Alan David Irvine - Selected Publications#
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis
Palmer CNA*, Irvine AD*, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJD, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WHI
Nature Genetics 2006; 38: 441 – 446 *Joint first authorship
Significance: First association of filaggrin mutations with both atopic dermatitis and asthma. The first definitive genetic predisposing factor for atopy. Showed that filaggrin mutations define an eczema-associated asthma endophenotype. Paradigm shift in our understanding of atopy from a purely immunological condition to a skin barrier disease. Of >23,000 PubMed papers on atopic dermatitis, this is the most cited paper ever published on this disease
Filaggrin mutations: Associations with Skin and Allergic Diseases
Irvine AD, McLean WHI, Leung DYM
N Eng J Med 2011; 365:1315-27
Significance: Major invited review of the field in a leading general medical journal. This invitation was extended on the basis of our 4 previous years’ work.
Skin Microbiome Prior to Development of Atopic Dermatitis: Early Colonization with Commensal Staphylococci at 2 months is Associated with a Lower Risk of Atopic Dermatitis at 1 year
Kennedy EA, Connolly J, Hourihane JO’B, Fallon PG, McLean WHI, Murray D, Jo J-H, Segre JA, Kong HH Irvine AD
Journal of Allergy and Clinical Immunology 2017 139(1):166-172. doi: 10.1016/j.jaci.2016.07.029. Epub 2016 Sep 5.
Significance: The normal human microbiome may be protective against inflammatory skin disease. This is the first publication to show this potential effect. This work is very consistent with other recent insights showing that commensal bacteria have the ability to both kill potential pathogens but also to directly regulate skin immunity.
Intragenic Copy Number Variation within Filaggrin Contributes to the Risk of Atopic Dermatitis with a Dose-Dependent Effect
Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E, Kezic S, Cordell HJ, McLean WH, Irvine AD
Journal of Investigative Dermatology 2012; 132: 98-104
Significance: Intragenic copy number variation in the filaggrin coding sequence identified previously was shown to be associated with atopy risk/protection in a dose-dependent manner, independent of null mutations. This provides genetic proof-of-concept for filaggrin upregulation therapy i.e. a 20% increase in filaggrin expression gives 40% reduction in eczema risk.
Raman Profiles of the Stratum Corneum Define Three FLG Genotype-determined Atopic Dermatitis Endophenotypes
O’Regan GM, Kemperman PMJH, Sandilands A, Chen H, Campbell LE, Kroboth K, Watson R, Rowland M, Puppels GJ, McLean WHI, Caspers PJ, Irvine AD
Journal of Allergy and Clinical Immunology 2010; 126: 574-80.e1
Significance: First identification of a null mutation in the murine filaggrin gene (flaky tail mouse mutant). Detailed immunological characterisation of this mouse showed for the first time in an experimental system that filaggrin deficiency leads to enhanced percutaneous allergen priming i.e. a “leaky” skin barrier drives systemic allergic sensitisation.
The burden of disease associated with filaggrin mutations: a population based, longitudinal birth cohort study
Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Davey Smith G, Palmer CNA, McLean WHI, Irvine AD
Journal of Allergy and Clinical Immunology 2008; 121: 872-7.
Significance: This was the first large-scale population-based study that looked at the contribution of FLG mutations to the entire range of atopy-associated diseases, including asthma and allergic rhinitis. We showed that FLG mutations make a significant contribution towards asthma occurring in association with atopic dermatitis but not asthma in the absence of AD and that FLG associated AD was likely to be more allergic, more persistent and carry a higher risk of asthma compared to non-FLG AD.
Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema
Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, Janecke AR, Elias PM, van Steensel MAM, Nagtzaam I, van Geel M, Steijlen PM, Munro CS, Bradley DG, Palmer CNA, Smith FJD, McLean WHI, Irvine AD
Nature Genetics 2007; 39: 650-4
Significance: First protocol for fully re-sequencing human filaggrin, identifying rare and common loss-of-function variants in different populations. This revealed filaggrin’s complex genetic architecture and why it is poorly tagged by GWAS SNPs. First sequencing of filaggin intragenic copy-number alleles. Discovery that 3’ mutations destabilise profilaggrin protein and are functional nulls.
Loss-of-function mutations in the filaggrin gene cause ichthyosis vulgaris
Smith FJD, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao L, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O’Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WHI
Nature Genetics 2006; 38: 337-342
Significance: Identification of the first two loss-of-function mutations in filaggrin (R501X and 2282del4) as the cause of ichthyosis vulgaris (IV), the most prevalent monogenic skin disorder. Showed for the first time that IV is a semi-dominant trait and that these mutations are surprisingly common in populations of European ancestry.
Mutations in SPINK5 encoding a novel serine protease inhibitor cause Netherton Syndrome.
Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, Bonafé J-L, Taïeb A, Barrandon Y, Harper JI, de Prost, Y, Hovnanian A (2000).
Nature Genetics 2000; 25: 141-142
Significance: This discovery was the first to link Mendelian single gene skin barrier defects with atopic dermatitis and systemic atopy. In this condition loss of control of proteolysis leads to unregulated breakdown of the stratum corneum with a resultant skin barrier defect that leads to a systemic disorder that includes atopic dermatitis-like skin inflammation, systemic allergies and failure to thrive.
Mutations in cornea-specific keratins K3 or K12 cause Meesmann's corneal dystrophy.
Irvine AD, Corden LD, Swensson O, Swensson B, Moore JE, Frazer DG, Smith FJD, Knowlton RG, Christophers E, Rochels R, Uitto J, McLean WHI.
Nature Genetics 1997; 16:184-187
Significance: First identification of a human keratin gene mutation in the cornea.
