Elevated expression and genetic association links the SOCS3 gene to atopic dermatitis

Abstract

In a systematic analysis of global gene-expression patterns, we found that SOCS3 messenger RNA was significantly more highly expressed in skin from patients with atopic dermatitis than in skin from healthy controls, and immunohistochemical analysis confirmed a similar elevation of SOCS3 protein. Furthermore, we found a genetic association between atopic dermatitis and a haplotype in the SOCS3 gene in two independent groups of patients (P<.02 and P<.03). These results strongly suggest that SOCS3, located in a chromosomal region previously linked to the disease (17q25), is a susceptibility gene for atopic dermatitis.

Figure 1

SOCS3 mRNA levels in skin from patients with AD and healthy controls, measured by cDNA microarray. We analyzed lesional skin and noninvolved PBS-patch-tested skin from patients with AD and normal skin and PBS-patch-tested skin from healthy controls. The results are displayed as the mean values of all measured SOCS3 mRNA levels for patients and controls in each group (e.g., mean values of seven lesional and six PBS-patch-tested skin samples from patients with AD and four normal skin and four PBS-patch-tested skin samples from controls). SE is indicated for each group. We found that SOCS3 mRNA levels were significantly more highly expressed in skin from patients with AD than in skin from healthy controls. R/G = red/green.

Figure 2

SOCS3 protein expression (arrows) in lesional skin (A) and nonlesional skin (B) from patients with AD and in normal skin from healthy controls (C). We found a higher expression of SOCS3 in dendritic cells and an increased number of SOCS3-positive cells in lesional AD skin (median 5.6 cells/mm; range 1.1–10.5 cells/mm) compared with nonlesional AD skin (median 1.1 cells/mm; range 0–5.6 cells/mm; P<.043) and normal skin (median 0.8 cells/mm; range 0–5.9 cells/mm; P<.00079). Frozen skin biopsy specimens were stained with antibodies to SOCS3 (dilution 1/250). Scale bar = 50 μm. Statistical tests used were the Wilcoxon matched-pairs test and Mann-Whitney U test.

Figure 3

Schematic overview of the location and distribution of the 10 SNPs genotyped in the SOCS3 gene and the LD structure in the region. Positions relative to the transcription start are indicated. The four SNPs marked with an asterisk (*) either were not polymorphic in the analysis (of 380 individuals) or failed to pass ABI's quality control. See main text for details on SNP selection. The number in each box in the LD plot corresponds to the pairwise LD coefficient D′ between respective SNPs, calculated using Unphased. Block 1 spans from rs8074003 to rs4969170, and block 2 from rs4969170 to rs4969168.