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- Localization of Psoriasis-Susceptibility Locus PSORS1 to a 6...Localization of Psoriasis-Susceptibility Locus PSORS1 to a 60-kb Interval Telomeric to HLA-C
The American Journal of Human Genetics, Volume 66, Issue 6, 1 June 2000, Pages 1833-1844
Rajan P. Nair, Philip Stuart, Tilo Henseler, Stefan Jenisch, Nicholas V.C. Chia, Eckhard Westphal, Nicholas J. Schork, Jane Kim, Henry W. Lim, Enno Christophers, John J. Voorhees and James T. Elder
AbstractRecent genome scans have established the presence of a major psoriasis-susceptibility locus in the human leukocyte antigen (HLA) complex on chromosome 6p21.3. To narrow the interval for candidate gene testing, we performed a linkage-disequilibrium analysis of 339 families, with the use of 62 physically mapped microsatellite markers spanning the major histocompatibility complex (MHC). As detected by use of the transmission/disequilibrium test (TDT), individual markers yielded significant linkage disequilibrium across most of the MHC. However, the strongest evidence for marker-trait disequilibrium was found in an ∼300-kb region extending from the MICA gene to the corneodesmosin gene. Maximum-likelihood haplotypes were constructed across the entire MHC in the original sample and across a 1.2-Mb region of the central MHC in an expanded sample containing 139 additional families. Short (two- to five-marker) haplotypes were subjected to the TDT using a “moving-window” strategy that reduced the variability of TDT values relative to the single-locus results. Furthermore, the expanded sample yielded a sharp peak of evidence for linkage disequilibrium that spanned ∼170 kb and that was centered 100 kb telomeric to HLA-C. The 1.2-Mb interval was further dissected by means of recombinant ancestral haplotype analysis. This analysis identified risk haplotype 1 (RH1), which is a 60-kb fragment of ancestral haplotype 57.1, on all identifiable HLA risk haplotypes. One of these haplotypes exhibits significant linkage disequilibrium with psoriasis but does not carry Cw6, which is the HLA allele most strongly associated with the disease. These results demonstrate that RH1 is highly likely to carry the disease allele at PSORS1, and they exclude HLA-C and corneodesmosin with a high degree of confidence.
Abstract | Full Text | PDF (163 kb) - Evidence for Interaction between Psoriasis-Susceptibility Lo...Evidence for Interaction between Psoriasis-Susceptibility Loci on Chromosomes 6p21 and 1q21
The American Journal of Human Genetics, Volume 65, Issue 6, 1 December 1999, Pages 1798-1800
Francesca Capon, Sabrina Semprini, Bruno Dallapiccola and Giuseppe Novelli
Full Text | PDF (52 kb) - Family-Based Analysis Using a Dense Single-Nucleotide Polymo...Family-Based Analysis Using a Dense Single-Nucleotide Polymorphism–Based Map Defines Genetic Variation at PSORS1, the Major Psoriasis-Susceptibility Locus
The American Journal of Human Genetics, Volume 71, Issue 3, 1 September 2002, Pages 554-564
Colin D. Veal, Francesca Capon, Michael H. Allen, Emma K. Heath, Julie C. Evans, Andrew Jones, Shanta Patel, David Burden, David Tillman, Jonathan N.W.N. Barker and Richard C. Trembath
AbstractPsoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, (iasis usceptibility ), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen–C [HLA-C], α-helix–coiled-coil–rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent–affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (<10), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the interval, the major susceptibility locus for psoriasis.
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Copyright © 2005 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 76, Issue 1, 164-171, 1 January 2005
doi:10.1086/426948
Report
Mapping of the Major Psoriasis-Susceptibility Locus (PSORS1) in a 70-Kb Interval around the Corneodesmosin Gene (CDSN)
Sandro Orrù1, 
, 
, Erika Giuressi2, Carlo Carcassi1, 2, Mirella Casula2 and Licinio Contu2
1 Genetica Medica–Dipartimento di Scienze Mediche, Università degli Studi di Cagliari, Italy
2 Centro Regionale Trapianti, Cagliari, Italy
Address for correspondence and reprints: Dr. Sandro Orrù, Genetica Medica–Dipartimento di Scienze Mediche, P.O. Binaghi, Via Is Guadazzonis 3, Cagliari, ItalyAbstract
Numerous putative susceptibility loci have been described for psoriasis. Among the loci confirmed in the literature, PSORS1 (the major histocompatibility complex at 6p21.3) has the strongest effect. Recent studies have highlighted a 200-kb candidate region. However, this region has not been well delimited, mainly because of the strong linkage equilibrium among the associated alleles. To finely map PSORS1, we set up a study using 17 polymorphic markers in a 525-kb interval around the human leucocyte antigen C locus (HLA-C). The results uncovered five loci with alleles strongly associated with psoriasis (Sidak-corrected P [Pc] values from 1.8 × 10−7 to .003), all structured in a psoriasis-susceptibility haplotype (PSH). Subsequent analysis of extended haplotypes showed that the PSH was not only present on the traditional psoriasis-susceptibility extended haplotypes (HLA-Cw6-B57, HLA-Cw6-B37, and HLA-Cw6-B13) but also on a haplotype of Sardinian origin (HLA-Cw7-B58) found to be associated with psoriasis (Pc=.0009) because of an ancestral recombination with one of the susceptibility haplotypes carrying the HLA-Cw6 allele. Comparisons of the regions identical by descent among associated and nonassociated haplotypes highlighted a minimum region of 70 kb not recombinant with PSORS1, around the corneodesmosin (CDSN) gene.
