represents the strongest genetic risk factor found to date for PA, a highly heritable disease,3Sicherer S.H. Furlong T.J. Maes H.H. Desnick R.J. Sampson H.A. Gelb B.D. Genetics of peanut allergy: a twin study.J Allergy Clin Immunol. 2000; 106: 53-56Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar with an estimated odds ratio (OR) between 1.9 (Canadian) and 5.3 (English, Dutch, and Irish combined).1Brown S.J. Asai Y. Cordell H.J. Campbell L.E. Zhao Y. Liao H. et al.Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol. 2011; 127: 661-667Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar Because there is no uniformly accepted definition of PA short of oral food challenge, it is worthwhile to examine whether the association between the FLG LOF mutations and PA varies with the diagnostic criteria for PA. Furthermore, the frequent coexistence of PA with other atopic conditions may mean that the association between PA and FLG LOF mutations is confounded. Although we controlled for eczema in the European populations in our previous work, data on eczema were not available for the Canadian control group; however, data on asthma were available. Asthma is a potential confounder, as it has known relationships with both PA4Liu A.H. Jaramillo R. Sicherer S.H. Wood R.A. Bock S.A. Burks A.W. et al.National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006.J Allergy Clin Immunol. 2010; 126: 798-806.e13Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar and FLG mutations.5Palmer C.N. Ismail T. Lee S.P. Terron-Kwiatkowski A. Zhao Y. Liao H. et al.Filaggrin null mutations are associated with increased asthma severity in children and young adults.J Allergy Clin Immunol. 2007; 120: 64-68Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar By using statistical sensitivity analyses, we examined the effect of PA diagnostic criteria and asthma on the relationship between PA and FLG LOF mutations in a Canadian PA case group. Because the PA case group was composed of both English- and French-speaking individuals, we also investigated whether the difference in OR between the Canadian and European populations could be due to some common French-Canadian mutations not yet identified in FLG.Caucasian subjects from a well-described Canadian pediatric PA case group were recruited (n = 679), and DNA was isolated from salivary samples.1Brown S.J. Asai Y. Cordell H.J. Campbell L.E. Zhao Y. Liao H. et al.Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol. 2011; 127: 661-667Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar One control group consisted of adult Caucasians recruited from the general population of Ontario, Canada; DNA was provided by the Ontario Population Genomics Platform at The Centre for Applied Genomics (Toronto) (n = 894). A second control group of newborn babies from Quebec City was sampled on the basis of French-Canadian surname (stored blood; n = 268).6Girouard J. Giguere Y. Delage R. Rousseau F. Prevalence of HFE gene C282Y and H63D mutations in a French-Canadian population of neonates and in referred patients.Hum Mol Genet. 2002; 11: 185-189Crossref PubMed Scopus (18) Google Scholar All samples were genotyped in Dundee, Scotland, for the 4 most common FLG LOF mutations found in Caucasians (R501X, 2282del4, R2447X, and S3247X). rs and accession numbers for mutations are available in the Online Repository at www.jacionline.org (see Table E1)."Mutation carriers" were defined as those with heterozygous, homozygous, or compound heterozygous mutations. Those individuals with none of the 4 FLG mutations were classified as "nonmutation carriers." The association between mutation status and PA was compared with the Ontario control group, the Quebec control group, and the combined control group. To evaluate whether the association between PA and mutation status changed with case definition, a continuum of PA case definitions was constructed and the resulting OR trends with case definition were examined by using the combined control groups. The methodology and rationale for these definitions are given in the Online Repository available at www.jacionline.org (see Tables E2 and E3). To increase power, case definitions were transformed into an ordered variable and the association between PA and FLG mutations was examined by using regression modeling through increasingly stringent definitions of PA to see whether the OR changed significantly.We also examined the effect of asthma on FLG mutation status and PA. Logistic regression using the Ontario control group was conducted with PA status, age, sex, asthma, and interaction terms for PA and age, PA and sex, and PA and asthma. Because there may be interaction between mutation status, asthma, and smoking,7Berg N.D. Husemoen L.L. Thuesen B.H. Hersoug L.G. Elberling J. Thyssen J.P. et al.Interaction between filaggrin null mutations and tobacco smoking in relation to asthma.J Allergy Clin Immunol. 