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Eczema Genetics: Current State of Knowledge and Future Goals Sara J

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Eczema Genetics: Current State of Knowledge and Future Goals Sara J View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector PERSPECTIVE Eczema Genetics: Current State of Knowledge and Future Goals Sara J. Brown1 and W.H. Irwin McLean2 Multiple genetic as well as environmental factors interact in the pathogenesis of eczema. Increased understanding of genetic predisposition in atopy and eczema has directed interest toward key pathogenic mechanisms including skin barrier dysfunction. This review provides a succinct update on the current state of knowledge regarding eczema genetics. We discuss the relevance of loss-of-function mutations in the filaggrin gene within the context of other candidate gene studies and suggest possible applications for future research. Knowledge of genetic factors in eczema may translate into a clearer understanding of pathogenic mechanisms and hence more focused therapeutic strategies, but this remains at present a distant possibility. Journal of Investigative Dermatology (2009) 129, 543–552; doi:10.1038/jid.2008.413 INTRODUCTION EVIDENCE FOR A GENETIC mediated through skin-specific genes, Eczema (Johansson et al., 2004) is a PREDISPOSITION IN ECZEMA rather than simply through systemic complex trait, that is, multiple genetic There is substantial evidence in support immune or ‘‘atopy’’ risk genes. Recent and environmental factors contribute to of a strong genetic component in atopic thinking has focused on the importance its pathogenesis. There is considerable eczema. Twin studies show concor- of epithelial barrier dysfunction in heterogeneity within the clinical phe- dance rates of 0.72–0.86 in monozygo- atopic eczema, directed by evidence notype of ‘‘eczema’’ and the disease is tic compared with 0.21–0.23 in from genetics as well as biochemical also likely to encompass significant dizygotic twin pairs (Larsen et al., and physiological studies (Cookson, etiological heterogeneity. The subclas- 1986; Schultz Larsen, 1993; Thomsen 2004; Hudson, 2006; Irvine and sification of atopic and nonatopic et al., 2007) and eczema as well as McLean, 2006; Jakasa et al., 2006, eczema is not clear-cut (Brown and asthma and allergic rhinitis show clus- 2007; Taieb et al., 2006). Reynolds, 2006) and the use of differ- tering within families (Kaiser, 2004). ent diagnostic criteria, focusing on Common features of the systemic im- STRATEGIES FOR INVESTIGATING different clinical and pathological fea- mune response link eczema with other THE GENETIC BASIS OF ATOPIC tures (Williams, 2003; Williams and atopic diseases, however several lines ECZEMA Johansson, 2005), has not facilitated a of investigation point to tissue-specific A large amount of research has been unified understanding of eczema genes, relating to the structure and undertaken worldwide in the search for pathogenesis. However, increasing function of skin, as etiological factors genetic factors in the etiology of atopy knowledge of the role of genetic pre- in eczema pathogenesis. Children and eczema. Three main approaches disposition in atopy and eczema has whose parents have eczema show a have been used: candidate gene asso- improved our understanding of this higher risk of developing eczema than ciation, selecting genes for study based complex trait and directed interest children whose parents have asthma or on a hypothesis of known biological toward key pathogenic mechanisms. hay fever (Moore et al., 2004; Wadon- function; genome-wide linkage This review aims to provide an da-Kabondo et al., 2004) and eczema screens, which are hypothesis free update on current understanding of can occur with increased severity along and compare the transmission of gene- the genetic basis of eczema, focusing Blaschko’s lines (Hladik et al., 2005), tic information between cases and on atopic eczema, and to suggest consistent with genetic mosaicism controls in family pedigrees; and DNA possible future research goals in this (Moss, 1999). These observations sup- microarray studies, which look at gene fast-moving field. port the concept that risk may be expression in selected regions of inter- 1Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK and 2Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK Correspondence: Professor W.H. Irwin McLean, Epithelial Genetics Group, Medical Sciences Institute, University of Dundee, Dundee DD1 5EH, UK. E-mail: [email protected] or Dr Sara J. Brown, Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. E-mail: [email protected] Abbreviations: FLG, filaggrin; SPINK5, serine protease inhibitor Kazal type 5; UCA, urocanic acid Received 29 July 2008; revised 12 November 2008; accepted 