Appendix 1: Search terms

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1 Appendix 1: Search terms Embase Medline 1 filaggrin.mp. filaggrin.mp. 2 profilaggrin.mp. profilaggrin.mp. 3 1q21.mp. 1q21.mp. 4 epidermal differentiation complex.mp. epidermal differentiation complex.mp. 5 R501X.mp. R501X.mp del4.mp. 2282del4.mp delA.mp. 3321delA.mp. 8 S2554X.mp. S2554X.mp. 9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 10 exp Hypersensitivity/ exp Hypersensitivity/ 11 allerg*.mp. allerg*.mp. 12 react*, allergic.mp. react*, allergic.mp. 13 reaction, allerg*.mp. reaction, allerg*.mp or 11 or 12 or or 11 or 12 or Asthma/ Asthma/ 16 asthma.mp. asthma.mp. 17 wheez*.mp. wheez*.mp. 18 Respiratory Hypersensitivity/ Respiratory Hypersensitivity/ 19 bronchial disorder.mp. bronchial disorder.mp. 20 hyper-responsiveness wheez*.mp. hyper-responsiveness wheez*.mp. 21 exp Food Hypersensitivity/ 15 or 16 or 17 or 18 or 19 or food allerg*.mp. exp Food Hypersensitivity/ 23 food hypersensitivity.mp. food allerg*.mp. 24 food hypersensitivities.mp. food hypersensitivity.mp. 25 allergy, food.mp. food hypersensitivities.mp or 22 or 23 or 24 or 25 allergy, food.mp. 27 Dermatitis, Atopic/ 22 or 23 or 24 or 25 or exp Eczema/ Dermatitis, Atopic/ 29 Neurodermatitis/ exp Eczema/ 30 eczema.mp. Neurodermatitis/ 31 dermatitis.mp. eczema.mp. 32 dermatitides.mp. dermatitis.mp. 33 atopic dermatitis.mp. dermatitides.mp. 34 atopic dermatitides.mp. atopic dermatitis.mp. 35 atopic eczema.mp. atopic dermatitides.mp. 36 eczematous dermatiti*.mp. atopic eczema.mp. 37 dermatiti*, eczematous.mp. eczematous dermatiti*.mp. 38 besnier* prurigo.mp. dermatiti*, eczematous.mp. 39 neurodermatitis.mp. besnier* prurigo.mp. 40 dermatitis, atopic.mp. neurodermatitis.mp. 41 dermatitides, atopic.mp. dermatitis, atopic.mp. 42 eczema, atopic.mp. dermatitides, atopic.mp or 28 or 29 or 30 or 31 or 32 or 33 eczema, atopic.mp. or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or hayfever.mp. 28 or 29 or 30 or 31 or 32 or 33 or 34 or 5 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or hay fever.mp. Rhinititis/

2 46 fever, hay.mp. Rhinitis Allergic Perrenial/ 47 seasonal allergic rhinitis.mp. Rhinitis, allergic, seasonal/ 48 allergic rhinitides.mp. hayfever.mp. 49 allergic rhinitis.mp. hay fever.mp. 50 rhiniti*.mp. fever, hay.mp. 51 pollinosis.mp. seasonal allergic rhinitis.mp. 52 pollenosis.mp. allergic rhinitides.mp. 53 pollen allergy.mp. allergic rhinitis.mp. 54 allergy, pollen.mp. rhiniti*.mp. 55 allergies, pollen.mp. pollinosis.mp. 56 Nasal Obstruction/ pollenosis.mp. 57 Anaphylaxis/ pollen allergy.mp. 58 anaphylaxis react*.mp. allergy, pollen.mp. 59 anaphylactic react*.mp. allergies, pollen.mp. 60 anaphylactic shock*.mp. Nasal Obstruction/ 61 anaphylactoid syndrome*.mp. 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or anaphylactoid react*.mp. Anaphylaxis/ 63 anaphylactic syndrome*.mp. anaphylaxis react*.mp. 64 anaphylactoid shock*.mp. anaphylactic react*.mp. 65 acute systemic allergic react*.mp. anaphylactic shock*.mp. 66 idiopathic anaphylaxis.mp. anaphylactoid syndrome*.mp. 67 systemic anaphylaxis.mp. anaphylactoid react*.mp or 58 or 59 or 60 or 61 or 62 anaphylactic syndrome*.mp. or 63 or 64 or 65 or 66 or sensitisation.mp. anaphylactoid shock*.mp. 70 epidermal dysfunction.mp. acute systemic allergic react*.mp or 16 or 17 or 18 or 19 or 20 idiopathic anaphylaxis.mp. 72 Rhinitis/ systemic anaphylaxis.mp. 73 Rhinitis, Allergic, Seasonal/ 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or Rhinitis, Allergic, Perennial/ sensitisation.mp or 45 or 46 or 47 or 48 or 49 skin prick test.mp. or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 72 or 73 or skin prick test.mp. Radioallergosorbent Test/ 77 Radioallergosorbent Test/ RAST.mp. 78 RAST.mp. Immunoglobulin E/ 79 Immunoglobulin E/ Specific Ige.mp. 80 Specific IgE.mp. epidermal dysfunction or 70 or 76 or 77 or 78 or 79 or or 75 or 76 or 77 or 78 or 79 or or 26 or 43 or 68 or 71 or 75 or or 21 or 27 or 44 or 61 or 73 or exp Respiratory Tract Allergy/ 9 and respiratory hypersensitivity.mp. from 83 keep Wheezing/ 86 exp Food Allergy/ 87 eczema/ or hand eczema/ or skin allergy/ 88 exp Rhinitis/ 89 skin sensitization/ or 83 or 84 or 85 or 86 or 87 or 88 or 89