2012; 129 (e1-2): 374-380Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and self-identified asthmatic patients may have significant misclassification, analyses controlled for smoking history in the controls and misclassification in the asthma variable in both controls and cases. A constructed atopic asthma variable was used to control for the effect of smoking with 4 assumptions: (1) Those individuals who have atopic asthma in childhood are less likely to smoke as adults. (2) Those adults who have asthma and have never smoked are more likely to have atopic asthma. (3) If a patient reports bronchial emphysema, he or she does not have atopic asthma. (4) Asthma reported in the case group is atopic. To examine the possibility of error due to self-report of asthma, we completed a sensitivity analysis taking into account data from the PA registry that found that 6% had "forgotten" previously noted atopic history, while 12% more reported atopic history on the current questionnaire than at baseline registry recruitment. Random sampling and subsequent logistic regression modeling was completed 100 times to see the overall effect of error in asthma reporting on the relationship of PA and FLG LOF mutations using these parameters.Finally, a similar sensitivity analysis of PA status was conducted, as PA status could be affected by the age disparity between the Ontario control group and the cases, because it is estimated that up to 20% of individuals with PA may have resolution of their allergy.8Skolnick H.S. Conover-Walker M.K. Koerner C.B. Sampson H.A. Burks W. Wood R.A. The natural history of peanut allergy.J Allergy Clin Immunol. 2001; 107: 367-374Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar This sensitivity analysis also took into account the 1% prevalence of PA in the general population.9Ben-Shoshan M. Harrington D.W. Soller L. Fragapane J. Joseph L. St Pierre Y. et al.A population-based study on peanut, tree nut, fish, shellfish, and sesame allergy prevalence in Canada.J Allergy Clin Immunol. 2010; 125: 1327-1335Abstract Full Text Full Text PDF PubMed Scopus (174) Google ScholarOf the 679 cases eligible to participate, 99.3% had good quality DNA. Demographic information is presented in Table I. The 674 cases had approximately twice as many mutations as the controls (20% vs 11%), and the OR for PA and FLG mutation status was similar in the Ontario and Quebec control groups (Table II). The genotype frequencies in cases and controls are shown in the Online Repository available at www.jacionline.org (see Table E4). Among the 13 case definitions, there was no significant difference in the OR for the relationship between PA and FLG mutation status. Seven representative case definitions are shown in Table III. Logistic regression of the ordered case definition criteria variable produced similar results.Table IDemographics: PA cases and controlsCharacteristicPA casesOntario controlsQuebec controlsNo. of subjects674894268Age (y)∗Age on January 1, 2009. Mean ± SD9.3 ± 4.065.5 ± 10.29.7 ± 0.5 Range0-2133-847-10 No. with missing data020Sex No. of males416281157 Proportion of males (CI)0.617 (0.580-0.654)0.315 (0.284-0.346)0.586 (0.526-0.645)∗ Age on January 1, 2009. Open table in a new tab Table IIFLG genotypes and statistical tests of PA cases compared with control groupsPA casesOntario controlsQuebec controlsCombined controlsNo. of analyzed subjects∗Genotyping failures occurred in 11 PA cases, 5 of the Ontario controls, and 1 of the Quebec controls.6638892671156No. of FLG heterozygotes†One FLG mutation detected.1129429123No. of FLG homozygotes/compound heterozygotes‡Two of the same (FLG homozygote) or 2 different (compound heterozygote) FLG mutations detected.18415Total no. with 1 or 2 FLG mutations1309830128Proportion with 1 or 2 FLG mutations0.1960.1100.1120.110ORNA1.971.931.9695% CINA1.47-2.651.24-3.061.49-2.58χ2 test (P value)NA22.33 (2.30 × 10−6)9.37 (2.21 × 10−3)25.22 (5.12 × 10−7)NA, Not applicable.∗ Genotyping failures occurred in 11 PA cases, 5 of the Ontario controls, and 1 of the Quebec controls.† One FLG mutation detected.