Fine Mapping of the Psoriasis Susceptibility Locus PSORS1 Supports HLA-C as the Susceptibility Gene in the Han Chinese Population

Abstract

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 (T∶NT = 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.

Fine mapping of eight psoriasis susceptibility loci

“…10,11 Although all three SNP signals in the MHC are allied with coding variants of nearby genes, our finding remains that the SNPs are more strongly associated with disease than the putative causative gene variants. For the best SNP signal, this stronger association was demonstrated to be an artifact of reduced imputation quality.…”

“…As assessed using phase I 1000 genomes data set, our primary signal in the MHC (rs114255771) exhibited complete LD (r 2 ¼ 1) with rs4406273 chr6.hg19.g.31266090G4A. This SNP was the primary hit in that meta-analysis and also happens to be an excellent surrogate for HLACw*0602, the leading candidate for the PSORS1 risk allele 10,11 (unpublished data). Our secondary MHC signal (rs6924962) is in close proximity (B8.9 kb) to and exhibits moderately strong LD (r 2 ¼ 0.56) with the secondary MHC signal from the GWASImmunochip meta-analysis (rs13437088 chr6.hg19.g.3135511T4C).…”

“…[4][5][6]9 Although GWAS provides an efficient strategy for identifying disease susceptibility loci, detailed assessments of the contribution of these loci to disease require systematic investigation of common and rare variants in each locus. Previous fine-mapping studies in psoriasis have focused on the MHC, helping localize the primary risk locus 10,11 and identify multiple psoriasis susceptibility alleles. 8,12 Using a combination of genotyping and imputation, 13 we examined in detail the genetic variation in each of the eight psoriasis susceptibility regions (MHC, IL12B, IL23A, IL23R, TNIP1, TNFAIP3, IL13 and RNF114) in a large sample of subjects of European ancestry, over 97% of whom were not previously subjected to fine-mapping.…”

Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene

“…This observation widens the spectrum of molecular defects causing PSS type B and shows that loss of five additional genes in the PSORS1 region does not result in an additional cutaneous phenotype. Fine-mapping studies have previously shown that the strongest predisposing gene to psoriasis within the PSORS1 region is HLA-CW6, while TCF19, CCHCR1 (HCR), PSORS1C1 (previous SEEK1), PSORS1C2 (SPR1), C6orf15 (STG) show a weaker association (6,7). Several of these genes have been associated with type 1 diabetes (TCF19, CCHCR1 and PSORS1C1) (8), systemic sclerosis (PSORS1C1) (9) or follicular lymphoma (C6orf15 or STG) (10) features which are not seen in our patient.…”

“…Oxazolone (OX) and 2,4-dinitrofluorobenzene (DNFB) are haptens inducing exacerbation of allergy accompanied with allergen-specific T cells (7,8). OX was applied to mouse ear with various schedules, and inflammatory cytokines mRNA expression was measured by quantitative PCR.…”