3 91 9 and from 91 keep 1-94 Web of science 1 Topic=((filaggrin OR profilaggrin OR 1q21 OR "epidermal differentiation complex" OR R501X OR 2282del4 OR 3321delA OR S2554X)) Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years Topic=(("atopic dermatitis" OR eczema OR neurodermatitis OR dermatitis OR dermatitides OR "atopic dermatitides" OR "atopic eczema" OR "eczematous dermatiti*" OR "besnier* prurigo" OR rhinitis OR "perrenial allergic rhinitis" OR "seasonal allergic rhinitis" OR hayfever OR " hay fever" OR "allergic rhinitis" OR "allergic rhinitides" OR rhiniti* OR pollinosis OR pollenosis OR "pollen allergy" OR "allergy, pollen" OR "nasal obstruction" OR anaphylaxis OR "anaphylaxis react*" OR "anaphylactic react*")) Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years 3 Topic=(("anaphylactic shock*" OR "anaphylactoid syndrome*" OR "anaphylactoid react*" OR "anaphylactic syndrome*" OR "anaphylactoid shock*" OR "acute systemic allergic react*" OR "idiopathic anaphylaxis" OR "systemic anaphylaxis" OR sensitisation OR "skin prick test" OR "radioallergosorbent test" OR RAST OR "immunoglobulin E" OR "specific IgE" OR "epidermal dysfunction")) Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years Topic=(allergy OR allergies OR allergic) Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years Topic=(hypersensitivit* OR "react*, allergic" OR "reaction, allerg*") Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years Topic=(asthma OR wheez* OR "respiratory hypersensitivity" OR "bronchial disorder" OR "hyper-responsiveness wheez*") Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years Topic=("food allerg*" OR "food hypersensitivit*" OR "allergy, food") Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years (#1) AND (#2 OR #3 OR #4 OR #5 OR #6 OR #7) Databases=SCI-EXPANDED, SSCI, A&HCI Timespan=All Years 112 Biosis 1 Topic=((filaggrin OR profilaggrin OR 1q21 OR "epidermal differentiation complex" OR R501X OR 2282del4 OR 3321delA OR S2554X)) Topic=(("atopic dermatitis" OR eczema OR neurodermatitis OR dermatitis OR dermatitides OR "atopic dermatitides" OR "atopic eczema" OR "eczematous dermatiti*" OR "besnier* prurigo" OR rhinitis OR "perrenial allergic rhinitis" OR "seasonal allergic rhinitis" OR hayfever OR " hay fever" OR "allergic rhinitis" OR "allergic rhinitides" OR rhiniti* OR pollinosis OR pollenosis OR "pollen allergy" OR "allergy, pollen" OR "nasal obstruction" OR anaphylaxis OR "anaphylaxis react*" OR "anaphylactic react*")) Topic=(("anaphylactic shock*" OR "anaphylactoid syndrome*" OR "anaphylactoid react*" OR "anaphylactic syndrome*" OR "anaphylactoid shock*" OR "acute systemic allergic react*" OR "idiopathic anaphylaxis" OR "systemic anaphylaxis" OR sensitisation OR "skin prick test" OR "radioallergosorbent test" OR RAST OR "immunoglobulin E" OR "specific IgE" OR "epidermal dysfunction")) Topic=(allergies) 5 Topic= (allergic)