‡ Two of the same (FLG homozygote) or 2 different (compound heterozygote) FLG mutations detected. Open table in a new tab Table IIIPA case definition analysis (PA cases compared with the combined control group)No. of subjectsOR95% CIMinimum criteria to be considered for inclusion:a.Convincing history of PA∗A convincing history was defined as a minimum of 2 mild symptoms/signs or either 1 moderate or 1 severe symptom/sign occurring within 120 min after peanut contact or ingestion. (1) Mild: pruritus, urticaria, flushing, and/or rhinoconjunctivitis. (2) Moderate: angioedema, throat tightness, change in voice, coughing, difficulty breathing (other than wheeze), nausea and/or vomiting, and/or abdominal pain. (3) Severe: wheezing, stridor, cyanosis, and/or circulatory collapse. and (i) SPT ≥3 mm or (ii) psIgE ≥ 0.35 kU/L orb.No history of peanut ingestion/uncertain history of allergy and (i) SPT ≥3 mm and (ii) psIgE ≥15 kU/L orc.Any history suggestive of an IgE-mediated reaction not compatible with anaphylaxis and (i) SPT ≥8 mm or (ii) SPT ≥4 mm if <2 y old or (iii) psIgE ≥15 kU/L ord.Positive OFC6741.961.49-2.58psIgE ≥15 kU/L or SPT ≥8 mm, or positive OFC†The definition used in our previous work1 required a history of anaphylaxis or a history suggestive of type I hypersensitivity to peanut along with SPT ≥8 mm and psIgE ≥15 kU/L.5261.971.47-2.65psIgE ≥57 kU/L or SPT ≥8 mm, or positive OFC4862.071.53-2.78psIgE ≥57 kU/L or SPT ≥15 mm, or positive OFC2672.071.42-2.96psIgE ≥15 kU/L, or SPT ≥8 mm AND anaphylaxis, or positive OFC2662.091.44-3.00psIgE ≥57 kU/L, or SPT ≥8 mm AND anaphylaxis, or positive OFC2532.211.52-3.18psIgE ≥57 kU/L, or SPT ≥15 mm AND anaphylaxis, or positive OFC1222.281.38-3.69OFC, Oral food challenge; psIgE, peanut-specific immunoglobulin E; SPT, skin prick test.∗ A convincing history was defined as a minimum of 2 mild symptoms/signs or either 1 moderate or 1 severe symptom/sign occurring within 120 min after peanut contact or ingestion. (1) Mild: pruritus, urticaria, flushing, and/or rhinoconjunctivitis. (2) Moderate: angioedema, throat tightness, change in voice, coughing, difficulty breathing (other than wheeze), nausea and/or vomiting, and/or abdominal pain. (3) Severe: wheezing, stridor, cyanosis, and/or circulatory collapse.† The definition used in our previous work1 required a history of anaphylaxis or a history suggestive of type I hypersensitivity to peanut along with SPT ≥8 mm and psIgE ≥15 kU/L. Open table in a new tab The self-reported prevalence of asthma was 11% in the Ontario controls, compared with 65% in the PA cases (see Table E5 in this article's Online Repository at www.jacionline.org). Univariate analysis found PA status to be the strongest predictor of a mutation, followed by asthma. Neither age nor gender had an appreciable relationship with the presence of FLG mutations on univariate or multivariate analysis and were not included in the final model. Multivariate logistic regression found no evidence for an effect of asthma (OR, 1.12; 95% CI, 0.79-1.59) on the relationship between PA (OR, 1.81; 95% CI, 1.29-2.55) and FLG LOF mutations. The proportion of mutations was similar in those PA cases with and without asthma. Peanut-allergic individuals with asthma had at least 1 mutation in 19.8% of the cases (95% CI, 0.159-0.236), while 18.7% (95% CI, 0.136-0.238) of the PA cases without asthma had at least 1 mutation.An additional analysis using a constructed atopic asthma variable to control for the effect of smoking yielded similar results. PA status remained significant (OR, 1.88; 95% CI, 1.27-2.80), while history of atopic asthma was not (OR, 1.44; 95% CI, 0.59-3.53). Results were also unchanged after the sensitivity analysis of the self-reported asthma variable, with only PA status remaining significant in the multivariate analysis. The sensitivity analysis on PA status similarly had little effect on the findings. While 20% resolution in cases alone finds that both PA and asthma status are nonsignificant, modeling 20% resolution of cases with 1% prevalence in the general population finds that only PA status remains significant in the multivariate model.This study substantiates the relationship between PA and FLG LOF mutations, and moreover this relationship appears independent of diagnostic criteria of PA and history of asthma, although residual confounding is always possible. All sets of diagnostic criteria used in this study were intended to define individuals with clinical allergy, although it is possible that some individuals who were merely sensitized could have been included in the less stringent definitions of PA. Despite this possibility, the association between the FLG LOF mutations and PA does not appear to vary with the diagnostic criteria for PA. Although the point estimates for the OR increase as the PA definition becomes more stringent, the sample size decreases and the CIs overlap; thus, the differences are not statistically significant.The similarity of the OR in the 2 control groups provides indirect evidence that it is unlikely that there are common FLG mutations not yet identified in French-Canadians, under the assumption of similar prevalence of PA. If unidentified common French-Canadian FLG variants exist, one would expect the observed OR to be higher when the