Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
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.
Nair
Rajan P
RP
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Stuart
Philip E
PE
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Nistor
Ioana
I
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Hiremagalore
Ravi
R
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Chia
Nicholas V C
NVC
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Jenisch
Stefan
S
Department of Immunology, University of Kiel, Kiel, Germany.
Weichenthal
Michael
M
Department of Dermatology, University of Kiel, Kiel, Germany.
Abecasis
Gonçalo R
GR
Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor.
Lim
Henry W
HW
Department of Dermatology, Henry Ford Hospital, Detroit.
Christophers
Enno
E
Department of Dermatology, University of Kiel, Kiel, Germany.
Voorhees
John J
JJ
Department of Dermatology, University of Michigan Medical School, Ann Arbor.
Elder
James T
JT
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.
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
C109656:CDSN protein, human; D006023:Glycoproteins; D015236:HLA-C Antigens; D036341:Intercellular Signaling Peptides and Proteins; C484393:PSORS1C1 protein, human; D011506:Proteins