Journal Article

Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR

Rice, John, Saccone, Nancy L., Taillon-Miller, Patricia, Gordon, Derek, Duan, Shenghui, Bowcock, Anne M., Helms, Cynthia, Kwok, Pui-Yan, Ott, Jurg, Fernandez-Vina, Marcelo A., Menter, Alan, Cao, Li, Hsu, Tony M., Daw, Jil A. Wright, Pierce, Brandon, Cao, Kai

2005

Overview

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.

• Publisher: Springer,Springer Nature B.V
• Subject: Analysis / Biological and medical sciences / Case-Control Studies / Chromosome Mapping / Classical genetics, quantitative genetics, hybrids / Dermatology / Disease / DNA binding proteins / Fundamental and applied biological sciences. Psychology / Genetic aspects / Genetic Predisposition to Disease / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Glycoproteins - genetics / Haplotypes / Histocompatibility antigens / HLA histocompatibility antigens / HLA-C Antigens - genetics / Human / Humans / Intracellular Signaling Peptides and Proteins / Localization / Medicine / Nuclear family / Pedigree / Polymorphism, Single Nucleotide / Proteins - genetics / Psoriasis / Psoriasis - genetics / Regression Analysis / Single nucleotide polymorphisms