Filaggrin gene mutation associations with peanut allergy persist despite variations in peanut allergy diagnostic criteria or asthma status

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 into data from the PA that found that atopic more reported atopic history on the at and regression modeling was completed to see the effect of error in asthma on the relationship of PA and FLG LOF mutations using these a sensitivity of PA status was as PA status could be by the between the Ontario control group and the it is estimated that to of individuals with PA may have of Sampson H.A. Burks Wood R.A. The history of peanut allergy.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar This sensitivity also into the prevalence of PA in the general J. Y. et on and allergy prevalence in Allergy Clin Immunol. 2010; Full Text Full Text PDF PubMed Scopus (174) Google the to is in Table The as mutations as the controls and the OR for PA and FLG mutation status was in the Ontario and Quebec control The in and controls are in the Online Repository available at www.jacionline.org (see Table the case there was no significant difference in the OR for the relationship between PA and FLG mutation case definitions are in Table Logistic regression of the ordered case definition criteria variable PA and of on with of of on in a Table and statistical of PA compared with control of in PA of the Ontario and of the Quebec of FLG FLG mutation of FLG of the or FLG mutations with or FLG with or FLG in PA of the Ontario and of the Quebec One FLG mutation of the or FLG mutations in a Table case definition compared with the combined control of criteria to be for history of history was defined as a of or or peanut or (1) (2) in (3) and or history of peanut history of allergy and and history of an not with and or or or or definition used in our previous a history of or a history of to peanut with and or or or or or or or or or or food skin A history was defined as a of or or peanut or (1) (2) in (3) The definition used in our previous a history of or a history of to peanut with and in a The prevalence of asthma was in the Ontario compared with in the PA (see Table in Online Repository at found PA status to be the strongest of a by asthma. an relationship with the of FLG mutations on or and were not in the regression found no for an effect of asthma on the relationship between PA and FLG LOF mutations. The of mutations was in those PA with and asthma. individuals with asthma at mutation in of the of the PA asthma at using a constructed atopic asthma variable to control for the effect of smoking PA status significant history of atopic asthma was not were also the sensitivity of the asthma with PA status significant in the The sensitivity on PA status effect on the in that both PA and asthma status are modeling of with prevalence in the general population that PA status significant in the the relationship between PA and FLG LOF and relationship of diagnostic criteria of PA and history of asthma, is All of diagnostic criteria used in were to individuals with it is that some individuals who were could have been in the less stringent definitions of PA. the association between the FLG LOF mutations and PA does not to with the diagnostic criteria for PA. Although the for the OR increase as the PA definition more the and the the are not of the OR in the control that it is that there are common FLG mutations not yet identified in the of prevalence of PA. If common French-Canadian FLG variants the OR to be the PA were compared with the Quebec due to a of mutations in the control group. as the of FLG in be of of the to by using genetic of were not available for the or of the identified FLG those examined are in European 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 in Online Repository at the of our case and control that population is not the of the difference in mutation in the and The of mutations in the control is to the in other general populations also to that we have not the This was also by the to asthma status by diagnostic and that the control group for we asthma and smoking history was a group of adults. not with age, the difference could have through of and PA status of or Asthma status could also be by of smoking to a history of childhood asthma, as as the possibility that have not yet asthma, there is a of PA who asthma. an to these sensitivity analyses of both PA and smoking status were found no on the of results of to the that in allergic in at some patients may through the J. J. 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 as that with peanut R. The prevalence of peanut 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 barrier or may allergic research in barrier and is to 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 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 into data from the PA that found that atopic more reported atopic history on the at and regression modeling was completed to see the effect of error in asthma on the relationship of PA and FLG LOF mutations using these a sensitivity of PA status was as PA status could be by the between the Ontario control group and the it is estimated that to of individuals with PA may have of Sampson H.A. Burks Wood R.A. The history of peanut allergy.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar This sensitivity also into the prevalence of PA in the general J. Y. et on and allergy prevalence in Allergy Clin Immunol. 2010; Full Text Full Text PDF PubMed Scopus (174) Google Scholar the to is in Table The as mutations as the controls and the OR for PA and FLG mutation status was in the Ontario and Quebec control The in and controls are in the Online Repository available at www.jacionline.org (see Table the case there was no significant difference in the OR for the relationship between PA and FLG mutation case definitions are in Table Logistic regression of the ordered case definition criteria variable food skin The prevalence of asthma was in the Ontario compared with in the PA (see Table in Online Repository at found PA status to be the strongest of a by asthma. an relationship with the of FLG mutations on or and were not in the regression found no for an effect of asthma on the relationship between PA and FLG LOF mutations. The of mutations was in those PA with and asthma. individuals with asthma at mutation in of the of the PA asthma at using a constructed atopic asthma variable