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| Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene |
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| Author(s): Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NVC, Jenisch S, Weichenthal M, Abecasis GR, Lim HW, Christophers E, Voorhees JJ, Elder JT |
| Source: AMERICAN JOURNAL OF HUMAN GENETICS Volume: 78 Issue: 5 Pages: 827-851 Published: MAY 2006 |
| Times Cited: 89 References: 98 |
| Abstract: Previous studies have narrowed the interval containing PSORS1, the psoriasis-susceptibility locus in the major histocompatibility complex (MHC), to an similar to 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Elder, JT (reprint author), Univ Michigan, Sch Med, Dept Dermatol, 3312 CCGC,Box 0932, Ann Arbor, MI 48109 USA |
Addresses:
1. Univ Michigan, Sch Med, Dept Dermatol, Ann Arbor, MI 48109 USA
2. Univ Michigan, Sch Med, Dept Radiat Oncol Canc Biol, Ann Arbor, MI 48109 USA
3. Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA
4. Ann Arbor Vet Affairs Hosp, Dept Dermatol, Ann Arbor, MI USA
5. Univ Kiel, Dept Immunol, D-2300 Kiel, Germany
6. Univ Kiel, Dept Dermatol, D-2300 Kiel, Germany
7. Henry Ford Hosp, Dept Dermatol, Detroit, MI 48202 USA |
| Publisher: UNIV CHICAGO PRESS, 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA |
| Subject Category: Genetics & Heredity |
| IDS Number: 032EH |
| ISSN: 0002-9297 |
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