Identification of a Psoriasis Susceptibility Candidate Gene by Linkage Disequilibrium Mapping with a Localized Single Nucleotide Polymorphism Map

doi:10.1006/geno.2002.6720

Genomics

Volume 79, Issue 3, March 2002, Pages 305-314

https://doi.org/10.1006/geno.2002.6720 Get rights and content

Abstract

Psoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Here we describe the creation of a single-nucleotide polymorphism (SNP) map spanning 900–1200 kb of chromosome 3q21, which had been previously recognized as containing a psoriasis susceptibility locus, PSORS5. We genotyped 644 individuals, from 195 Swedish psoriatic families, for 19 polymorphisms. Linkage disequilibrium (LD) between marker and disease was assessed using the transmission/disequilibrium test (TDT). In the TDT analysis, alleles of three of these SNPs showed significant association with disease (P<0.05). A 160-kb interval encompassing these three SNPs was sequenced, and a coding sequence consisting of 13 exons was identified. The predicted protein shares 30–40% homology with the family of cation/chloride cotransporters. A five-marker haplotype spanning the 3′ half of this gene is associated with psoriasis to a P value of 3.8<10⁻⁵. We have called this gene SLC12A8, coding for a member of the solute carrier family 12 proteins. It belongs to a class of genes that were previously unrecognized as playing a role in psoriasis pathogenesis.

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Psoriasis is an immune mediated inflammatory skin disease with complex etiology involving interplay between environmental and genetic risk factors as disease initiating event. Enhanced understanding on genetic risk factors, differentially expressed genes, deregulated proteins and pathway-targeted therapeutics have established multiple axis of psoriasis pathogenesis. So far, loci in 424 genes are reported to be associated with psoriasis alongside copy number variations and epigenetic alterations. From clinical perspective, presence of specific genetic trigger(s) in individual psoriasis patient could aid in devising a personalized therapeutic strategy. Therefore, the review presents an updates on reported genomic alterations and their subsequent course of cutaneous inflammations that potentially drive to psoriasis.
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Psoriasis is a chronic inflammatory skin disease whose prevalence varies among different populations worldwide. It is a complex multi-factorial disease and the exact etiology is largely unknown. Family based studies have indicated a genetic predisposition; however they cannot fully explain the disease pathogenesis. In addition to genetic susceptibility, environmental as well as gender and age related factors were also been found to be associated. Recently, imbalances in epigenetic networks are indicated to be causative elements in psoriasis. The present knowledge of epigenetic involvement, mainly the DNA methylation, chromatin modifications and miRNA deregulation is surveyed here. An integrated approach considering genetic and epigenetic anomalies in the light of immunological network may explore the pathogenesis of psoriasis.
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Le psoriasis est une maladie multifactorielle qui fait intervenir des facteurs génétiques, des facteurs immunologiques et des facteurs environnementaux. Durant les dix dernières années plusieurs études par tour de génome sur des familles ou sur des cas/témoins ont permis de mettre en évidence une dizaine de loci PSORS localisés sur des chromosomes différents et contenant plusieurs gènes candidats. Le psoriasis apparaît comme étant une maladie génétique qui suit le modèle mixte avec l’implication d’un gène majeur (le locus PSORS1) et un ensemble de gènes mineurs dont la pénétrance est variable selon le locus considéré. Les données génétiques ont mis l’accent sur l’implication du système immunitaire dans la physiopathologie du psoriasis. Il est aujourd’hui admis que le psoriasis est une maladie immunologique impliquant les profils de réponses TH1 et TH17. Beaucoup reste encore à faire pour mieux élucider les mécanismes impliqués dans la genèse des lésions psoriasiques afin de retrouver de nouvelles cibles thérapeutiques.
Psoriasis is a multifactorial disease that involves genetic, immunological and environmental factors. During the last decade, several studies by genome scan on families or cases/controls helped to highlight more than ten loci “PSORS” located on different chromosomes and containing several candidate genes. Psoriasis appears as a genetic disease that follows the mixed model with the involvement of a major gene (PSORS1) and a set of minor genes with a variable penetrance depending on the locus. Genetic data have focused on the involvement of the immune system in the pathogenesis of psoriasis. It is now accepted that psoriasis is an immunological disease involving the response profiles TH1 and TH17. Much remains to be done to better elucidate the mechanisms involved in the genesis of psoriatic lesions to find new therapeutic targets.

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^*: Present address: MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

^‡: To whom correspondence and reprint requests should be addressed. Fax: (+46) 31 84 21 60. E-mail: [email protected].

^†: Present address: Variagenics Inc., 60 Hampshire St., Cambridge, Massachusetts 02139, USA

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Regular ArticleIdentification of a Psoriasis Susceptibility Candidate Gene by Linkage Disequilibrium Mapping with a Localized Single Nucleotide Polymorphism Map

Abstract

Am. J. Hum. Genet.

J. Invest. Dermatol.

Am. J. Hum. Genet.

Genet. Anal. Techn. Appl.

Am. J. Hum. Genet.

J. Mol. Biol.

J. Biol. Chem.

Lancet

Curr. Opin. Biotechnol.

Am. J. Hum. Genet.

Genomics

Genomics

Clinical Dermatology

The genetics of psoriasis: a complex disorder of the skin and immune system

Hum. Mol. Genet.

Age at onset and different types of psoriasis

Br. J. Dermatol.

Psoriasis and HLA-Cw6

Br. J. Dermatol.

HLA B13, B17, B37 and Cw6 in psoriasis vulgaris: association with age of onset

Arch. Dermatol. Res.

Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis

Hum. Mol. Genet.

Evidence that a locus for familial psoriasis maps to 4q

Nat. Genet.

Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q

Science

Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan

Hum. Mol. Genet.

Regular Article
Identification of a Psoriasis Susceptibility Candidate Gene by Linkage Disequilibrium Mapping with a Localized Single Nucleotide Polymorphism Map