Meta-Analysis Confirms the LCE3C_LCE3B Deletion as a Risk Factor for Psoriasis in Several Ethnic Groups and Finds Interaction with HLA-Cw6

Abstract

A multicenter meta-analysis including data from 9389 psoriasis patients and 9477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in European populations [OROverall = 1.21 (1.15–1.27)], and for the first time directly demonstrated the deletion's association with psoriasis in [Chinese OR = 1.27 (1.16–1.34); Mongolian OR = 2.08 (1.44–2.99)] populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.

Analysis of protein–protein interaction between late cornified envelope proteins and corneodesmosin

“…Previous studies showed a genetic interaction between LCE3C_LCE3B-del and HLA-C*06 in populations from the Netherlands, USA and China (10)(11)(12). In addition, epistasis between PSORS1 and PSORS4 loci has been reported in an Italian cohort (13).…”

Psoriasis Risk Genes of the Late Cornified Envelope-3 Group Are Distinctly Expressed Compared with Genes of Other LCE Groups

“…Heterozygous or homozygous deletion of LCE3B and LCE3C, which is observed in greater than 90% of patients with psoriasis, could potentially affect skin barrier properties (compared with the homozygous ancestral status of two intact chromosomes), in particular under conditions of stress. 7 Thus, concerning the relevance for psoriasis, there is deletion of two of five LCE3 genes rather than two of 18 LCE genes. Because LCE3B and LCE3C are expressed at low levels, if at all, in normal skin, the situation is different from the filaggrin (FLG) gene and atopic dermatitis.…”

“…Its reported epistasis with HLA-Cw6 in at least some white populations makes it a major risk factor for psoriasis. 7 Inasmuch as all LCE genes are similar and would be predicted to exert similar functions, the question arises as to why deletion of 2 of 18 quite similar LCE genes could have a role in the etiology of psoriasis. Herein it was demonstrated that four of the five LCE3 genes are differently expressed compared with other LCE groups.…”

“…5 This association has been widely replicated in cohorts of European and Asian origin. 6,7 The LCE genes are located on chromosome 1q21 in a region called the epidermal differentiation complex. 8 This region is enriched for genes expressed during epidermal differentiation including loricrin, involucrin, filaggrin, the small proline-rich protein genes, and the LCE genes.…”

Genetic Characteristics of Rheumatic Patients Developing Inflammatory Skin Lesions Induced by Biologic Therapy

“…4,[8][9][10] But what stands out is that all patients with ISL had at least one copy of the LCE3C LCE3B deleted alleles (absence of nondeleted homozygous individuals). In the general population, the frequency of non-deleted homozygotes is around 18% 4,9,10 and disruption of the skin barrier occurs in relation to the number of copies of LCE3C LCE3B, being undetectable in carriers of the homozygous deletion 4 and reduced in heterozygotes.…”