Introduction
Atopy is defined as familial tendency to develop characteristic IgE-mediated allergic diseases on the basis of skin and mucuous membrane hyperreactivity (1). Epidemiologic studies showed a world-wide increase of the prevalence of atopic diseases (atopic eczema (AE), asthma, rhinoconjunctivitis) over the last decades (2). AE is one of the most common inflammatory, chronically relapsing skin diseases caused by combined influences of multiple genetic and environmental factors. It commonly represents the initial clinical manifestation of allergic disease and often precedes the onset of respiratory allergies. Family and twin studies clearly indicate that the genetic contribution is substantial (3). In recent years it has become clear that there are subpopulations of AE patients with regard to clinical parameters (e.g. age of onset, skin lesion morphology) and pathophysiology (extrinsic versus intrinsic AE) (4). In the context of genetics this is crucial. Therefore, in NGFN I large samples of trio families and single cases have been phenotyped on the basis of precise consensus criteria (5) that allow distinction of various subgroups of AE including intermediate phenotypes. Extensive phenotyping allowed unambiguous grouping of patients based on sensitization patterns and revealed a clear female preponderance for intrinsic AE, suggesting sex-related influence factors on disease expression. By detection of exclusively allergen-specific IgE against microbial components in a subgroup of patients with low serum IgE levels, a more precise differentiation between extrinsic and intrinsic type of disease was obtained. Further investigations showed that the surface expression of the high and low affinity IgE-receptor and of the interleukin-4-receptor alpha chain were significantly elevated in monocytes from patients with intrinsic AE. In addition, serum levels of IL-13 were significantly increased in these patients. Distinct AE subgroups could also be distinguished on the basis of reaction patterns towards climatic factors and exposure to allergens (6).

Results/Project Status
STAT6: Several studies have shown linkage of chromosome 12q 13-24 with atopy-related phenotypes. Among the candidate genes in this region is STAT6  (“signal transducer and activator of transcription”), which is essential for Th2-cell differentiation, recruitment and effector function. We evaluated 6 previously identified polymorphisms of STAT6 for evidence of associations with serum IgE levels and atopic diseases within our population-based cross-sectional cohort of 1407 German adults (KORA S3). Genotyping was performed using MALDI-TOF MS. A significant association with total serum IgE levels (p = 0.015) was observed for one polymorphism in intron 2 (rs324011) where two transcription factor binding sites for NF#B are found close to each other suggesting a regulatory function of this region for the transcription of STAT6. In addition, a STAT6 risk haplotype for elevated IgE levels showing odds ratios of 1.7 (p=0.015) for IgE cut-off 100 kU/l, and 1.54 (p = 0.032), 1.6 (p = 0.025), 2.54 (p = 0.007) for IgE percentiles 50%, 66%, 90%, was detected. The increased risk of this haplotype was strongly confirmed by linear haplotype trend regression on log-transformed IgE values (p = 0.007). Analyses further revealed a risk haplotype for specific sensitization and a risk haplotype for asthma. Thus, it could be demonstrated that STAT6 polymorphisms play a role in IgE expression and thereby are a factor in expression of the allergic or "atopic" state (8). The findings of this study have been highlighted by the Faculty of 1000 Biology (http://www.f1000biology.com).
IL-18: Human IL-18 is a potent proinflammatory cytokine that plays a role in atopic diseases by enhancing the IL-4 and IL-13 production and stimulating the synthesis of immunoglobulin E (IgE). The gene for human IL-18 is located on chromosome 11q22.2-22.3, a region that has been linked to atopy-related traits. IL18  polymorphisms have been reported to be associated with specific sensitisation and allergic rhinoconjunctivitis. To evaluate associations with AE, we genotyped SNPs in the regulatory region of the IL18 gene in 225 AE patients and 175 healthy controls. Analysis revealed significant associations of SNPs 113G and 127T in Exon 1, and -137C and -133G in the promoter regions with AE. On the functional level active IL-18 in the sera of AE patients was enhanced at disease exacerbation. Furtheron IL-18 in the supernatant of PBMC of AE patients stimulated with S.aureus enterotoxin B was significantly higher than in controls. Our data suggest that SNPs in the regulatory region of the IL18 gene might be involved in the development of AE by contributing to a dysregulation of the IL-18 production (9).
Chymase: Mast cell chymase is a proinflammatory serine protease abundantly expressed by dermal mast cells. Expression of chymase is decreased in non-leasional skin of AE patients and further decreased in leasional skin suggesting a role of chymase in suppressing skin inflammation. Association analyses between the promoter polymorphism rs1800875 in the chymase gene (CMA1) and atopy-related traits have yielded inconsistent results. Therefore we sequenced the CMA1 locus in 24 unrelated healthy individuals with serum IgE levels < 50% percentile and 24 individuals with AE and serum IgE levels > 90% percentile. 7 CMA1 SNPs were evaluated for associations with atopic phenotypes within our large population-based cohorts of German adults (n=1875). Polymorphism rs1800875 showed significant association with AE. No associations between any other SNP and atopic traits could be detected. These results confirm previous observations of a significant association between the CMA1 promoter polymorphism rs1800875 and AE, but not with other atopic phenotypes, and support the hypothesis that CMA1 serves as candidate gene for AE (10).
NOD1 and NOD2: Bacterial cell wall muramyl peptides can signal via recently discovered intracellular pathogen-recognition receptors of the innate immune system, NOD1 (CARD4) and NOD2 (CARD15). Interestingly, for polymorphisms of both NOD1 and NOD2 associations with susceptibility to Crohn's disease, a predominantly Th1-mediated condition, have recently been shown  (11, 12).  In a tandem approach using our large population-based cohort of German adults (n=1417), a case-control population for AE (n=454), and our cohort of parent-offspring trios for AE (189 trios), we could show that genetic variants within NOD1 (13) as well as NOD2 (14) are also important determinants of atopy susceptibility. In the case of NOD1 it is noteworthy that one polymorphism which showed replicated association with atopic traits is located in intron 9, where two putative transcription factor binding sites for Pax1 are found, and alters Pax1 binding probability. These results strengthen the hypothesis that inflammatory barrier diseases (eg inflammatory bowel disease, asthma, AE, psoriasis) share disease genes and regulatory mechanisms in the interaction between susceptibility and trigger factors and underline the importance of variations in innate immunity genes for both Th1- and Th2-mediated immunoregulatory disorders.

 

Fig 1: Genetic basis of pathophysiological and dermatological phenotype expression in atopy and atopic eczema (Project NUW-S31T05). Timelines.

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