H Blakeway1, V Van-de-Velde2, V B Allen3, G Kravvas2, L Palla4, M J Page5, C Flohr6, R B Weller2, A D Irvine7,8,9, T McPherson10, A Roberts11, H C Williams12, N Reynolds13,14, S J Brown15,16, L Paternoster17, S M Langan18,19. 1. Faculty of Health Sciences, University of Bristol, Bristol Medical School, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, U.K. 2. Department of Dermatology, Lauriston Building, Lauriston Place, Edinburgh, EH3 9HA, U.K. 3. Department of Infection, St. Thomas' Hospital, Westminster Bridge Rd, Lambeth, London, SE1 7EH, U.K. 4. Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, U.K. 5. School of Public Health and Preventive Medicine, Monash University, Level 4, 553 St Kilda Road, Melbourne, 3004, Australia. 6. Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, Guy's & St Thomas' NHS Foundation Trust & King's College London, Strand, London, WC2R 2LS, U.K. 7. Clinical Medicine, Trinity College Dublin, Dublin, Ireland. 8. The National Children's Research Centre, Crumlin, Ireland. 9. Dermatology, Children's Health Ireland, Crumlin, Ireland. 10. Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, U.K. 11. Nottingham Support Group for Carers of Children with Eczema, Nottingham, U.K. 12. Centre of Evidence-Based Dermatology, University of Nottingham, Nottingham, NG7 2NR, U.K. 13. Dermatology, Royal Victoria Infirmary, NHS Foundation Trust, Newcastle upon Tyne, U.K. 14. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K. 15. Skin Research Group, Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, U.K. 16. Department of Dermatology, Ninewells Hospital, Dundee, DD1 9SY, U.K. 17. MRC Integrative Epidemiology Unit at the University of Bristol, Population Health Sciences, Bristol Medical School, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, U.K. 18. Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, U.K. 19. Health Data Research UK, London, U.K.
Abstract
BACKGROUND: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis (AD). OBJECTIVES: To review the evidence for gene-environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations. METHODS: A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis. RESULTS: Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions. CONCLUSIONS: Evidence on FLG-environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.
BACKGROUND: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis (AD). OBJECTIVES: To review the evidence for gene-environment interactions in AD aetiology, focusing on filaggrin (FLG) loss-of-function mutations. METHODS: A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS-I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis. RESULTS: Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P-value for interaction ≤ 0·05), including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss-of-function mutations and exposure to specific environmental factors, and variation in exposure definitions. CONCLUSIONS: Evidence on FLG-environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411.
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