Advances in the Search for Psoriasis Susceptibility Genes

doi:10.1006/mgme.2000.3031

Molecular Genetics and Metabolism

Volume 71, Issues 1–2, September 2000, Pages 250-255

https://doi.org/10.1006/mgme.2000.3031 Get rights and content

Abstract

Psoriasis (PS) is a common skin disorder affecting approximately 2% of the Caucasian population. Despite the established influence of several environmental factors, epidemiological data and twin studies have long demonstrated a genetic basis for psoriasis susceptibility. Moreover an association between PS and HLA-Cw6 has been reported in different ethnic groups. In recent years, the availability of statistical methods for complex disease linkage analysis has prompted many researchers to carry out genome-wide scans. Their results have been conflicting and linkage replication has seldom been documented. However, a few chromosome regions have been confirmed in independent studies. In particular, compelling evidence supports the existence of a susceptibility locus within the HLA region. Moreover, loci on chromosomes 17q and 1q have been reported in at least two independent genome scans. Several groups have undertaken the refinement of regions identified during genome scans, using linkage disequilibrium data. This approach has allowed the fine mapping of the 6p21 locus, now restricted to a 60-kb genomic segment. As critical regions get smaller, candidate gene analysis becomes an attractive approach. So far, three genes have been extensively investigated: S100A7 on chromosome 1q and CDSN and HCR on chromosome 6p21. Even though several SNPs have been identified within these genes, none of them seems to meet the requirement needed to prove an involvement in PS pathogenesis. These criteria include association replication in different populations and functional studies of SNP biological significance. Thus, only a collaborative and multidisciplinary approach will allow the identification of PS susceptibility genes.

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Cited by (28)

