TY - JOUR
T1 - Localization of PSORS1 to a haplotype block harboring HLA-C and distinct from corneodesmosin and HCR
AU - Helms, Cynthia
AU - Saccone, Nancy L.
AU - Cao, Li
AU - Wright Daw, Jil A.
AU - Cao, Kai
AU - Hsu, Tony M.
AU - Taillon-Miller, Patricia
AU - Duan, Shenghui
AU - Gordon, Derek
AU - Pierce, Brandon
AU - Ott, Jurg
AU - Rice, John
AU - Fernandez-Vina, Marcelo A.
AU - Kwok, Pui Yan
AU - Menter, Alan
AU - Bowcock, Anne M.
N1 - Funding Information:
Acknowledgements We thank Melodie Young, Christina Zhao, Margaret Wright, Rebecca Cochran, Nahid Attar, Shari Lander and Laura Kuykendahl for family collection and technical help. We are also indebted to the many physicians, physician assistants and families with psoriasis for family identification and blood collection. We thank Mary Akin for help in preparation of this manuscript. This work was supported in part by funding from National Psoriasis Foundation (NPF) to AMB and AM, and NIH grants AR44577, AR04904901 (AMB) and HG01720 (PYK).
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-005-0048-2
DO - 10.1007/s00439-005-0048-2
M3 - Article
C2 - 16235096
AN - SCOPUS:30844473103
SN - 0340-6717
VL - 118
SP - 466
EP - 476
JO - Human genetics
JF - Human genetics
IS - 3-4
ER -