Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis

Abstract

Psoriasis is a common inflammatory skin disease with a prevalence of 2-3% in individuals of European ancestry. In a genome-wide search for copy number variants (CNV) using a sample pooling approach, we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster. The absence of LCE3B and LCE3C (LCE3C_LCE3B-del) is significantly associated (P = 1.38E-08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the United States, and in a family-based study (P = 5.4E-04). LCE3C_LCE3B-del is tagged by rs4112788 (r(2) = 0.93), which is also strongly associated with psoriasis (P < 6.6E-09). LCE3C_LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function has a role in psoriasis susceptibility.

Figure 1. Region of the LCE cluster containing the LCE3C_LCE3B-del associated with psoriasis

The region shows 200 kb of the genomic region between LCE5A and LCE2A on human chromosome 1. The 11 genes of these regions are shown with their transcription orientation. Vertical yellow arrows indicate the position of the SNPs that showed association with psoriasis and with LCE3C_LCE3B-del. Vertical grey arrows indicate the position of those SNPs that did not show association with psoriasis. The location of the rs4112788 SNP is shown with a red arrow. The location of the Agilent probes that showed variability in aCGH experiments are shown as vertical bars. The CNV regions described in other studies are indicated. The LCE3C_LCE3B-del deletion, which spans 32,199 bp is highlighted. The genes for which TaqMan assays were developed are shown on a yellow background.

Figure 2. Patterns of mRNA expression of LCE3C in the epidermis of psoriatic and control subjects

(a) Evaluation of the expression profiles of LCE3C and LCE3E in the skin of control subjects (C1 to C7) and patients with psoriasis (P1 to P9). (b) Evaluation of the expression of LCE3C and LCE3E in uninvolved (UI) skin of psoriatic patients vs. involved lesional (I) skin. Expression levels (relative to the endogenous gene RPLP0) of LCE3E and LCE3C are represented by left and right Y-axis values respectively. The genotypes 0/0, 0/1 and 1/1 correspond to the LCE3C_LCE3B-del homozygotes, heterozygotes, and homozygotes for the presence of LCE3C and LCE3B. (c) Induction of expression of LCE3C and LCE3E in normal skin (N) by the tape-stripping (TS) model, which removes the stratum corneum of the epidermis.