Co-Localization of Susceptibility Loci for Psoriasis (PSORS4) and Atopic Dermatitis (ATOD2) on Human Chromosome 1q21

Abstract

Psoriasis (PS) is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and altered differentiation. Atopic dermatitis (ATOD) is a chronic inflammatory, pruritic and eczematous disease frequently associated with respiratory atopy. These diseases are associated with distinct immunologic abnormalities and represent typical examples of complex diseases triggered by both genetic and environmental factors, as demonstrated by independent twin studies. Genome wide linkage studies have mapped susceptibility loci on several chromosomes (PSORS1–9; ATOD1–5). Four of them overlap on chromosomes 1q21, 3q21, 17q25 and 20p although ATOD is quite distinct from PS and these two diseases rarely occur together in the same patient. An association fine-mapping study has been performed to refine PSORS4 and ATOD2 susceptibility loci on chromosome 1q21 analyzing two independently collected cohorts of 128 PS and 120 ATOD trios. Genotype and haplotype analysis of PSORS4 and ATOD2 led us to detect significant p value for haplotypes defined by MIDDLE and ENDAL16 markers in both PS (p = 0.0000036) and ATOD (p = 0.0276), suggesting a strict co-localization within an interval of 42 kb. This genomic interval contains a single gene, LOR, encoding for loricrin. Polymorphic markers mapping in regulatory and coding regions did not show evidence of association in neither of the two diseases. However, expression profiles of LOR in skin biopsies have shown reduced levels in PS and increased levels in ATOD, suggesting the existence of a specific misregulation in LOR mRNA production.

Is FCRL3 a New General Autoimmunity Gene?

“…The chromosome 1q21-q23 was found to harbor a susceptibility locus for several autoimmune diseases including SLE [10], psoriasis, and atopic dermatitis [11]. However, because of the clustering of Fc␥R II/III and FCRL genes and extended blocks of linkage disequilibrium (LD) within the gene clusters, it is difficult to resolve a true disease-associated gene variant(s) in this genomic region.…”

Replication of LCE3C–LCE3B CNV as a Risk Factor for Psoriasis and Analysis of Interaction with Other Genetic Risk Factors

“…This locus is of special interest for PsV, because it comprises the epidermal differentiation complex, a group of genes expressed in the upper strata of the epidermis. Although several genes at PSORS4-e.g., LOR, LCE1C, PGLYRP, SPRR genes, PRR9 genes, and IVL-have been suggested to account for psoriasis susceptibility (Giardina et al, 2006;Chen et al, 2009;Liu et al, 2008;Kainu et al, 2009), very recently, a CNV within the late cornified envelope (LCE) gene cluster was identified by a genome-wide scan using pooled DNAs. The deletion of two LCE genes (LCE3C and LCE3B) was shown to be at higher frequency in 1,426 psoriasis patients from several European countries than in controls and to be associated with psoriasis in a large family-based cohort (de Cid et al, 2009).…”

Deletion of LCE3C and LCE3B genes at PSORS4 does not contribute to susceptibility to psoriatic arthritis in German patients

“…While several genes at PSORS4 (for example, LOR , LCE1C , PGLYRP , SPRR genes, PRR9 genes and IVL ) have been proposed to account for psoriasis susceptibility,15–18 very recently, a copy number variation (CNV) within the late cornified envelope ( LCE ) gene cluster was identified by a genome-wide scan using pooled DNAs. The deletion of 2 late cornified envelope genes ( LCE3C and LCE3B ) was shown to be enriched in 1426 patients with psoriasis and to be associated in a large family-based cohort 19.…”