Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR.
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.
Helms
Cynthia
C
Department of Genetics, Washington University School of Medicine, Box 8232, 4566 Scott Avenue, St. Louis, Missouri, 63110, USA.
Saccone
Nancy L
NL
Cao
Li
L
Daw
Jil A Wright
JA
Cao
Kai
K
Hsu
Tony M
TM
Taillon-Miller
Patricia
P
Duan
Shenghui
S
Gordon
Derek
D
Pierce
Brandon
B
Ott
Jurg
J
Rice
John
J
Fernandez-Vina
Marcelo A
MA
Kwok
Pui-Yan
PY
Menter
Alan
A
Bowcock
Anne M
AM
D016022:Case-Control Studies; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics*; D012044:Regression Analysis
C412616:CCHCR1 protein, human; C109656:CDSN protein, human; D006023:Glycoproteins; D015236:HLA-C Antigens; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C484393:PSORS1C1 protein, human; D011506:Proteins