Summary To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and NF-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

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In a 12.5 cM genome-wide scan for psoriasis susceptibility loci, recombination-based tests revealed linkage to the HLA region (Zmax = 3.52), as well as suggestive linkage to two novel regions: chromosome 16q (60-83.1 cM from pter, Zmax = 2.50), and chromosome 20p (7.5-25 cM from pter, Zmax = 2.62). All three regions yielded P values < or = 0.01 by non-parametric analysis. Recombination-based and allele sharing methods also confirmed a previous report of a dominant susceptibility locus on distal chromosome 17q (108.2 cM from pter, Zmax = 2.09, GENEHUNTER P = 0.0056). We could not confirm a previously reported locus on distal chromosome 4q; however, a broad region of unclear significance was identified proximal to this proposed locus (153.6-178.4 cM from pter, Zmax = 1.01). Taken together with our recent results demonstrating linkage to HLA-B and -C, this genome-wide scan identifies a psoriasis susceptibility locus at HLA, confirms linkage to 17q, and recommends two novel genomic regions for further scrutiny. One of these regions (16q) overlaps with a recently-identified susceptibility locus for Crohn's disease. Psoriasis is much more common in patients with Crohn's disease than in controls, suggesting that an immunomodulatory locus capable of influencing both diseases may reside in this region.

Recent genome scans have established the presence of a major psoriasis-susceptibility locus in the human leukocyte antigen (HLA) complex on chromosome 6p21.3. To narrow the interval for candidate gene testing, we performed a linkage-disequilibrium analysis of 339 families, with the use of 62 physically mapped microsatellite markers spanning the major histocompatibility complex (MHC). As detected by use of the transmission/disequilibrium test (TDT), individual markers yielded significant linkage disequilibrium across most of the MHC. However, the strongest evidence for marker-trait disequilibrium was found in an ∼300-kb region extending from the MICA gene to the corneodesmosin gene. Maximum-likelihood haplotypes were constructed across the entire MHC in the original sample and across a 1.2-Mb region of the central MHC in an expanded sample containing 139 additional families. Short (two-to five-marker) haplotypes were subjected to the TDT using a "moving-window" strategy that reduced the variability of TDT P values relative to the single-locus results. Furthermore, the expanded sample yielded a sharp peak of evidence for linkage disequilibrium that spanned ∼170 kb and that was centered 100 kb telomeric to HLA-C. The 1.2-Mb interval was further dissected by means of recombinant ancestral haplotype analysis. This analysis identified risk haplotype 1 (RH1), which is a 60-kb fragment of ancestral haplotype 57.1, on all identifiable HLA risk haplotypes. One of these haplotypes exhibits significant linkage disequilibrium with psoriasis but does not carry Cw6, which is the HLA allele most strongly associated with the disease. These results demonstrate that RH1 is highly likely to carry the disease allele at PSORS1, and they exclude HLA-C and corneodesmosin with a high degree of confidence.

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Although psoriasis is strongly associated with certain human leukocyte antigens (HLAs), evidence for linkage to HLA markers has been limited. The objectives of this study were (1) to provide more definitive evidence for linkage of psoriasis to HLA markers in multiplex families; (2) to compare the major HLA risk alleles in these families with those determined by previous case-control studies; and (3) to localize the gene more precisely. By applying the transmission/disequilibrium test (TDT) and parametric linkage analysis, we found evidence for linkage of psoriasis to HLA-C, -B, -DR, and -DQ, with HLA-B and -C yielding the most-significant results. Linkage was detectable by parametric methods only when marker-trait disequilibrium was considered. Case-control association tests and the TDT identified alleles belonging to the EH57.1 ancestral haplotype as the major risk alleles in our sample. Among individuals carrying recombinant ancestral haplotypes involving EH57. 1, the class I markers were retained selectively among affecteds four times more often than among unaffecteds; among the few affected individuals carrying only the class II alleles from the ancestral haplotype, all but one also carried Cw6. These data show that familial and "sporadic" psoriasis share the same risk alleles. They also illustrate that substantial parametric linkage information can be extracted by accounting for linkage disequilibrium. Finally, they strongly suggest that a major susceptibility gene resides near HLA-C.

Patch test preparations should reliably elicit positive allergic reactions in sensitized persons. An ideal preparation should also evoke neither irritant (toxic) reactions (IR) nor questionable (doubtful) reactions (? + ), though such unwanted reactions are, in practice, quite common, more so from some preparations than from others. Although usually not reported(1-6), the contribution of IR and ?+ reactions to the total number of reactions to any test preparation should be quantified.To this end, we propose the use of a reaction index (RI), defined as:where a is the number of allergic reactions, q the number of questionable reactions, and i the number of irritant reactions obtained with the same patch test preparation. To obtain reliable results, the sum a+q+i should be larger than 100.In Fig. 1, the ratio of allergic (a) to unwanted (q+z) reactions appears in a logarithmic scale on the x-axis, while the RI is shown in a linear scale on the y-axis. With equal numbers of allergic and unwanted reactions (ratio a/(q+z)=l), RI is zero. With a decreasing proportion of allergic reactions, RI decreases asymptotically towards -1. With an increasing proportion of allergic reactions, the RI rises asymptotically towards + 1. An ideal patch test preparation would have an RI of I, and an acceptable patch test preparation a positive RI. Patch test preparations with negativeRis produce more unwanted than allergic reactions and should be improved. An RI value of -1 characterizes an unacceptable preparation that elicits unwanted reactions only.For each patch test preparation, a specific RI can be calculated, if its numbers of allergic, questionable and irritant reactions are known. Table 1 shows RI values recalculated from recent data (7) in 5766 patients. RI values range from 0.651 (nickel sulphate 2.5%) to -0.035 (formaldehyde 1%). Low positive Rls of this study are mostly due to questionable Rl 0.5 r----Reaction Index Rl Rl•a-(q+i)/(a+(q+i)) /