4 6 Topic =(allergic disorder) 7 Topic=(allergy) different time span 8 Topic = (hypersensitivity* OR react*, allergic OR reaction, allerg* ) 9 Topic = (asthma OR wheez* OR respiratory hypersensitivity OR bronchial disorder OR hyper-responsiveness wheez* ) 10 Topic = ( food allerg* OR food hypersensitivit* OR allergy, food ) 11 (#1) AND (#2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10) 151

5 Appendix 2: Quality assessment form Yes Unclear No Not applicable 1. Purpose of study clearly defined 2. Appropriateness of study design 3. Phenotype clearly defined Analytic validity of genotyping 4. Description of types of samples used (for cases and controls) - specimen source processing 5. Timing of sample collection and analysis, by study group* (cases vs. controls) 6. Success rate in extracting DNA, by study group* (cases vs. controls) 7. Definition of the genotype(s) investigated; when there are multiple alleles, those tested for should be specified 8. Genotyping method used (reference; for polymerase chain reaction methods - primer sequences,* thermocyle profile,* no. of cycles*) - description of method of primer selection and specification of steps taken to ensure that they are not in a sequence that contains another polymorphism 9. Percentage of potentially eligible subjects for whom valid genotypic data were obtained, by study group (cases vs. controls) 10. If pooling was used, strategy for pooling of specimens from cases and controls 11. Quality control measures * - blinding of laboratory staff to phenotypic date 12. Degree of reproducibility between quality control replicates 13. Samples from each group of subjects compared (e.g., cases and

6 controls) included in each batch analyzed * Selection of study subjects 14. Geographic area from which subjects were recruited 15. The recruitment period 16. Recruitment methods for subjects whose genotypes were determined, such as random population-based sampling, blood donors and hospitalized subjects with reasons for hospitalization (controls) 17. Definition of cases and method of ascertainment 18. No. of cases recruited from families and methods used to account for related subjects 19. Exclusion criteria for cases and controls 20. Recruitment rates 21. Mean age and standard deviation or age range of study subjects and the distribution by sex for cases and controls 22. Similarity of sociodemographic (or other) characteristics of subjects for whom valid genotypic data were obtained with characteristics of subjects for whom such data were not obtained* 22. Steps taken to ensure that controls are non-cases* Confounding, including population stratification 23. Design - description of efforts to address potential sources of bias 24. If other than a case-family control design, matching for ethnicity or adjustment for ethnicity in analysis - eligibility criteria case/controls - controls match to cases: age, gender, race, ethnicity

7 25. Potential correlates of the genotype identified and taken into consideration in design of analysis Statistical issues 26. Pre-hoc effect size estimation and power calculation 27. Distinguish clearly a priori hypotheses and hypotheses generated 28. If haplotypes used, specify how these were constructed 29. No of subjects included in the analysis 30. Method of analysis, with reference and software used to do this 31. Confidence intervals of measures of association with the genotype 32. Assessment of goodness-of-fit of the model used* 33. Notes Overall Assessment of Quality * Additional information recorded (ideally in Web-based methods register) but not necessarily presented in journal article

8 Appendix 3: Statistical appendix Where possible, we used the summary data provided in studies, contacting authors in an attempt to obtain further information if necessary. In some cases, we needed to calculate odds ratios and 95% confidence intervals from case control and familybased studies. For case control studies, we used the normal approximation of the Mantel-Haenszel statistic. When there was a zero in the contingency table we added 0.5 to every number. For family-based studies, we considered transmission of possible alleles A and B from parents to an affected offspring in a trio setting; the ratio of transmitted A and untransmitted B alleles (T) to untransmitted A and transmitted B alleles (U) could then be interpreted as an odds ratio and were calculated as follows: OR =T/U. The standard error of these odds ratios were calculated using the formula: E (logor)= (1/T+1/U). Two examples are reproduced in the table below. a b c d e f g h i Example T U Ratio TUR (T/U) (a2/b2) Log TUR 1.34 (lnc2) SE log TUR 0.34 Wortel (1/a2 + 1/b2) LCL UCL OR Confidence intervals 1.97 Exp (d2-1.96*e2) 7,42 Exp (d * e2) 04 (02 to 07) (02 to 04) Meta-analyses were undertaken, where appropriate, using random effects modeling. In the case of identifying significant heterogeneity (I 2 >40%), we sought to investigate the sources of this using a priori defined sensitivity/subgroup analyses. Assessments of the risk of publication bias were undertaken visually using funnel plots.

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