PA cases were compared with the Quebec controls, due to a lower detection of mutations in the control group. However, further evidence such as the sequencing of FLG in French-Canadians would be of interest.Limitations of this study include the inability to verify ethnicity by using genetic markers of ethnicity, which were not available for either the cases or controls. However, of the 47 identified FLG mutations, those examined here are shared in many European populations2Irvine A.D. McLean W.H. Leung D.Y. Filaggrin mutations associated with skin and allergic diseases.N Engl J Med. 2011; 365: 1315-1327Crossref PubMed Scopus (812) Google Scholar (see Table E6 in this article's Online Repository at www.jacionline.org), including the expected ancestries of our case and control groups, giving us confidence that population stratification is not the cause of the difference in mutation frequency in the cases and controls. The rate of mutations in the control groups is comparable to the number seen in other Caucasian general populations (Table E6), which also leads us to believe that we have not overestimated the association. This study was also impeded by the inability to confirm asthma status by diagnostic means and that the only control group for which we had asthma and smoking history was a group of adults. While genotype will not change with age, the age difference could have affected ethnicity (eg, through different times of immigration) and PA status because of generational lifestyle, dietary, or environmental differences. Asthma status could also be affected by this age difference, because of smoking history, failure to remember a history of childhood asthma, as well as the possibility that cases have not yet developed asthma, although there is already a large proportion of PA cases who report asthma. In an effort to address these issues, sensitivity analyses of both PA and smoking status were undertaken, which found no appreciable effects on the findings of this study.The results of this study lend credence to the hypothesis that sensitization in allergic in at least some patients may through the J. J. I. R. to peanut oral and allergic PubMed Scopus Google Scholar peanut is a risk factor for the of H. peanut as a risk factor for the of peanut allergy.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar and may be a for the of peanut for a young to peanut may be to to such as that with peanut R. M. The prevalence of peanut sensitization in childhood is due to to 2011; PubMed Scopus Google Scholar filaggrin is not the to these through the skin or could result in to If the to either barrier or may allergic research in barrier and environmental is to further of the of atopic Recently, our research team found a strong and significant association between loss-of-function (LOF) mutations in filaggrin (FLG), a gene that encodes a skin barrier protein, in European and Canadian individuals with peanut allergy (PA).1Brown S.J. Asai Y. Cordell H.J. Campbell L.E. Zhao Y. Liao H. et al.Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol. 2011; 127: 661-667Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar These mutations result in a barrier defect and have been associated with atopic dermatitis, asthma, and allergic rhinitis.2Irvine A.D. McLean W.H. Leung D.Y. Filaggrin mutations associated with skin and allergic diseases.N Engl J Med. 2011; 365: 1315-1327Crossref PubMed Scopus (812) Google Scholar This finding represents the strongest genetic risk factor found to date for PA, a highly heritable disease,3Sicherer S.H. Furlong T.J. Maes H.H. Desnick R.J. Sampson H.A. Gelb B.D. Genetics of peanut allergy: a twin study.J Allergy Clin Immunol. 2000; 106: 53-56Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar with an estimated odds ratio (OR) between 1.9 (Canadian) and 5.3 (English, Dutch, and Irish combined).1Brown S.J. Asai Y. Cordell H.J. Campbell L.E. Zhao Y. Liao H. et al.Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol. 2011; 127: 661-667Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar Because there is no uniformly accepted definition of PA short of oral food challenge, it is worthwhile to examine whether the association between the FLG LOF mutations and PA varies with the diagnostic criteria for PA. Furthermore, the frequent coexistence of PA with other atopic conditions may mean that the association between PA and FLG LOF mutations is confounded. Although we controlled for eczema in the European populations in our previous work, data on eczema were not available for the Canadian control group; however, data on asthma were available. Asthma is a potential confounder, as it has known relationships with both PA4Liu A.H. Jaramillo R. Sicherer S.H. Wood R.A. Bock S.A. Burks A.W. et al.National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006.J Allergy Clin Immunol. 