Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Update on risk factors for food allergy

The MALT1 locus and peanut avoidance in the risk for peanut allergy

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

Food allergy: Are we getting closer to a cure?

Relationship of IgE to basophil phenotypes in peanut-sensitized adults

The usefulness of peanut specific IgE levels for diagnosing peanut allergy has not been studied in primary and secondary care where most cases of suspected peanut allergy are being evaluated. We aimed to determine the relationship between peanut-specific IgE levels and clinical peanut allergy in peanut-sensitized children and how this was influenced by eczema, asthma and clinical setting (primary or secondary care). We enrolled 280 children (0–18 years) who tested positive for peanut-specific IgE (> 0.35 kU/L) requested by primary and secondary physicians. We used predefined criteria to classify participants into three groups: peanut allergy, no peanut allergy, or possible peanut allergy, based on responses to a validated questionnaire, a detailed food history, and results of oral food challenges.Fifty-two participants (18.6%) were classified as peanut allergy, 190 (67.9%) as no peanut allergy, and 38 (13.6%) as possible peanut allergy. The association between peanut-specific IgE levels and peanut allergy was significant but weak (OR 1.46 for a 10.0 kU/L increase in peanut-specific IgE, 95% CI 1.28-1.67). Eczema was the strongest risk factor for peanut allergy (aOR 3.33, 95% CI 1.07-10.35), adjusted for demographic and clinical characteristics. Asthma was not significantly related to peanut allergy (aOR 1.93, 95% CI 0.90-4.13). Peanut allergy was less likely in primary than in secondary care participants (OR 0.46, 95% CI 0.25-0.86), at all levels of peanut-specific IgE.The relationship between peanut-specific IgE and peanut allergy in children is weak, is strongly dependent on eczema, and is weaker in primary compared to secondary care. This limits the usefulness of peanut-specific IgE levels in the diagnosis of peanut allergy in children.

BackgroundHistory and severity of atopic dermatitis (AD) are risk factors for peanut allergy. Recent evidence suggests that children can become sensitized to food allergens through an impaired skin barrier. Household peanut consumption, which correlates strongly with peanut protein levels in household dust, is a risk factor for peanut allergy.ObjectiveWe sought to assess whether environmental peanut exposure (EPE) is a risk for peanut sensitization and allergy and whether markers of an impaired skin barrier modify this risk.MethodsPeanut protein in household dust (in micrograms per gram) was assessed in highly atopic children (age, 3-15 months) recruited to the Consortium of Food Allergy Research Observational Study. History and severity of AD, peanut sensitization, and likely allergy (peanut-specific IgE, ≥5 kUA/mL) were assessed at recruitment into the Consortium of Food Allergy Research study.ResultsThere was an exposure-response relationship between peanut protein levels in household dust and peanut skin prick test (SPT) sensitization and likely allergy. In the final multivariate model an increase in 4 log2 EPE units increased the odds of peanut SPT sensitization (1.71-fold; 95% CI, 1.13- to 2.59-fold; P = .01) and likely peanut allergy (PA; 2.10-fold; 95% CI, 1.20- to 3.67-fold; P < .01). The effect of EPE on peanut SPT sensitization was augmented in children with a history of AD (OR, 1.97; 95% CI, 1.26-3.09; P < .01) and augmented even further in children with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P < .01); the effect of EPE on PA was also augmented in children with a history of AD (OR, 2.34; 95% CI, 1.31-4.18; P < .01).ConclusionExposure to peanut antigen in dust through an impaired skin barrier in atopically inflamed skin is a plausible route for peanut SPT sensitization and PA.

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Lack G, Fox D, Northstone K, Golding J. N Engl J Med. 2003;348:977–985Because peanut allergy has increased in prevalence and is an important cause of life-threatening reactions, the authors sought to investigate possible determinants of peanut allergy.Data were obtained from the Avon Longitudinal Study of Parents and Children. This geographically defined cohort included 13 971 preschool-aged children. Forty-nine of those children had a history of peanut allergy. Thirty-six of those 49 underwent skin testing, and 29 demonstrated positive results. Peanut allergy was confirmed for 23 children with double-blind, placebo-controlled, food challenge.Pregnant women were enrolled and questioned about their allergy history before delivery and were given serial questionnaires throughout their children’s infancy and childhood. The authors prospectively identified 49 children with a history of reactions to peanuts. Twenty-three children were then confirmed as being allergic to peanuts with skin testing and double-blind, placebo-controlled, food challenge. There were 2 control groups, including children with eczema in the first 6 months of life whose mothers also had eczema and 140 children without peanut allergy who were randomly selected from the cohort. Cord blood samples stored at birth were retrieved and analyzed for peanut-specific and total immunoglobulin E (IgE) for the children with peanut allergy. Retrospective data on maternal consumption of peanuts during pregnancy and lactation, family history of peanut allergy, and the use of specific lotions and creams (the interviewer was not aware of which products contained peanut oil) were then obtained.Peanut allergy was found to be independently associated with eczematous dermatitis (rash over joints and creases or oozing crusted rash) in the first 6 months of life, intake of soy products, family history of peanut allergy, and the use of skin preparations containing peanut oil. Neither maternal peanut consumption during pregnancy and lactation nor duration of breastfeeding was found to be associated with the development of peanut allergy. Additional evidence not supporting previous concepts of in utero sensitization came from undetectable peanut-specific IgE and normal total IgE levels in cord blood.Sensitization to peanut antigens appeared to be through inflamed atopic skin, rather than via the gastrointestinal tract, possibly from the use of skin preparations with even trace amounts of peanut oil. With respect to the independent association between intake of soy products and peanut allergy, soy protein fractions have shown homology to major peanut proteins and cross-sensitization could result from exposure to a common T cell epitope.With the increase in peanut allergy and other food allergies, elucidation of risk factors for prevention of sensitization offers new strategies to combat this food allergy epidemic. Allergic sensitization through the skin has also been proposed for the development of asthma and has been demonstrated in mouse models of atopic dermatitis. Additional studies are needed to determine whether topical peanut oil treatment is definitely a risk factor for peanut allergy; however, it seems prudent to avoid the topical use of peanut oil-containing products among children with atopic dermatitis. The finding of soy consumption being associated with peanut allergy may be attributable to the increased likelihood of food-allergic children receiving soy products, rather than a specific association with peanut allergy. Confirmation of this association is needed.

