Molecular Genetics of Psoriasis

Kati Asumalahti, MD Biomedicum, Department of Medical Genetics, Molecular Medicine Research Program, PO Box 63 (Haartmaninkatu 8) Room B317a, FIN-00014 University of Helsinki, Finland. Tel: +358-9-191 25633, Fax: +358-9-191 25624. e-mail: [email protected]

Abstract

Psoriasis is a chronic inflammatory skin disease. Based on family studies, a strong genetic component exists in the etiology of psoriasis, but environmental factors are also needed to trigger the disease onset. Both linkage and association Kari Asumalahti defended her thesis on April 3, 2003 in Helsinki Medical Faculty. Faculty analyses have assigned the major Opponent was James T. Elder, MD, PhD, Professor of Dermatology, Department of Dermatology, University of Michigan, Michigan, USA and Supervisor has been Professor, locus for psoriasis susceptibility, Juha Kere, MD, PhD, Department of Biosciences at Novum and Clinical Research Center, PSORS1, to 6p21.3 in all populations Karolinska Institute, Sweden and Department of Medical Genetics, University of Helsinki studied. The PSORS1 locus has been narrowed down to an approximately 200 kb region in the centromeric part of the MHC class I region. susceptibility alleles were found to these could be used to differentiate belong to the same extended the three alleles. GP was shown to In this study, a novel candidate gene susceptibility haplotype and their have a similar but even stronger at the PSORS1 locus, HCR (Pg8), was separation was not possible even association with PSORS1 suscepti- cloned and found to be highly with a sample size of almost 1700 bility alleles than PV, however, it did polymorphic. In a large trio family chromosomes. not help in separating the three material from seven different genes. PPP was not associated with populations, a specific allele of the any of the PSORS1 alleles, suggesting The three PSORS1 susceptibility HCR gene, HCR*WWCC, was shown a different etiology or molecular alleles were also studied in two to be strongly associated with mechanism than for PV or GP. clinical variants of psoriasis, guttate chronic plaque psoriasis (PV). psoriasis (GP) and palmoplantar However, two previously identified pustulosis (PPP), to see whether the Functional evidence for HCR as a susceptibility alleles of the locus, locus was involved in the patho- potential psoriasis gene was also HLA-Cw*6 and CDSN*5, showed a genesis of subtypes and whether gained. Expression of the HCR mRNA similar association. These three

Forum for Nord Derm Ven Vol. 8 August 2003 82 and protein was altered in the different populations. In this study, for psoriasis near HLA-C, HCR (Pg8), keratinocytes of lesional psoriatic a genome-wide scan in Finnish is highly polymorphic with a disease- associated susceptibility allele. skin compared with non-lesional psoriasis families not associated Human Mol Gen 2000; 9 : 1533–1542. psoriatic and normal skin. In with PSORS1 was performed to find II Asumalahti K, Veal C, Laitinen T, addition, the HCR*WWCC allele was other susceptibility loci. A minor Suomela S, Allen M, Elomaa O, et al. Coding haplotype analysis supports predicted to adopt an altered susceptibility locus for psoriasis was HCR as the putative susceptibility secondary structure compared with mapped to 18p. The 18p locus has gene for psoriasis at the MHC PSORS1 the wild-type allele, which could previously been suggested as a locus. Human Mol Gen 2002; 11: 589– affect the antigenic properties of the susceptibility locus for psoriasis in 597. III Asumalahti K, Ameen M, Suomela S, protein. a British population. Taken together, Hagforsen E, Michaëlsson G, Evans J, these two mapping results yield et al. Genetic analysis of PSORS1 sufficient evidence to name 18p as distinguishes guttate psoriasis and The PSORS1 locus is estimated to a new candidate locus for psoriasis. palmoplantar pustulosis. J Invest account for 30–50% of familial Dermatol (in press). psoriasis, thus other susceptibility IV Asumalahti K, Laitinen T, Lahermo P, Suomela S, Itkonen-Vatjus R, Jansen loci likely exist. In genome-wide List of original publications C, et al. Psoriasis susceptibility locus linkage analyses, several minor on 18p revealed by genome scan in putative psoriasis susceptibility loci This thesis is based on the following Finnish families not associated to have been identified (PSORS2-7), but original publications. PSORS1. (Submitted). similar to other complex diseases, I Asumalahti K, Laitinen T, Itkonen- Vatjus R, Lokki M-L, Suomela S, most of them have not been Snellman E, et al. A candidate gene replicated in subsequent studies in

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