Atopic dermatitis (AD or eczema) is a chronic inflammatory skin disorder and a major manifestation of allergic disease. In the industrialized countries, the prevalence of AD is approximately 15 % with a steady increase over the past decades1. Genetic and environmental factors interact to determine disease susceptibility2, and family and twin studies indicate that the genetic contribution is substantial3. The molecular mechanisms underlying eczema are not fully understood. Skin barrier defect as well as systemic and cutaneous immune dysfunction in response to allergens or bacterial products are thought to play an important role4.

We conducted a genome-wide association study in 939 individuals with AD and 975 controls as well as 270 complete nuclear families with 2 affected siblings. SNPs consistently associated with AD in both discovery sets were then investigated in two additional independent replication sets totalling 2637 cases and 3957 controls. Highly significant association was found with rs7927894 on chromosome 11q13.5 (Pcombined = 3.1 x 10-10). Approximately 13% of individuals of European origin are homozygous for the risk allele, and their risk of developing AD is 1.47 times that of noncarriers5.

The objective of this study is to evaluate this novel eczema susceptibility variant at the at the general population level in the ALSPAC cohort in order to

1) replicate the initially reported association with eczema.

The ALSPAC cohort (n=7000) carries sufficient power to replicate the original finding:

Under the assumption of a moderate odds ratio of 1.3 and a disease prevalence of 10%, the power to detect an association is 94%.

2) assess the population-attibutable risk of this variant for eczema.

in contrast to the affected families and cases/controls used in the GWAS, the ALSPAC cohort will enable us to estimate the population attributable risk fraction (PARF) which indicates the proportion of cases in the population attributable to the rs7927894 risk allele.

3) evaluate this variant for association with other atopic disorders.

Interestingly, this variant has also been reported to be a risk factor for Crohn's Disease6, extending the number of overlapping risk variants for different chronic inflammatory diseases and highlighting the importance of shared molecular pathogenic pathways. The ALSPAC cohort will allow us to test this variant for association with other atopic disorders including asthma, and hayfever. An association analysis with Crohn's Disease may be attempted. However, due to the expected low prevalence of Crohn's disease, the ALSPAC cohort may not carry sufficient power to yield conclusive results.

4) evaluate epistatic effects between this variant and Filaggrin loss-of-function mutations.

Loss-of-function mutations in the filaggrin gene are strongly associated with eczema7,8. We have detected an epistatic effect between rs7927894 and the filaggrin loss-of-function mutations in the German Multicenter Allergy Study (MAS 90). However, only 871 of the original 1300 MAS children were available for genetic studies. The ALSPAC cohort is significantly larger than the MAS cohort and will allow us to replicate this finding and to estimate the effect size more accurately.

Reference List

1. Taylor, B., Wadsworth, J., Wadsworth, M., & Peckham, C. Changes in the reported prevalence of childhood eczema since the 1939-45 war. Lancet 2, 1255-1257 (1984).

2. Cookson, W. The alliance of genes and environment in asthma and allergy. Nature 402, B5-11 (1999).

3. Schultz, L. F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J.Am.Acad.Dermatol. 28, 719-723 (1993).

4. Bieber, T. Atopic dermatitis. N.Engl.J.Med. 358, 1483-1494 (2008).

5. Esparza-Gordillo, J. et al.A common variant on chromosome 11q13 is associated with atopic dermatitis. Nature Genetics in press (2009).

6. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat.Genet. 40, 955-962 (2008).

7. Palmer, C. N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat.Genet. 38, 441-446 (2006).

8. Brown, S. J. & McLean, W. H. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 129, 543-552 (2009).

Concept Specific measure Person Source Time point(s)

eczema Doctor's diagnosis of eczema child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

eczema eczema child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

asthma Doctor's diagnosis of asthma child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

asthma asthma child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

hayfever Doctor's diagnosis of hayfever child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

hayfever hayfever child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

atopy Elevated spec. IgE or Skin Prick test child evaluation Age 0-5 years

Age 6-10 years

Age greater than 10 years

Chronic inflamm. bowel disease (IBD) Doctor's diagnosis of IBD child questionnaire ever