title: Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
abstract: Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an approximately 300-kb region containing HLA-C and at least 10 other genes. In an effort to identify the PSORS1 gene, we cloned and completely sequenced this region from both chromosomes of five individuals. Two of the sequenced haplotypes were associated with psoriasis (risk), and the other eight were clearly unassociated (nonrisk). Comparison of sequence of the two risk haplotypes identified a 298-kb region of homology, extending from just telomeric of HLA-B to the HCG22 gene, which was flanked by clearly nonhomologous regions. Similar haplotypes cloned from unrelated individuals had nearly identical sequence. Combinatorial analysis of exonic variations in the known genes of the candidate interval revealed that HCG27, PSORS1C3, OTF3, TCF19, HCR, STG, and HCG22 bore no alleles unique to risk haplotypes among the 10 sequenced haplotypes. SPR1 and SEEK1 both had messenger RNA alleles specific to risk haplotypes, but only HLA-C and CDSN yielded protein alleles unique to risk. The risk alleles of HLA-C and CDSN (HLA-Cw6 and CDSN*TTC) were genotyped in 678 families with early-onset psoriasis; 620 of these families were also typed for 34 microsatellite markers spanning the PSORS1 interval. Recombinant haplotypes retaining HLA-Cw6 but lacking CDSN*TTC were significantly associated with psoriasis, whereas recombinants retaining CDSN*TTC but lacking HLA-Cw6 were not associated, despite good statistical power. By grouping recombinants with similar breakpoints, the most telomeric quarter of the 298-kb candidate interval could be excluded with high confidence. These results strongly suggest that HLA-Cw6 is the PSORS1 risk allele that confers susceptibility to early-onset psoriasis.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor.
authors.forename: Rajan P
authors.initials: RP
authors.lastname: Nair
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Stuart
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor.
authors.forename: Ioana
authors.initials: I
authors.lastname: Nistor
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor.
authors.forename: Ravi
authors.initials: R
authors.lastname: Hiremagalore
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor.
authors.forename: Nicholas V C
authors.initials: NVC
authors.lastname: Chia
authors.affiliation: Department of Immunology, University of Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jenisch
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weichenthal
authors.affiliation: Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Department of Dermatology, Henry Ford Hospital, Detroit.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Department of Dermatology, University of Kiel, Kiel, Germany.
authors.forename: Enno
authors.initials: E
authors.lastname: Christophers
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor; Department of Radiation Oncology (Cancer Biology), University of Michigan Medical School, Ann Arbor; Department of Dermatology, Ann Arbor Veterans Affairs Hospital, Ann Arbor. Electronic address: jelder@umich.edu.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
mesh_terms: D000328:Adult; D001483:Base Sequence; D016000:Cluster Analysis; D015331:Cohort Studies; D005787:Gene Frequency; 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; D010375:Pedigree; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics*; D012326:RNA Splicing; D012306:Risk; D014158:Transcription, Genetic
chemical_list: C109656:CDSN protein, human; D006023:Glycoproteins; D015236:HLA-C Antigens; D036341:Intercellular Signaling Peptides and Proteins; C484393:PSORS1C1 protein, human; D011506:Proteins