Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population.
PSORS1 (psoriasis susceptibility gene 1) is a major susceptibility locus for psoriasis. Several fine-mapping studies have highlighted a 300-kb candidate region of PSORS1 where multiple biologically plausible candidate genes were suggested. The most recent study has indicated HLA-Cw6 as the primary PSORS1 risk allele within the candidate region in a Caucasian population. In this study, a family-based association analysis of the PSORS1 locus was performed by analyzing 10 polymorphic microsatellite markers from the PSORS1 region as well as HLA-B, HLA-C and CDSN loci in 163 Chinese families of psoriasis. Five marker loci show strong evidence (P<10(-3)), and one marker locus shows weak evidence (P = 0.04) for association. The haplotype cluster analysis showed that all the risk haplotypes are Cw6 positive and share a 369-kb region of homologous marker alleles which carries all the risk alleles, including HLA-Cw6 and CDSN*TTC, identified in this study. The recombinant haplotype analysis of the HLA-Cw6 and CDSN*TTC alleles in 228 Chinese families showed that the HLA-Cw6(-)/CDSN*TTC(+) recombinant haplotype is clearly not associated with risk for psoriasis (TratioNT = 29:57, p = 0.0025) in a Chinese population, suggesting that the CDSN*TTC allele itself does not confer risk without the presence of the HLA-Cw6 allele. The further exclusion analysis of the non-risk HLA-Cw6(-)/CDSN*TTC(+) recombinant haplotypes with common recombination breakpoints has allowed us to refine the location of PSORS1 to a small candidate region. Finally, we performed a conditional linkage analysis and showed that the HLA-Cw6 is a major risk allele but does not explain the full linkage evidence of the PSORS1 locus in a Chinese population. By performing a series of family-based association analyses of haplotypes as well as an exclusion analysis of recombinant haplotypes, we were able to refine the PSORS1 gene to a small critical region where HLA-C is a strong candidate to be the PSORS1 susceptibility gene.
Fan
Xing
X
Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.
Yang
Sen
S
Huang
Wei
W
Wang
Zhi-Min
ZM
Sun
Liang-Dan
LD
Liang
Yan-Hua
YH
Gao
Min
M
Ren
Yue-Qing
YQ
Zhang
Kai-Yue
KY
Du
Wen-Hui
WH
Shen
Yu-Jun
YJ
Liu
Jian-Jun
JJ
Zhang
Xue-Jun
XJ
D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D011506:Proteins / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology*; D011995:Recombination, Genetic
C109656:CDSN protein, human; D006023:Glycoproteins; D015236:HLA-C Antigens; D036341:Intercellular Signaling Peptides and Proteins; C484393:PSORS1C1 protein, human; D011506:Proteins