Early origins of allergic disease.

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2011

BackgroundPeanut allergy has not been well characterized in Italy.ObjectiveOur aim was to better define the clinical features of peanut allergy in Italy and to detect the peanut proteins involved in allergic reactions.MethodsA total of 22 centers participated in a prospective survey of peanut allergy over a 6-month period. Clinical histories were confirmed by in vivo and/or in vitro diagnostic means in all cases. Potential risk factors for peanut allergy occurrence were considered. Levels of IgE to Arachis hypogea (Ara h) 1, 2, 3, 6, 8, and 9 and profilin were measured.ResultsA total of 395 patients (aged 2-80 years) were enrolled. Of the participants, 35% reported local reactions, 38.2% reported systemic reactions, and 26.6% experienced anaphylaxis. The sensitization profile was dominated by Ara h 9 (77% of patients were sensitized to it), whereas 35% were sensitized to pathogenesis-related protein 10 (PR-10) and 26% were sensitized to seed storage proteins (SSPs). Sensitization to 2S albumins (Ara h 2 and Ara h 6) or lipid transfer protein (LTP) was associated with the occurrence of more severe symptoms, whereas profilin and PR-10 sensitization were associated with milder symptoms. Cosensitization to profilin reduced the risk of severe reactions in both Ara h 2– and LTP-sensitized patients. SSP sensitization prevailed in younger patients whereas LTP prevailed in older patients (P < .01). SSP sensitization occurred mainly in northern Italy, whereas LTP sensitization prevailed in Italy's center and south. Atopic dermatitis, frequency of peanut ingestion, peanut consumption by other family members, or use of peanut butter did not seem to be risk factors for peanut allergy onset.ConclusionsIn Italy, peanut allergy is rare and dominated by LTP in the country's center and south and by SSP in the north. These 2 sensitizations seem mutually exclusive. The picture differs from that in Anglo-Saxon countries.

A Synopsis of the Synopses, 2020–2021

BackgroundUnderstanding risk factors for peanut allergy (PA) is essential to develop effective preventive measures.ObjectiveThe objective was to ascertain associates and predictors of PA, and the relationship between PA and asthma severity.MethodsIn a population‐based birth cohort, we investigated the association between objectively confirmed PA with early‐life environmental exposures, filaggrin (FLG)‐loss‐of‐function mutations and other atopic disease. We then examined the association of PA with longitudinal trajectories of sensitization, wheeze and allergic comorbidities, which were previously derived using machine learning. Finally, we ascertained the relationship between PA and asthma severity.ResultsPA was confirmed in 30/959 participants with evaluable data. In the multivariate analysis, eczema in infancy (OR = 4.4, 95% CI 1.5–13.2, p = 0.007), egg sensitization at age 3 years (OR = 9.7, 95% CI 3.3–29.9, p < 0.001) and early‐life cat ownership (OR = 3.0, 95% CI 1.1–8.4, p = 0.04) were independent associates of PA. In the stratified analysis among 700 participants with genetic information, in children with early‐life eczema there was no difference in FLG mutations between children with and without PA (3/18 [16.7%] vs. 42/220 [19.1%], p = 1.00). In contrast, among children without eczema, those with PA were almost eight times more likely to have FLG mutations (2/6 [33.3%] vs. 27/456 [5.9%], p = 0.049). We observed associations between PA and multiple allergic sensitization profiles derived using machine learning, with ~60‐fold increase in risk among individuals assigned to multiple early sensitization. PA was significantly associated with persistent wheeze (but not other wheeze phenotypes), and with trajectories of atopic disease characterized by co‐morbid persistent eczema and wheeze (but not with transient phenotypes). Children with PA were more likely to have asthma, but among asthmatics we found no evidence of an association between PA and asthma severity.ConclusionsPeanut allergy is associated with multiple IgE sensitization and early‐onset persistent eczema and wheeze. FLG loss‐of‐function mutations were associated with peanut allergy in children without eczema.

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