CCHCR1 interacts with EDC4, suggesting its localization in P-bodies
2014, Experimental Cell Research
Citation Excerpt :
It is believed to be a candidate biomarker for psoriasis, a common skin disease that affects 1–2% of the population [1]. Linkage and association studies on CCHCR1 as the psoriasis susceptibility gene have, however, produced mixed results [2–4], most likely because of their small sample sizes and the use of dissimilar populations and different forms of statistical analysis. The CCHCR1 protein is predicted to have α-helical coiled-coil rod domains [5], a common protein motif, but it exhibits little homology with other known proteins [6].
Coiled‐coil alpha‐helical rod protein 1 (CCHCR1) is suggested as a candidate biomarker for psoriasis for more than a decade but its function remains poorly understood because of the inconsistent findings in the literature. CCHCR1 protein is suggested to be localized in the cytoplasm, nucleus, mitochondria, or centrosome and to regulate various cellular functions, including steroidogenesis, proliferation, differentiation, and cytoskeleton organization. In this study, we attempted to find a consensus between these findings by identifying the interaction partners of CCHCR1 using co-immunoprecipiation with a stable cell line expressing EGFP-tagged CCHCR1. Out of more than 100 co-immunoprecipitants identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), the enhancer of mRNA-decapping protein 4 (EDC4), which is a processing body (P-body) component, was particularly found to be the major interacting partner of CCHCR1. Confocal imaging confirmed the localization of CCHCR1 in P-bodies and its N-terminus is required for this subcellular localization, suggesting that CCHCR1 is a novel P-body component. As P-bodies are the site for mRNA metabolism, our findings provide a molecular basis for the function of CCHCR1, any disruption of which may affect the transcriptome of the cell, and causing abnormal cell functions.
Replication of association between interleukin-23 receptor (IL-23R) and its ligand (IL-12B) polymorphisms and psoriasis in the Chinese Han population
2010, Human Immunology
Citation Excerpt :
As with other immune-mediated diseases, such as Crohn's disease, rheumatoid arthritis, multiple sclerosis, and juvenile-onset diabetes, psoriasis is regarded as a T-cell–mediated autoimmune disease [1]. Epidemiologic data and twin studies have demonstrated that in addition to environmental factors there is a genetic basis for psoriasis susceptibility [2]. Linkage and association analyses have provided considerable support for a major predisposing area, lying within the major histocompatibility complex (MHC), but the characterization of non-MHC disease loci is still controversial, owing to the small effects of the underlying genetic variants.
Psoriasis is an inflammatory skin disease with a multifactorial genetic basis. A recent genome-wide association study identified several psoriasis-predisposing loci, including IL-12B, which encodes the common p40 subunit of interleukin (IL)–12 and IL-23 and the IL-23 receptor gene (IL-23R). To investigate the relationships of these predisposing polymorphisms with psoriasis in the Chinese Han population, we genotyped three representative variants (rs6887695, rs11465817, and rs1343152) in 217 unrelated patients and 288 control subjects using direct sequencing, We further replicated the positive polymorphism, rs6887695, in a larger combined sample that included 578 patients and 1422 controls. We found the single nucleotide polymorphism, rs6887695 (odds ratio = 1.33, 95% confidence interval 1.03–1.73, p = 0.028) of IL-2B to be significantly associated with psoriasis, and a novel halotype A-A of rs11465817-rs1343152 also showed a positive association. Our study confirms the effects of IL-12B and IL-23R variants on psoriasis in East Asian populations, and provides a reference point for further investigation of the role of the IL-12/IL-23 pathway in chronic epithelial inflammation in Asian and other ethnic populations.
Association of skin barrier genes within the PSORS4 locus is enriched in Singaporean Chinese with early-onset psoriasis
2009, Journal of Investigative Dermatology
Citation Excerpt :
For example, only the PSORS1, PSORS9 (Zhang et al., 2002; Fan et al., 2008), 9q33-34 (Sun et al., 2007), and 2p22.3-11.2 (Sun et al., 2008) regions have been reported as susceptibility loci in the Han Chinese. Moreover, the existence of more than one major susceptibility gene is likely to decrease the ability to detect linkage (Capon et al., 2000). PSORS4, localized within chromosome 1q21, first emerged as a potential PSORS from American and Italian family studies (Bhalerao and Bowcock, 1998; Capon et al., 1999).
Psoriasis (OMIM#177900) is a common polygenic skin disorder affecting approximately 2% of the northern European population and 0.1% of the Han Chinese. Psoriasis patients suffer from chronic skin inflammation, manifested by erythematous scaly lesions. PSORS1–PSORS9 have been confirmed as psoriasis susceptibility loci in independent genetic studies on predominantly Caucasian populations, with psoriasis susceptibility loci (PSORS1, PSORS9) and additional loci at 9q33-34 and 2p22.3-11.2 reported in Han Chinese patients. In this study, we show the association of PSORS4 with psoriasis in Singaporean Chinese. Dense genotyping of single-nucleotide polymorphism-tagging candidate genes within the epidermal differentiation complex revealed significant association in the proximity of the involucrin gene (IVL); the strongest association was seen in early-onset psoriasis patients (P=0.0014). A follow-up genome-wide association screen localized the psoriasis susceptibility region to ∼360 kb along chromosome 1 in the vicinity of IVL, small proline-rich region (SPRR) and proline-rich region 9 (PRR9) genes. The study of interactions between the causative variant(s) in this locus will provide insights into a possible role for epidermal barrier formation in the pathogenesis of psoriasis.
Psoriasis in childhood with total remission × chronic disease: Clinical application of HLA class I markers
2007, Journal of Dermatological Science
Cutaneous diseases in Native Americans
2003, Dermatologic Clinics
Psoriasiform dermatitis susceptibility in Itgb2<sup>tm1Bay</sup> PL/J mice requires low-level CD18 expression and at least two additional loci for progression to severe disease
2003, American Journal of Pathology
Itgb2^tm1Bay PL/J mice express low levels of the β₂ integrins and, unlike Itgb2^tm1Bay C57BL/6J mice, spontaneously develop psoriasiform dermatitis with several similarities to human psoriasis. To define the genetic requirements for skin disease susceptibility we analyzed more than 500 F2 progeny from an Itgb2^tm1Bay (PL/J × C57BL/6J) intercross. We found that 23.5% developed chronic inflammatory skin disease, although significant differences in severity were observed. Another CD18 mutation, Itgb2^tm2Bay, has now been generated that completely eliminates CD18 expression. Surprisingly, of 10 Itgb2^tm2Bay homozygote PL/J N4 mice generated, none showed clinical or histopathological evidence of disease. However, Itgb2^tm1Bay/Itgb2^tm2Bay PL/J mice developed dermatitis indistinguishable from Itgb2^tm1Bay PL/J mice. In addition, approximately half of Itgb2^tm1Bay/Itgb2^tm2Bay (C57BL/6J × PL/J)F1 mice were found to develop mild psoriasiform dermatitis identical to the early stages of disease seen in Itgb2^tm1Bay PL/J mice. Collectively, these results suggest a complex inheritance pattern of psoriasiform dermatitis in this model that involves lowered, but not absent, CD18 expression and at least two additional PL/J loci for the development of severe disease. The susceptibility allele can act in either a heterozygous or homozygous state, dependent on the level of CD18 expression.

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^☆: This review is dedicated to the memory of Stefano Gatti, professor of dermatology, at “Tor Vergata” University of Rome.

²: To whom correspondence should be addressed at Cattedra di Genetica, ed. E nord piano terra, Facoltà di Medicina, via di Tor Vergata 135, 00133 Roma, Italy. Fax: +390620427313; E-mail: [email protected].

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MinireviewAdvances in the Search for Psoriasis Susceptibility Genes☆

Abstract

Lancet

J Am Acad Dermatol

Am J Hum Genet

J Invest Dermatol

Am J Hum Genet

J Invest Dermatol

Hum Immunol

Int J Biochem Cell Biol

Lancet

J Invest Dermatol

Epidemiology of psoriasis: Clinical issues

J Invest Dermatol

Epidemiology: Natural history and genetics

Psoriasis: Prevalence, Sponatneous Course and Genetics

Psoriasis: The Prevalence in Sex, Age, and Occupational Groups in Total Population in Sweden: Morphology, Inheritance and Association with Other Skin and Rheumatic Diseases

Psoriasis in monozygotic twins: Variations in expression in individuals with identical genetic constitution

Acta Dermat

Of genes and antigens: The inheritance of psoriasis

J Invest Dermatol

Minireview
Advances in the Search for Psoriasis Susceptibility Genes☆