Genetic mechanisms in atopic eczema

Research

Genetic mechanisms in atopic eczema

Atopic eczema is an itchy inflammatory skin disease. It can cause significant morbidity and accounts for approximately 25% of children referred to a hospital dermatology department. However, the choice of therapeutic options is currently limited.

Eczema is a complex disorder, resulting from the interplay of multiple genetic, environmental and immunological effects. In 2006 the McLean laboratory & collaborators reported that loss of function mutations in the filaggrin gene (FLG) are associated with increased risk of atopic eczema. Filaggrin is expressed in the outermost layers of skin and this discovery has placed new emphasis on the role of skin barrier function in the pathogenesis of atopic eczema. A fuller understanding of genetic mechanisms in eczema would clarify the pathogenesis of this complex trait and may facilitate the development of novel treatments.

My work aims to identify additional genetic factors affecting FLG expression in human skin and to define other genes involved in the development of childhood eczema and atopic disease.

We have recently shown that FLG mutations significantly increase risk of peanut allergy; this is the first genetic risk factor for peanut allergy that has been confirmed in more than one population. I am currently studying copy number variation in and around the FLG locus and using next generation sequencing to investigate the transcriptome of atopic eczema skin.

Publications

Brown SJ, Asai Y, Cordell HJ, Campbell LE, Zhao Y, Liao H, Northstone K, Henderson J, Alizadehfar R, Ben-Shoshan M, Morgan K, Roberts G, Masthoff LJ, Pasmans SG, van den Akker PC, Wijmenga C, Hourihane JO, Palmer CN, Lack G, Clarke A, Hull PR, Irvine AD, McLean WH. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol. 2011 Mar;127(3):661-7.

Common JE, Brown SJ (joint first authors), Haines RL, Goh CS, Chen H, Balakrishnan A, Munro CS, Tan AW, Tan HH, Tang MB, Lane EB. Filaggrin null mutations are not a protective factor for acne vulgaris. J Invest Dermatol. 2011 Jun;131(6):1378-80. Epub 2011 Feb 17. PubMed PMID: 21326297; PubMed Central PMCID: PMC3094589.

O'Regan GM, Campbell LE, Cordell HJ, Irvine AD, McLean WH, Brown SJ. Chromosome 11q13.5 variant associated with childhood eczema: an effect supplementary to filaggrin mutations. J Allergy Clin Immunol. 2010 Jan;125(1):170-4.

Brown SJ, Relton CL, Liao H, Zhao Y, Sandilands A, McLean WH, Cordell HJ, Reynolds NJ. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children. Br J Dermatol. 2009 Oct;161(4):884-9.

Rodriguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, Irvine AD, Weidinger S. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J Allergy Clin Immunol. 2009 Jun;123(6):1361-70.

Van Limbergen J, Russell RK, Nimmo ER, Zhao Y, Liao H, Drummond HE, Davies G, Gillett PM, McGrogan P, Bisset WM, Mahdi G, Wilson DC, Brown SJ, McLean WH, Satsangi J. Filaggrin loss-of-function variants are associated with atopic comorbidity in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2009 Oct;15(10):1492-8.

Brown SJ, Relton CL, Liao H, Zhao Y, Sandilands A, Wilson IJ, Burn J, Reynolds NJ, McLean WH, Cordell HJ. Filaggrin null mutations and childhood atopic eczema: a population-based case-control study. J Allergy Clin Immunol. 2008 Apr;121(4):940-46.

Brown SJ, Sandilands A, Zhao Y, Liao H, Relton CL, Meggitt SJ, Trembath RC, Barker JN, Reynolds NJ, Cordell HJ, McLean WH. Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J Invest Dermatol. 2008 Jun;128(6):1591-4.