15 November 2008 & 2009 The Society for Investigative Dermatology www.jidonline.org 543 SJ Brown and WH Irwin McLean Genetics of Eczema est, or across the whole genome. Each the epidermal differentiation complex) against other serine proteases that are of these strategies has added under- show different levels of expression in allergenic (Walley et al., 2001). Poly- standing to the field of eczema genet- eczema lesional skin compared with morphisms in SPINK5 have shown ics. controls (Sugiura et al., 2005). These association with atopic eczema in It is of paramount importance to findings suggest that S100A7 and cohorts from Britain and Japan (Walley replicate previously reported findings S100A8 (showing increased expres- et al., 2001; Kato et al., 2003; Nishio using different methodology, indepen- sion) plus filaggrin and loricrin (show- et al., 2003), but this association has dent population groups, and larger ing reduced expression) may be not been replicated in subsequent sample sizes, to confirm a robust and responsible at least in part for the studies (Folster-Holst et al., 2005), with clinically relevant association (Hoffjan epidermal barrier dysfunction that is the exception of a minor parent-of- and Epplen, 2005; Morar et al., 2006b). characteristic of atopic eczema. An- origin effect when maternally inherited Many striking preliminary discoveries other independent microarray analysis (Weidinger et al., 2008a). have failed to be replicated in has shown an increase in the expres- The stratum corneum chymotrypic subsequent studies. sion of genes encoding CC chemokines enzyme is involved in the proteolytic in eczematous skin (Nomura et al., degradation of corneodesmosomes, POINTERS FROM GENOME-WIDE 2007), known to attract TH2 cells and regulating desquamation from the skin STUDIES eosinophils. The functional signifi- surface (Ekholm et al., 2000). The Genome-wide linkage screens have cance of these plus other genes and stratum corneum chymotrypic enzyme been reported in families with atopic partial DNA sequences identified by gene has been reported as a candidate eczema from five different populations DNA microarray analysis remain to be in atopic eczema (Vasilopoulos et al., (Lee et al., 2000; Cookson et al., 2001; elucidated (Saito, 2005). 2004) but again this association has not Bradley et al., 2002; Haagerup et al., been replicated in our larger cohort 2004; Enomoto et al., 2007). Regions CANDIDATE GENES FOR ECZEMA study (Weidinger et al., 2008a). on chromosomes 3q, 3p, 17q, and 18q AND ATOPY There are many other candidate show evidence of linkage in two or Many different candidate genes have genes that showed interesting associa- more studies, suggesting candidate sites been studied because of their theore- tions that have failed to be replicated for eczema genes (Hoffjan and Epplen, tical roles in the etiology of atopic by subsequent studies. Examples in- 2005). Interestingly, only two of these eczema; most candidate studies have clude the high-affinity IgE receptor four regions have shown linkage to focused on immunological mechan- (FCeR1-b), which showed linkage to asthma or other atopic disorders in isms and several genes known to be atopy but inconsistent findings in ecze- more than one study (Cookson, 2004; associated with asthma/atopy have ma (Coleman et al., 1993; Sandford Hoffjan and Epplen, 2005) indicating been investigated for linkage with et al., 1993; Soderhall et al., 2001); that separate genes may be responsible atopic eczema. At least 20 genes have nucleotide-binding oligomerization do- for eczema. Furthermore, the regions been reported as showing a statistically main proteins 1 and 2, which are on 1q21, 3q21, 17q25, and 20p linked significant association with eczema, intracellular receptors for bacterial to atopic eczema overlap with known but only six associations have been peptides (Kabesch et al., 2003; Wei- psoriasis susceptibility loci (Cookson, replicated in two or more independent dinger et al., 2005a, b); and toll-like 2004) although a subsequent investiga- studies (Maintz and Novak, 2007; receptor 2, which is expressed on tion of the 17q25 locus failed to Kiyohara et al., 2008). These findings human keratinocytes (McInturff et al., demonstrate variants in the known are summarized in Figure 1. 2005) and recognizes pathogen-asso- PSORS2 psoriasis locus in children Three genes within the 5q31–33 ciated molecular patterns (Ahmad- with atopic eczema (Morar et al., locus show evidence of association Nejad et al., 2004; Weidinger et al., 2006a). The colocalization of eczema with atopic eczema: the cytokines 2006b; Merx et al., 2007). These and psoriasis genes supports the con- IL-4 and IL-13 and a protease inhibitor, conflicting reports and lack of replica- cept that
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