2010; 126: 798-806.e13Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar and FLG mutations.5Palmer C.N. Ismail T. Lee S.P. Terron-Kwiatkowski A. Zhao Y. Liao H. et al.Filaggrin null mutations are associated with increased asthma severity in children and young adults.J Allergy Clin Immunol. 2007; 120: 64-68Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar By using statistical sensitivity analyses, we examined the effect of PA diagnostic criteria and asthma on the relationship between PA and FLG LOF mutations in a Canadian PA case group. Because the PA case group was composed of both English- and French-speaking individuals, we also investigated whether the difference in OR between the Canadian and European populations could be due to some common French-Canadian mutations not yet identified in Caucasian subjects from a well-described Canadian pediatric PA case group were recruited (n = 679), and DNA was isolated from salivary samples.1Brown S.J. Asai Y. Cordell H.J. Campbell L.E. Zhao Y. Liao H. et al.Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.J Allergy Clin Immunol. 2011; 127: 661-667Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar One control group consisted of adult Caucasians recruited from the general population of Ontario, Canada; DNA was provided by the Ontario Population Genomics Platform at The Centre for Applied Genomics (Toronto) (n = 894). A second control group of newborn babies from Quebec City was sampled on the basis of French-Canadian surname (stored blood; n = 268).6Girouard J. Giguere Y. Delage R. Rousseau F. Prevalence of HFE gene C282Y and H63D mutations in a French-Canadian population of neonates and in referred patients.Hum Mol Genet. 2002; 11: 185-189Crossref PubMed Scopus (18) Google Scholar All samples were genotyped in Dundee, Scotland, for the 4 most common FLG LOF mutations found in Caucasians (R501X, 2282del4, R2447X, and S3247X). rs and accession numbers for mutations are available in the Online Repository at www.jacionline.org (see Table carriers" were defined as those with heterozygous, homozygous, or compound heterozygous mutations. Those individuals with none of the 4 FLG mutations were classified as "nonmutation carriers." The association between mutation status and PA was compared with the Ontario control group, the Quebec control group, and the combined control group. To evaluate whether the association between PA and mutation status changed with case definition, a continuum of PA case definitions was constructed and the resulting OR trends with case definition were examined by using the combined control groups. The methodology and rationale for these definitions are given in the Online Repository available at www.jacionline.org (see Tables E2 and E3). To increase power, case definitions were transformed into an ordered variable and the association between PA and FLG mutations was examined by using regression modeling through increasingly stringent definitions of PA to see whether the OR changed also examined the effect of asthma on FLG mutation status and PA. Logistic regression using the Ontario control group was conducted with PA status, age, sex, asthma, and interaction terms for PA and age, PA and sex, and PA and asthma. Because there may be interaction between mutation status, asthma, and smoking,7Berg N.D. Husemoen L.L. Thuesen B.H. Hersoug L.G. Elberling J. Thyssen J.P. et al.Interaction between filaggrin null mutations and tobacco smoking in relation to asthma.J Allergy Clin Immunol. 2012; 129 (e1-2): 374-380Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and self-identified asthmatic patients may have significant misclassification, analyses controlled for smoking history in the controls and misclassification in the asthma variable in both controls and cases. A constructed atopic asthma variable was used to control for the effect of smoking with 4 assumptions: (1) Those individuals who have atopic asthma in childhood are less likely to smoke as adults. (2) Those adults who have asthma and have never smoked are more likely to have atopic asthma. (3) If a patient reports bronchial emphysema, he or she does not have atopic asthma. (4) Asthma reported in the case group is atopic. To examine the possibility of error due to self-report of asthma, we completed a sensitivity analysis taking into account data from the PA registry that found that 6% had "forgotten" previously noted atopic history, while 12% more reported atopic history on the current questionnaire than at baseline registry recruitment. Random sampling and subsequent logistic regression modeling was completed 100 times to see the overall effect of error in asthma reporting on the relationship of PA and FLG LOF mutations using these a similar sensitivity analysis of PA status was conducted, as PA status could be affected by the age disparity between the Ontario control group and the cases, because it is estimated that up to 20% of individuals with PA may have resolution of their allergy.8Skolnick H.S. Conover-Walker M.K. Koerner C.B. Sampson H.A. Burks W. Wood R.A. The natural history of peanut allergy.J Allergy Clin Immunol. 