Finemapping of susceptibility loci for atopic dermatitis on chromosome 1q21.3 and chromosome 11q13.5
Zusammenfassung der Projektergebnisse
Genome-wide association studies (GWAS) have been very successful in the identification of common single nucleotide polymorphisms (SNPs) associated with complex traits and diseases. The associated loci demand additional exploration in order to refine signals and identify potentially functional alleles. We therefore resequenced two well-established susceptibility loci for atopic dermatitis (AD) on chromosome 11q13.5 (chr11:75,800,000- 76,070,000) and on chromosome 1q21.3 (EDC, chr1:150,200,000-151,900,000) in a total of 61 AD patients from the original GWAS selected by severe and early-onset phenotype, absence of common FLG mutations, and presence of GWAS tag SNP risk haplotypes. We identified and validated 6 and 18 missense mutations of a total of 10 and 257 exonic SNVs for 11q13.5 and the EDC, respectively. These variants were subsequently tested for association with AD within an independent case-control collection comprising 1072 patients and 1099 healthy controls. Whereas none of the very rare missense variants from within the EDC showed a robust association with AD, 1 low frequency and 5 rare missense mutations within the gene LRRC32 on chromosome 11 showed significantly higher risk allele rates in AD cases and gene collapsing analysis yielded a significant association with AD (combined carrier frequency in cases=0.070; combined carrier frequency in controls=0.036; P= 5.5x10-4; OR 2.01). Structural protein modelling of GARP, the protein encoded by LRRC32, predicted an effect of these mutations on protein instability and/or protein transport via interference with posttranslational modifications. GARP is expressed on activated Treg cells where it binds to the inactive form of TGF-beta, thereby controlling its activation and abundance. The identified missense mutations are therefore biologically plausible candidates and are currently being analyzed in larger cohorts and further examined for their precise effects in functional assays.
