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% to 3% in Caucasians1. 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 cluster2. 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 USA, and in a family-based study (p=5.4E-04). LCE3C-LCE3B-del is tagged by rs4112788 (r2=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 plays a role in psoriasis susceptibility.

Implications of gene copy-number variation in health and diseases

“…The absence of the well characterized 32 199 bp region was significantly associated (P¼1.38E À08 ) with risk of psoriasis when studied in family-based samples from Spain, The Netherlands, Italy and the United States (P¼5.4E À04 ). 43 Immunity-related GTPase family, M was found to be associated with CD through earlier SNP studies. Recently, a 20-kb deletion has been found to attribute susceptibility to CD.…”

“…41 In contrast, the increased copy number of b-defensin genes was shown to be associated with psoriasis, which is a chronic autoimmune skin disease with a prevalence of 2-3% in individuals of the European ancestry. 42,43 Apart from b-defensin genes, individuals with deletion in LCE3B and LCE3C genes of late cornified envelope (LCE) gene cluster are found to be susceptible to psoriasis. The absence of the well characterized 32 199 bp region was significantly associated (P¼1.38E À08 ) with risk of psoriasis when studied in family-based samples from Spain, The Netherlands, Italy and the United States (P¼5.4E À04 ).…”

A population-based study of copy number variants and regions of homozygosity in healthy Swedish individuals

“…35,36 The high deletion frequency of loci overlapping with LCE3C and LCE3B (82.76%), UGT2B17 (47.13%) and WWOX (79.76%) requires further studies to investigate their associations with complex diseases such as psoriasis, rheumatoid arthritis and graftversus-host disease for hematopoietic stem cell transplantation patients. For example, the mismatch of the copy numbers of UGT2B17 was found to be associated with graft-versus-host disease in patients with hematopoietic stem cell transplantation.…”

Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes

“…2 Genome-wide linkage scans have unambiguously mapped a primary disease susceptibility locus (PSORS1) to the major histocompatibility complex (MHC), 3 where refinement studies and resequencing efforts point to HLA-C as the most likely PSORS1 candidate. 4,5 More recently, the advent of genome-wide association scans has allowed the identification of several non-MHC susceptibility genes, including IL12B, IL23R, RNF114, TNFAIP3, TNIP1, IL4/IL13 and LCE3B/3C [6][7][8][9][10][11] Of these, IL12B and IL23R harbour variants that also confer susceptibility to Crohn's disease (CD) 12 and ankylosing spondylitis. 13 Similarly, TNFAIP3 alleles have been associated with rheumatoid arthritis, 14 systemic lupus erythematosus 15 and type I diabetes.…”