2001; 107: 367-374Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar This sensitivity analysis also took into account the 1% prevalence of PA in the general population.9Ben-Shoshan M. Harrington D.W. Soller L. Fragapane J. Joseph L. St Pierre Y. et al.A population-based study on peanut, tree nut, fish, shellfish, and sesame allergy prevalence in Canada.J Allergy Clin Immunol. 2010; 125: 1327-1335Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar the 679 cases eligible to participate, 99.3% had good quality DNA. Demographic information is presented in Table I. The 674 cases had approximately twice as many mutations as the controls (20% vs 11%), and the OR for PA and FLG mutation status was similar in the Ontario and Quebec control groups (Table II). The genotype frequencies in cases and controls are shown in the Online Repository available at www.jacionline.org (see Table E4). Among the 13 case definitions, there was no significant difference in the OR for the relationship between PA and FLG mutation status. Seven representative case definitions are shown in Table III. Logistic regression of the ordered case definition criteria variable produced similar results. Not Oral food challenge; psIgE, peanut-specific immunoglobulin E; SPT, skin prick The self-reported prevalence of asthma was 11% in the Ontario controls, compared with 65% in the PA cases (see Table E5 in this article's Online Repository at www.jacionline.org). Univariate analysis found PA status to be the strongest predictor of a mutation, followed by asthma. Neither age nor gender had an appreciable relationship with the presence of FLG mutations on univariate or multivariate analysis and were not included in the final model. Multivariate logistic regression found no evidence for an effect of asthma (OR, 1.12; 95% CI, 0.79-1.59) on the relationship between PA (OR, 1.81; 95% CI, 1.29-2.55) and FLG LOF mutations. The proportion of mutations was similar in those PA cases with and without asthma. Peanut-allergic individuals with asthma had at least 1 mutation in 19.8% of the cases (95% CI, 0.159-0.236), while 18.7% (95% CI, 0.136-0.238) of the PA cases without asthma had at least 1 additional analysis using a constructed atopic asthma variable to control for the effect of smoking yielded similar results. PA status remained significant (OR, 1.88; 95% CI, 1.27-2.80), while history of atopic asthma was not (OR, 1.44; 95% CI, 0.59-3.53). Results were also unchanged after the sensitivity analysis of the self-reported asthma variable, with only PA status remaining significant in the multivariate analysis. The sensitivity analysis on PA status similarly had little effect on the findings. While 20% resolution in cases alone finds that both PA and asthma status are nonsignificant, modeling 20% resolution of cases with 1% prevalence in the general population finds that only PA status remains significant in the multivariate

Vitamin D and Atopy

Staphylococcus aureus is an opportunistic pathogen and variable component of the human microbiota. A characteristic of atopic eczema (AE) is colonization by S. aureus, with exacerbations associated with an increased bacterial burden of the organism. Despite this, the origins and genetic diversity of S. aureus colonizing individual patients during AE disease flares is poorly understood. To examine the microevolution of S. aureus colonization, we deep sequenced S. aureus populations from nine children with moderate to severe AE and 18 non-atopic children asymptomatically carrying S. aureus nasally. Colonization by clonal S. aureus populations was observed in both AE patients and control participants, with all but one of the individuals carrying colonies belonging to a single sequence type. Phylogenetic analysis showed that disease flares were associated with the clonal expansion of the S. aureus population, occurring over a period of weeks to months. There was a significant difference in the genetic backgrounds of S. aureus colonizing AE cases versus controls (Fisher exact test, P = 0.03). Examination of intra-host genetic heterogeneity of the colonizing S. aureus populations identified evidence of within-host selection in the AE patients, with AE variants being potentially selectively advantageous for intracellular persistence and treatment resistance.

Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis

Patient characteristics associated with allergen immunotherapy initiation and adherence

Atopic dermatitis (AD) is the most common skin disease in childhood and the first step of atopic march. This study aimed to investigate whether AD in children could be better predicted by biologic markers (cord blood IgE [cbIgE], LT-αNcoI alleles, and FcεRI-β E237G genotypes) and maternal mentality during pregnancy, taking into account gender, socio-demographic factors, and parental atopy. From 2001 to 2005, 1264 mother-infant pairs were recruited to participate in a birth cohort study. Prenatal questionnaire was used to collect family history, maternal gestational conditions and mentality, and environmental exposures. Cord blood was collected and assayed for genotypes and IgE levels. Phone interviews at 6 months and 2 yrs of age were conducted to inquire children's health status, including AD occurrence. In addition to the known risk factors such as gender, maternal education, and parental atopy, biomarkers and maternal mentality during pregnancy were screened by logistic regression as candidate predictors of AD. Area-under-curve (AUC) statistic from receiver-operating characteristic (ROC) curve analysis was used to compare two predicting models with and without biomarkers and maternal mentality. A total of 730 pairs completed the prenatal questionnaire and phone interview and were included in final analysis. The prevalence of ever having physician-diagnosed AD by 2-yr-olds was 5.9%. Elevated cbIgE levels (≥0.5 kU/l), LT-αNcoI alleles, FcεRI-β E237G genotype, and maternal psychologic stress during pregnancy were significantly associated with AD. Comparison with AUCs of the classic model (including gender, maternal education, and parental atopy), the model adding cbIgE levels, genotypes in cytokine genes, and maternal stress (model 2) showed higher ability to discriminate between children with and without AD (AUC statistics: 0.63 [95% CI = 0.60-0.67] vs. 0.73 [95% CI = 0.70-0.76], respectively; model comparison, p = 0.027). We conclude that elevated cbIgE, LT-α and FcεRI-β genotypes, and maternal stress during pregnancy were associated with ever having physician-diagnosed AD in 2-yr-old children and increased the predictive ability for AD after taking into account gender, maternal education, and parental atopic history.

Allergy to ingested mycoprotein in a patient with mold spore inhalant allergy

Serotonin Activates Human Monocytes and Prevents Apoptosis

In mouse Paneth cells, alpha-defensins, termed cryptdins (Crps), are activated by matrix metalloproteinase-7-mediated proteolysis of inactive precursors (pro-Crps) to bactericidal forms. The activating cleavage step at Ser(43) downward arrow Ile(44) in mouse pro-Crp4-(20-92) removes nine acidic amino acids that collectively block the membrane-disruptive behavior of the Crp4 moiety of the proform. This inhibitory mechanism has been investigated further to identify whether specific cluster(s) of electronegative amino acids in pro-Crp4-(20-43) are responsible for blocking bactericidal activity and membrane disruption. To test whether specific cluster(s) of electronegative amino acids in pro-Crp4-(20-43) have specific positional effects that block bactericidal peptide activity and membrane disruption, acidic residues positioned at the distal (Asp(20), Asp(26), Glu(27), and Glu(28)), mid (Glu(32) and Glu(33)), and proximal (Glu(37), Glu(38), and Asp(39)) clusters in pro-Crp4-(20-92) were mutagenized, and variants were assayed for differential effects of mutagenesis on bactericidal peptide activity. Substitution of the mid and proximal Asp and Glu clusters with Gly produced additive effects with respect to the induction of both bactericidal activity and membrane permeabilization of live Escherichia coli ML35 cells. In contrast, substitution of distal Glu and Asp residues with Gly or their deletion resulted in pro-Crp4-(20-92) variants with bactericidal and membrane-disruptive activities equal to or greater than that of fully mature Crp4. These findings support the conclusion that the most distal N-terminal anionic residues of pro-Crp4-(20-92) are primarily responsible for blocking Crp4-mediated membrane disruption in the precursor.

Rhinitis with negative skin tests and absent serum allergen-specific IgE: More evidence for local IgE?

Disease characteristics, comorbidities, treatment patterns and quality of life impact in children <12 years old with atopic dermatitis: Interim results from the PEDISTAD Real-World Registry

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Advances in pediatric asthma in 2009: Gaining control of childhood asthma