Gene mapping of atopic dermatitis

Abstract

Atopic dermatitis is a hereditary, pruritic, inflammatory and chronic skin disease that typically presents in early childhood. It is often associated with other atopic manifestations, such as asthma, allergic rhinoconjunctivitis, and elevated total and/or allergen-specific serum lgE levels. In urbanised societies, a marked increase has occurred in its prevalence during the past decades. In Sweden, the prevalence of atopic dermatitis in schoolchildren has more than doubled between 1979 and 1991, and is now one of the highest in the world; approximately 15%. Twin studies support the role of a strong genetic contribution with a concordance rate of 0.86 in monozygotic twins and 0.21 in dizygotic twins. When both parents have atopic dermatitis, children have a risk of up to 75% to develop the disease. This thesis includes studies that aim to identify genetic components contributing to the development of atopic dermatitis.

A genome-wide linkage analysis was performed with 367 microsatellite markers in 109 pedigrees forming 193 full-sib pairs and 9 half-sib pairs affected with atopic dermatitis. In total, five chromosome regions reaching the level for suggestive linkage (p<7.4x10-4) were identified. Four of these chromosome regions: 3q, 13q14, 15q14-15 and 17q21 were linked to a severity score of atopic dermatitis. Two other phenotypes: atopic dermatitis combined with allergen-specific serum lgE levels (sp-IgE+) and a more severe form of atopic dermatitis (extreme AD) showed linkage to chromosome region 18q21, reaching the level for suggestive linkage for sp-IgE+. Another region on this chromosome, 18p, showed linkage to extreme AD, while 3p24-22 showed linkage to the phenotype atopic dermatitis (AD). Weaker evidence of linkage was observed to chromosome regions 1p32 (sp-IgE+), 4q24-26 (sp-IgE+), 5p13 (AD), 6p (sp-IgE+), 6q16 (AD), 7p14 (Extreme AD), 10p13-12 (AD), 11q13 (Extreme AD), 21q21 (Extreme AD) and Xp 11 (Extreme AD).

In 406 families, 572 sib pairs and 30 half-sib pairs, affected with atopic dermatitis were tested for linkage to genetic markers in seven candidate chromosome regions (2q35, 5q31-33, 6p21, 11q13, 14q11, 16p12 and Xp11). The region on 14q11 showed evidence in favour of linkage, but not association to the phenotype AD (NPL-score 2.36, p<0.009). However, a polymorphism in the candidate gene. CMA1 that previously has been associated to atopic dermatitis was neither linked nor associated in this material. An intragenic marker in the beta subunit of the high-affinity lgE receptor (FCERIbeta) located at 11q13 was associated to sp-IgE+ (p<0.009). No differences could be seen between transmissions of maternal and paternal alleles.

Evidence in favour of linkage to chromosome region 5q31-33 for the severity score of atopic dermatitis was obtained. A polymorphism in the promoter region of the IL4 gene at 5q31-33 gave evidence in favour of linkage to this phenotype. We therefore speculate that this chromosome region may contain a gene controlling the severity of atopic dermatitis. For the Wiskott-Aldrich syndrome gene (WAS) at Xp11, weak evidence of linkage was also found to the severity score of atopic dermatitis. For AD and sp-IgE+ the presence of a susceptibility gene with a major effect could be excluded. Neither linkage nor association was seen to the chromosome regions 2q35, 6p21 or 16p12 to any of the phenotypes. This suggests that major effects on the disease development of genes in these chromosome regions could be excluded in this material.