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- Title
Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR.
- Authors
Helms, Cynthia; Saccone, Nancy L.; Li Cao; Daw, Jil A. Wright; Kai Cao; Hsu, Tony M.; Taillon-Miller, Patricia; Shenghui Duan; Gordon, Derek; Pierce, Brandon; Ott, Jurg; Rice, John; Fernandez-Vina, Marcelo A.; Pui-Yan Kwok; Menter, Alan; Bowcock, Anne M.
- Abstract
Psoriasis is a complex inflammatory disease of the skin affecting 1–2% of the Caucasian population. Associations with alleles from the HLA class I region (now known as PSORS1), particularly HLA-Cw*0602, were described over 20 years ago. However, extensive linkage disequilibrium (LD) within this region has made it difficult to identify the true susceptibility allele from this region. A variety of genes and regions from a 238-kb interval extending from HLA-B to corneodesmosin (CDSN) have been proposed to harbor PSORS1. In order to identify the minimum block of LD in the MHC class I region associated with psoriasis we performed a comprehensive case/control and family-based association study on 242 Northern European psoriasis families and two separate European control populations. High resolution HLA typing of HLA-A, -B and -C alleles was performed, in addition to the genotyping of 18 polymorphic microsatellites and 36 SNPs from a 772-kb segment of the HLA class I region harboring the previously described interval. This corresponded on average to one SNP every 7 kb in the candidate 238 kb region. With all tests, the association was the strongest with single markers and haplotypes from a block of LD harboring HLA-C and SNP n.9. Logistic regression analyses indicated that association seen with candidate genes from the interval such as CDSN and HCR was entirely dependent on association with HLA-Cw*0602 and SNP n.9-G alleles. The previously reported association with CDSN and HCR was observed to be due to the existence of the associated alleles lying on the most commonly over-transmitted haplotype. Rare over-transmitted haplotypes also harbored HLA-Cw*12 alleles. HLA-Cw*12 family members are closely related to HLA Cw*0602, sharing identical sequences in their alpha-2 domains, peptide-binding pockets A, D and E and all 3′ introns. The introduction of a potential binding site for the RUNX/AML family of transcription factors in intron 7, is also specific to these HLA-C alleles. These variants need to be investigated further for their role as PSORS1.
- Subjects
PSORIASIS; PSORIATIC arthritis; SKIN inflammation; HLA histocompatibility antigens; GENETIC testing; PEPTIDES; TRANSCRIPTION factors
- Publication
Human Genetics, 2005, Vol 118, Issue 3/4, p466
- ISSN
0340-6717
- Publication type
Article
- DOI
10.1007/s00439-005-0048-2