Linkage of atopic dermatitis to chromosomes 4q22, 3p24 and 3q21

Abstract

Atopic dermatitis (AD) is a common, itchy skin disease of complex inheritance characterized by dermal and epidermal inflammation. The heritability is considerable and well documented. To date, four genome scans have examined the AD phenotype, showing replicated linkage at 3p26-22, 3q13-21 and 18q11-21. Our previous AD scan showed evidence of linkage to loci at 3p and 18q, and furthermore at 4p15-14. In order to further investigate the genetic basis of AD, we collected and analysed a new Danish family sample consisting of 130 AD sib pair families (555 individuals including 295 children with AD). AD was diagnosed after clinical examination, AD severity was scored and specific IgE was determined. A linkage scan of chromosome 3, 4 and 18 was performed using 91 microsatellite markers. Linkage analyses were performed of dichotomous phenotypes and semi-quantitative traits including the AD severity score. We analysed the novel AD sample alone and together with the previously examined sample. AD severity showed a maximum Z-score of 3.7 at 4q22.1 suggesting the localization of a novel gene for AD severity. A maximum MOD score of 4.6 was obtained at 3p24 for the AD phenotype, providing the first significant linkage of AD at this locus. A maximum MLS score of 3.3 was obtained at 3q21 for IgE-associated AD, and evidence of linkage was also obtained at 3p22.2-21.31, 3q13, 4q35, and 18q12. The results presented should provide a firm basis for gene-targeting studies of AD and related disorders.

An update on the genetics of atopic dermatitis: Scratching the surface in 2009

“…Follow-up fine-mapping of eight markers in the 11p14 locus suggested a pleiotropic effect for the three allergic diseases, AD, asthma and allergic rhinitis. More recently, the Danish team followed up on their previous evidence for linkage at the 3p, 4q and 18q loci, in addition to previous evidence for linkage at 3q, in an independent sample of 130 AD sib-pair families, and concluded the strongest evidence for linkage was to 3p34, 3q21, and 4q2221. From these follow-ups, however, conclusions are speculative at best, given that each of the regions where significant evidence of linkage has been identified contains multiple candidate genes.…”

Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing TH2 and TH17 T-cell differentiation

“…45 Runx3 resides on human chromosome 1p36.1, 46 which maps to a region containing susceptibility genes for asthma, 47 and on mouse chromosome 4, 48 which contains a susceptibility gene for atopic dermatitis. 49 Loss of Runx3 results in spontaneous development of inflammatory bowel disease, 14 as well as constitutive airway hyperreactivity and eosinophilic inflammation. 43 We demonstrated that Runx3 (but not Runx1 or Runx2 ) expression was downregulated in the jejunums of sensitized and challenged WT and Runx3 +/− mice and that the increases in Pim1 kinase mRNA and protein levels were greater in the jejunums of peanut-sensitized and challenged Runx3 +/− mice than in WT mice.…”

Molecular Genetic of Atopic Dermatitis : An Update

“…(34) Genome-wide linkage analysis had been used in different populations to date, and multiple candidate regions on multiple chromosomes had been associated with AD. (35)(36)(37)(38)(39) The linkage regions vary in different populations, and there is no extensive overlap among studies. Some candidate regions are close to functional genes linked to the various phenotypes of AD.…”

“…Systemic, well-powered, genome-wide surveys using GWAS and immunochip analyses have estimated the relationship between SNP and susceptibility to AD. (31,39,40) It is well established that common loss of function variants of FLG are a major predisposing factor for AD. As for example, the FLG mutations are involved in AD and are featured in some review articles.…”