Genetic studies of atopic dermatitis

Abstract

Known from ancient times, atopic dermatitis is now the most prevalent chronic inflammatory skin disease in Swedish children. This is the result of a marked increase over the past few decades. Atopic dermatitis is viewed as a multifactorial disorder caused by the combined influence of genes and environment, the relative contributions, however, being unknown. Twin studies show a concordance rate of 86% in monozygotic twins and 21% in dizygotic twins, which suggests a strong genetic component.

The overall aim of this study was to identify genetic susceptibility loci for atopic dermatitis. We recruited families with at least two siblings affected with atopic dermatitis. DNA was obtained from 1097 affected siblings that together formed 650 affected sib pairs and 49 affected half-sib pairs. These were all examined and phenotyped. Of the affected siblings, 74% had raised total and/or allergen-specific serum IgE levels. We performed a genome-wide linkage analysis with 367 microsatellite markers, using a non- parametric affected relative pair method. In the analysis 109 pedigrees were included, forming 193 affected full-sib pairs and 9 affected half-sib pairs (470 individuals). We also studied linkage and association to six chromosomal regions (2q35, 3q21, 5q31, 6p21, 11q13, and 14q11), previously implicated as candidate regions in atopic, diseases, and one new candidate gene, the gene for Wiskott-Aldrich syndrome located on Xp 11. These candidate genes were investigated in 572 affected sib pairs and 30 affected half-sib pairs (1514 individuals).

We studied the following four phenotypes in the affected siblings. 1. Atopic dermatitis as diagnosed according to the UK Working Party's Diagnostic Criteria (AD). 2. Atopic dermatitis in combination with elevated allergen-specific serum IgE levels (sp-1gE+). 3. Atopic dermatitis with a more severe phenotype (extreme AD) 4. The severity score of atopic dermatitis.

For the phenotype sp-IgE+ suggestive linkage (p<7x10-4) was found to chromosome region 18q21. For the phenotype, severity score of atopic dermatitis, suggestive linkage was found to chromosome regions 3q14, 13q14, 15q14-15 and 17q21. For the phenotype AD, almost suggestive linkage to chromosome region 3p24-22 was found.

In the candidate genes, the region on 14q1 1 gave evidence for linkage to the phenotype AD (p<0.009). In the 11 q 13 region, there was an association to an intragenic marker in the high-affinity lgE receptor for the phenotype sp-IgE+ (p<0.009). For the severity score of atopic dermatitis, evidence in favor of linkage was found to the 5q31-33 region with the highest linkage close to the marker D5S458 (p<0.005). We also found linkage to the phenotype extreme AD (p<0.005), in the WAS region. We could not replicate the previous findings of a major susceptibility to AD on 3q2 1.

In conclusion, we have identified chromosome regions linked to susceptibility genes for atopic dermatitis. This provides a platform from which the search for atopic dermatitis genes can proceed.