to control for the effect of smoking PA status significant history of atopic asthma was not were also the sensitivity of the asthma with PA status significant in the The sensitivity on PA status effect on the in that both PA and asthma status are modeling of with prevalence in the general population that PA status significant in the This the relationship between PA and FLG LOF and relationship of diagnostic criteria of PA and history of asthma, is All of diagnostic criteria used in were to individuals with it is that some individuals who were could have been in the less stringent definitions of PA. the association between the FLG LOF mutations and PA does not to with the diagnostic criteria for PA. Although the for the OR increase as the PA definition more the and the the are not The of the OR in the control that it is that there are common FLG mutations not yet identified in the of prevalence of PA. If common French-Canadian FLG variants the OR to be the PA were compared with the Quebec due to a of mutations in the control group. as the of FLG in be of of the to by using genetic of were not available for the or of the identified FLG those examined are in European 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 in Online Repository at the of our case and control that population is not the of the difference in mutation in the and The of mutations in the control is to the in other general populations also to that we have not the This was also by the to asthma status by diagnostic and that the control group for we asthma and smoking history was a group of adults. not with age, the difference could have through of and PA status of or Asthma status could also be by of smoking to a history of childhood asthma, as as the possibility that have not yet asthma, there is a of PA who asthma. an to these sensitivity analyses of both PA and smoking status were found no on the of The results of to the that in allergic in at some patients may through the J. J. 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 as that with peanut R. The prevalence of peanut 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 barrier or may allergic research in barrier and is to of the of atopic not of the of the skin is to the of on food S.J. A.H. et skin to with severity of peanut 2007; PubMed Scopus Google J. of peanut food of the peanut skin and Allergy Immunol. 2010; PubMed Scopus Google Scholar the of is to on food and of to peanut in 2007; PubMed Scopus Google Scholar of the case definitions were by using the criteria in Table and accession numbers of FLG in a Table and used for case of food allergy children with atopic Allergy Immunol. 2000; 11: PubMed Scopus Google Lee J. R.A. et allergy: a Allergy Asthma Immunol. Full Text PDF PubMed Scopus Google peanut allergy with skin and Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google H.A. of in food allergy.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google Y. et of in the of food Allergy Clin Immunol. 2010; Full Text Full Text PDF PubMed Scopus Google F. for peanut allergy by the combined of skin and Allergy Clin Immunol. 2002; Full Text Full Text PDF PubMed Scopus (174) Google R. Y. The of a skin to peanut in Allergy Asthma Immunol. Full Text PDF PubMed Scopus Google Lee J. R.A. et allergy: a Allergy Asthma Immunol. Full Text PDF PubMed Scopus Google peanut allergy with skin and Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google H.A. of in food allergy.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google R. of skin in food to and peanut in 2000; PubMed Scopus Google of for allergy in in relation to allergy or PubMed Scopus Google F. for peanut allergy by the combined of skin and Allergy Clin Immunol. 2002; Full Text Full Text PDF PubMed Scopus (174) Google A. skin skin and in the of peanut allergy in Allergy Immunol. 2007; PubMed Scopus Google food Lee J. R.A. et allergy: a Allergy Asthma Immunol. Full Text PDF PubMed Scopus Google and H.A. A. Campbell Bock S.A. A. et on the definition and of National of Allergy and Allergy and Med. Full Text Full Text PDF PubMed Scopus Google Scholar in a Table case definitions of history of an allergic to peanut and of to peanut or history of peanut history of PA and of and history of an not with as defined and of or of of R. of skin in food to and peanut in 2000; PubMed Scopus Google the for food in young a of in with in PubMed Scopus Google Scholar or or or or or or or or or or or or or or and or or and or or and or or and or or and or or and or food skin in a Table of subjects with FLG in PA and none of the 4 FLG mutations none of the 4 FLG mutations in a Table emphysema, and smoking PA and of with with asthma with with bronchial with bronchial with of of with in a Table mutation in European S.J. Liao H. Zhao Y. A. McLean W.H. et al.Filaggrin is highly and is associated with increased severity of of the skin in a of J PubMed Scopus Google J. Lee S.P. Liao H. Zhao Y. et of associated with filaggrin a study.J Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google A. Terron-Kwiatkowski A. et of the gene filaggrin and mutations in and atopic Genet. 2007; PubMed Scopus Google C.N. A.D. Terron-Kwiatkowski A. Zhao Y. Liao H. Lee S.P. et loss-of-function variants of the barrier filaggrin are a factor for atopic Genet. PubMed Scopus Google H. J. A. et of the and genetic of identified and filaggrin to eczema Allergy Clin Immunol. Full Text Full Text PDF PubMed Scopus Google R. Filaggrin mutations and in J Genet. 2007; PubMed Scopus Google J.P. A. T. et association between null mutations in the filaggrin gene and to and other in the general J 2010; PubMed Scopus Google Thyssen J.P. T. H. of atopic by filaggrin gene mutation status the of in a 2012; PubMed Scopus Google T. A. H. et of and FLG in a atopic 2007; PubMed Scopus Google J. R. Y. et of filaggrin mutations on and of the in to atopic 2012; PubMed Scopus Google J. A. F. A. et al.Filaggrin gene are risk factors for atopic asthma in a a in 2011; PubMed Scopus Google Scholar in a Although not of the of the skin is to the of on food S.J. A.H. et skin to with severity of peanut 2007; PubMed Scopus Google J. of peanut food of the peanut skin and Allergy Immunol. 2010; PubMed Scopus Google Scholar the of is to on food and of to peanut in 2007; PubMed Scopus Google Scholar of the case definitions were by using the criteria in Table food skin

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