Human Molecular Genetics, 2002, Vol. 11, No. 5 589-597
© 2002 Oxford University Press
Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus
1Departments of Medical Genetics and Dermatology, and Finnish Genome Center, University of Helsinki, 00014 Helsinki, Finland, 2Division of Medical Genetics, Departments of Medicine and Genetics, University of Leicester, Leicester LE1 7RH, UK, 3St John’s Institute of Dermatology, King’s College, London, SE1 7EH, UK, 4Medical and Molecular Genetics Center, Institut de Recerca Oncologica, Gran Via s/n, Km 2.7, Barcelona 08907, Spain, 5Department of Biosciences at Novum, Center for Nutrition and Toxicology and Clinical Research Centre, Karolinska Institutet, 141 57 Huddinge, Sweden, 6Department of Dermatology, Jichi University, Jichi, Japan and 7Dipartimento di Biopatologia e Diagnostica Per Immagini, Sezione di Genetica, Università di Roma ‘Tor Vergata’, Via di Tor Vergata 135, Rome, Italy
PSORS1, near HLA-C, is the major genetic determinant of psoriasis. We present genetic and structural evidence suggesting a major role for the HCR gene at the PSORS1 locus. Genotyping of 419 families from six populations revealed that coding single-nucleotide polymorphisms of HCR formed a conserved allele HCR*WWCC that associated highly significantly with psoriasis and with the HLA-Cw6 allele in all populations. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the two genes could not be genetically distinguished by this sample size. However, the variant HCR allele was predicted to differ in secondary structure from the wild-type protein. HCR protein expression in lesional psoriatic skin differed considerably from that observed in normal skin. These results provide strong evidence for the HCR*WWCC allele as a major genetic determinant for psoriasis, probably by a mechanism impacting on keratinocyte proliferation.
+ To whom correspondence should be addressed at: Department of Biosciences at Novum, Karolinska Institute, 14157 Huddinge, Sweden. Tel: +358 50 5319123; Fax: +358 91 9125478; Email: juha.kere@biosci.ki.se. Correspondence may also be addressed to: Richard Trembath, Division of Medical Genetics, Departments of Medicine and Genetics, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, UK. Email: rtrembat@hgmp.mrc.ac.uk +The Psoriasis Consortium is: D.B.Burden, D.Tillman, S.H.Powis, N.Balendran, M.Ameen, R.W.Vaughan, E.K.Heath (UK); R.Itkonen-Vatjus, C.Jansen, J.Karvonen, S.-L.Karvonen, K.Kivekäs, T.Reunala, E.Snellman, T.Uurasmaa (Finland); R.Toftgård (Sweden); T.Murakami, M.Otsuki, A.Asahina, H.Saeki (Japan); E.Barberà, C.Ferrándiz, A.Giménez Arnau, F.Grimalt, S.Puig, A.Sánchez, A.Palacios, J.A.Pujol, M.Sánchez, E.Simal, F.Vázquez, B.Ramírez (Spain). The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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