title: An in-depth characterization of the major psoriasis susceptibility locus identifies candidate susceptibility alleles within an HLA-C enhancer element.
abstract: Psoriasis is an immune-mediated skin disorder that is inherited as a complex genetic trait. Although genome-wide association scans (GWAS) have identified 36 disease susceptibility regions, more than 50% of the genetic variance can be attributed to a single Major Histocompatibility Complex (MHC) locus, known as PSORS1. Genetic studies indicate that HLA-C is the strongest PSORS1 candidate gene, since markers tagging HLA-Cw*0602 consistently generate the most significant association signals in GWAS. However, it is unclear whether HLA-Cw*0602 is itself the causal PSORS1 allele, especially as the role of SNPs that may affect its expression has not been investigated. Here, we have undertaken an in-depth molecular characterization of the PSORS1 interval, with a view to identifying regulatory variants that may contribute to disease susceptibility. By analysing high-density SNP data, we refined PSORS1 to a 179 kb region encompassing HLA-C and the neighbouring HCG27 pseudogene. We compared multiple MHC sequences spanning this refined locus and identified 144 candidate susceptibility variants, which are unique to chromosomes bearing HLA-Cw*0602. In parallel, we investigated the epigenetic profile of the critical PSORS1 interval and uncovered three enhancer elements likely to be active in T lymphocytes. Finally we showed that nine candidate susceptibility SNPs map within a HLA-C enhancer and that three of these variants co-localise with binding sites for immune-related transcription factors. These data indicate that SNPs affecting HLA-Cw*0602 expression are likely to contribute to psoriasis susceptibility and highlight the importance of integrating multiple experimental approaches in the investigation of complex genomic regions such as the MHC.
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Clop
authors.forename: Anna
authors.initials: A
authors.lastname: Bertoni
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Spain
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Venu
authors.initials: V
authors.lastname: Pullabhatla
authors.forename: Raul
authors.initials: R
authors.lastname: Tonda
authors.forename: Christian
authors.initials: C
authors.lastname: Hundhausen
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.forename: Pieter
authors.initials: P
authors.lastname: De Jong
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Hayday
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
authors.forename: Robert J A
authors.initials: RJ
authors.lastname: Bell
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping / Q000379:methods; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D015236:HLA-C Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D011565:Psoriasis / Q000235:genetics*; D062085:RNA, Long Noncoding; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D015236:HLA-C Antigens; C491620:HLA-C*06:02 antigen; C484393:PSORS1C1 protein, human; C517504:PSORS1C3 lncRNA, human; D011506:Proteins; D062085:RNA, Long Noncoding