¹Members of the Cluster 17 Collaboration (in alphabetical order): Goncalo Abecasis, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USAMichael Allen, St John's Institute of Dermatology, London, UKJonathan N. W. N. Barker, St John's Institute of Dermatology, London, UKDavid Burden, Department of Dermatology, Western Infirmary, Glasgow, Scotland Francesa Capon, Department of Genetics, University of Leicester, Leicester, UKEnno Christophers, Department of Dermatology, University of Kiel, Kiel, GermanyJames T. Elder, Departments of Dermatology and Radiation Oncology, University of Michigan, and Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, USAJudith Fischer, Centre National de Genotypage, Evry, FranceEmiliano Giardina, Department of Biopathology, University of Rome "Tor Vergata", Rome, ItalyJohann E. Gudjonsson, Landspitali University Hospital, Reykjavik, IcelandUlrike Hüffmeier, Department of Human Genetics, University of Erlangen, Erlangen, GermanyStefan Jenisch, Department of Immunology, University of Kiel, Kiel, GermanyAri Karason, DeCODE Genetics, Reykjavik, IcelandJuha Kere, Department of Biosciences at Novum, Karolinska Institutet, Huddinge, SwedenRajan P. Nair, Department of Dermatology, University of Michigan, Ann Arbor, MI, USAGiuseppe Novelli, Dipartimento di Biopatologia e Diagnostica per Immagini, Università di Roma "Tor Vergata", Rome, ItalyJean-François Prud'homme, Généthon, Evry, FranceZhaohui S. Qin, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USALena Samuelsson, Department of Clinical Genetics, Sahlgrenska University Hospital, Gothenburg, SwedenFabio Sanchez, Department of Dermatology, Karolinska Institute, Stockholm, SwedenUlpu Saarialho-Kere, Department of Dermatology, University of Helsinki, Finland, and Karolinska Institutet at Stockholm Soder Hospital, Stockholm, SwedenMona Ståhle, Department of Dermatology, Karolinska Institute, Stockholm, SwedenPhilip Stuart, Department of Dermatology, University of Michigan, Ann Arbor, MI, USADavid Tillman, Department of Dermatology, WesternInfirmary, Glasgow, ScotlandHeiko Traupe, Department of Dermatology, University of Muenster, Muenster, GermanyRichard Trembath, Department of Genetics, University of Leicester, Leicester, UKHelgi Valdimarsson, Landspitali University Hospital, Reykjavik, IcelandColin Veal, Department of Genetics, University of Leicester, Leicester, UKJohn J. Voorhees, Department of Dermatology, University of Michigan, Ann Arbor, MI, USAMichael Weichenthal, Department of Dermatology, University of Kiel, Kiel, Germany

Received 28 August 2004; Revised 18 October 2004; Accepted 24 November 2004.

Abstract

Human leukocyte antigen (HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identified multiple risk haplotypes carrying HLA-Cw6 and one haplotype (cluster 17, HLA-Cw8-B65) that appeared to carry risk for psoriasis but did not carry HLA-Cw6. This haplotype was very similar to other risk haplotypes for at least 60 kb telomeric to HLA-C, suggesting identity by descent with the remaining risk chromosomes. The association, however, between psoriasis and this haplotype as assessed by the transmission/disequilibrium test (TDT) was of borderline significance (p-value 0.048). In order to better assess the risk associated with cluster 17, a multicenter collaboration typed additional subjects for a single marker (M6S161) for which one allele (249 bp) was found only on cluster 17. The new sample included 1275 pedigrees as well as 300 cases and 913 controls. Transmission of this allele to affected individuals was examined using the TDT and the pedigree disequilibrium test (PDT), and case–control samples were analyzed by a trend test across genotype categories. By all methods, the newly acquired genotypes failed to confirm the association originally reported, despite adequate power. In contrast, the 248 bp allele, which is found on all HLA-Cw6-positive risk haplotypes as well as several non-risk haplotypes, shows significant excess transmission for all cohorts. Taken together, these results indicate that cluster 17 does not carry a psoriasis-susceptibility allele, and expand the PSORS1 risk interval to approximately 300 kb.