Genetics of Psoriasis and Psoriatic Arthritis James T. Elder Department of Dermatology University of Michigan PsA Working Group Meeting New York, NY April 14, 2003

Genetic Epidemiology: Summary Most data supports polygenic inheritance Low penetrance of disease alleles (low GRR) “Many genes means common genes” Low penetrance and high frequency cause problems for linkage Common genes  founder effect  LD methods

Published Psoriasis Loci

Chromosome 16q--the Crohn’s Disease Connection? Psoriasis is 7 times more common in Crohn’s disease patients than in controls Our 16q linkage peak mapped very close to a confirmed linkage peak for Crohn’s disease NOD2 maps to the 16q peak and has been confirmed as a Crohn’s susceptibility gene NOD2 recognizes pathogens and activates NF-B (innate immunity) But--little or no evidence for association with major Crohn’s disease alleles (3 studies)

Confirmation of Linkage to 17q Originally reported by Bowcock et al. (Science 1994) Also found by us in two separate groups of families, and in Swedish families Possible gene reported 6/03 by Bowcock--needs confirmation

Strategy for Identification of PSORS1 (Nair et al, AJHG 66:1833-44,2000) 62 microsatellites spanning the MHC (more around HLA-C) Haplotypes deduced from pedigrees and clustered to identify ancestral chromosomes Clusters tested for risk using TDT Find shortest region common to risk Sequence risk region in risk vs. non-risk chromosomes

Physical Map of PSORS1 Region RH1 is repeat-rich, encodes no known genes 7 known genes found in RH2 RH1 and RH2 are separated by two closely spaced markers (M6S111 and M6S169)

Refined PSORS1 Risk Region Refined risk interval includes OTF3, TCF19, HCR, SPR1, and SEEK1, but not CDSN Risk interval could be larger depending on risk status of Cluster 17 (T:NT = 21:10, TDT p value = 0.048)

Cluster 17 Collaboration: Methods Objective: to determine whether Cluster 17 is a risk chromosome Type marker M6S161, whose allele 3 is specific for cluster 17--frequency only 1.5%, so many subjects needed 10 psoriasis genetics centers [Finland, Germany, Iceland, Italy, Sweden (2), UK (2), France, Ann Arbor/Kiel] Analysis by transmission disequilibrium test (TDT)

Refined PSORS1 Risk Region Based on conclusion that Cluster 17 is non-risk Redefined risk interval includes HLA-C, OTF3, TCF19, HCR, SPR1, SEEK1, CDSN, and STG Region is still small enough to analyze by DNA sequencing

Sequencing Strategy Genomic fosmid library (~40 kb inserts) Screen with region-specific probes Fosmid clones for each allele Shear fosmid DNA (~1 kb) Clone into plasmid GATCGATC GATCCATC Seq 1000 clones Assemble

Testing of Candidate Genes HLA-Cw6 is specific for risk chromosomes If cluster 17 is non-risk, then one combination of 3 variants in CDSN is specific for risk (“Allele 5”, T619-T1236-C1243) No significant association of any coding CDSN variants with psoriasis in Japan (Tissue Antigens 60:77, 2002) or in Taiwan (Br J Dermatol 148:418, 2003), despite significant associations with HLA-Cw6

Is HLA-Cw6 the PSORS1 Disease Allele? HLA-Cw1-B46 in Oriental psoriasis HLA-B38/39 in psoriatic arthritis

HLA Associations with PsV in Thailand (Choonhakarn et al HLA Associations with PsV in Thailand (Choonhakarn et al., Int J Dermatol 41:330, 2002) HLA-B46-Cw1 haplotype is strongly associated with psoriasis in Thailand and Japan (odds ratio  4) B46-Cw1 is common in Asians (HF = 14% in controls), rare in Caucasians (HF <<1%) HLA-Cw6 is common in Thai psoriatics, rare in Thai controls (odds ratio  10) B46-Cw1 is equally prevalent in early- and late-onset Thai psoriatics (HF = 24.7 vs 26.7) HLA-Cw6 is more common in early-onset Thai psoriatics (HF = 17.4 vs. 8.9) Thus, Cw6 and B46-Cw1risk alleles do not appear to be identical by descent, and differ in phenotype

HLA-B38/39 in PsV and PsA: Compilation of 15 Studies

Haplotype Frequencies (HLA 1991) Note high prevalence of Cw7-B39 haplotype in Japan, low prevalence in Caucasian populations Cw7 associations generally limited to Japan/Orient Primary association may be with B38/B39, rather than Cw7

Psoriasis Genes: 2003 Evidence for PSORS1 very strong, but cannot account for all genetic effects in psoriasis (s = 5-10, s,MHC = 1.6) Coding variants of all RH2 genes except CDSN have been ruled out B46-Cw1 haplotype genetically and functionally distinct--further study needed HLA-B38/B39 may confer risk for PsA--better ascertainment of PsA needed Association studies on large case-control cohorts and linkage studies on large (>10 affected) pedigrees will be needed to identify multiple non-MHC genes

Supported by NIAMS and NPF Collaborators Ann Arbor Rajan Nair Phil Stuart John Voorhees Detroit Henry Lim (HFH) Psoriasis Genetics Consortium Jonathan Barker (London) Richard Trembath (Leicester) Anne Bowcock (Wash Univ) Kiel Michael Wiechenthal Stefan Jenisch Tilo Henseler Enno Christophers San Diego Nik Schork Caroline Nievergelt Cluster 17 Collaboration International Psoriasis Genetics Committee Supported by NIAMS and NPF

How Might Specific HLA Class I Alleles Cause Disease? Clonal TCR rearrangements suggest response to specific antigen(s) Class I molecules should be presenting intracellular proteins of the APC They may be very good a presenting certain self-antigens They may be very poor at presenting certain self-antigens, leading to failure of thymic elimination of anti-self T-cells Alternatively, they may mis-regulate NK cells, leading to overproduction of IFN-g

Finding the Non-MHC Genes Genome-wide association studies Haplotype block mapping Coding sequence variation Case-control design OK Identifying heterogeneous loci Large families essential for initial identification Create dense marker maps, build haplotypes Search for these haplotypes in case-control or TDT studies Incorporate MHC data into analyses