D Tillman

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis

Psoriasis [MIM 177900] is a chronic and disfiguring skin disorder, which is inherited as a multifactorial trait.1 Genome wide scans have repeatedly mapped a major disease susceptibility locus (PSORS1) to the Major Histocompatibility Complex (MHC), on chromosome 6p21 (reviewed by Capon et al2). Outside of the MHC, at least eight additional susceptibility intervals have been reported (PSORS2-9) (reviewed by Capon et al2). The PSORS2 interval [MIM 602723] was originally mapped to chromosome 17q25, in a sample of extended pedigrees presenting with disease segregation across multiple generations.3 Linkage to PSORS2 was later replicated in independently ascertained cohorts.4–6 Conversely, two distinct genome wide scans carried out by our group failed to detect any evidence for linkage to PSORS2, in United Kingdom cohorts of European descent.7,8 High density genetic analysis of the PSORS2 interval recently identified two distinct association peaks, both defined by a small number of non-coding single nucleotide polymorphisms (SNPs).9 The proximal peak spans a 20 kb genomic segment where a putative susceptibility allele, mapping between the SLC9AR1 and NAT9 genes, abolishes a RUNX1 binding site. The less characterised distal region of association lies 6 Mb away, within intron 3 of the RAPTOR gene [MIM *607130].9 To define the relevance of PSORS2 genetic variation …

Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility

Psoriasis (MIM *177900) is a hyperproliferative skin disorder, characterised by inflammatory cell dermal infiltration, disruption of keratinocyte terminal differentiation, and premature desquamation of the stratum corneum.1 Although the disease pathogenesis is poorly understood, it is well recognised that genetic factors underlie psoriasis susceptibility, as documented by family clustering of the disease and increased concordance rates in monozygotic twin pairs.2,3 To date, genome wide scans have identified seven distinct psoriasis susceptibility regions ( PSORS 1-7 4) and have provided compelling evidence for a major role of the PSORS1 locus on chromosome 6p21.5–9 Linkage disequilibrium (LD) based studies of microsatellite maps have refined the PSORS1 boundaries to a 150 kb interval10–12 harbouring three sets of coding polymorphisms that have repeatedly shown association with psoriasis: HLA-Cw*0602, HCR*269, and CDSN*TTC.13–18 In a recent analysis of a UK family cohort, we have shown that the most common psoriasis susceptibility chromosomes (cluster E) carry HCR*269, CDSN*TTC, and two SNPs (defined as n7 and n9) lying proximal to HLA-C and showing extremely significant disease association. We also observed a rare haplotype (cluster D), marginally over-transmitted to affected patients and likely to have originated from cluster E by a double recombination event, replacing HCR*269 while preserving SNPs 7/9 and CDSN*TTC.19 This observation suggested that CDSN SNPs might be required to confer psoriasis susceptibility, in conjunction with determinants lying in the HLA-C genomic region. CDSN is also a very attractive biological candidate, since corneodesmosin is a desmosomal protein involved in keratinocyte cohesion/desquamation.20–22 With this study, we have sought to validate the hypothesis of CDSN involvement in psoriasis by: (1) confirming that cluster D is a risk haplotype, through the analysis of an independent population, originating from the Gujurat region of northern India; and (2) defining CDSN genetic variation …

IgA anticardiolipin antibodies associated with Henoch-Schönlein purpura

Henoch-Schönlein purpura is associated with the deposition of immune complexes containing IgA. The nature of the antigen in these immune complexes is uncertain but in some reported cases has included autoantigens such as IgA rheumatoid factor and IgA antineutrophil cytoplasmic antibody. We report the finding of an IgA class anticardiolipin antibody in a 51-year-old patient with Henoch-Schönlein purpura. A potential role for IgA autoantibodies in Henoch-Schönlein purpura needs to be further explored.

Stage II melanoma in the West of Scotland, 1976–1985: Prognostic factors for survival

The outcome of 142 patients undergoing therapeutic lymphadenectomy for clinical stage II malignant melanoma was retrospectively assessed. 5 year survival was 26%, and survival was not altered in the 25 patients who received two courses of adjuvant combination chemotherapy after lymphadenectomy. On univariate analysis, the most significant determinants of survival were the number of malignant nodes removed at lymphadenectomy (P = 0.00004), the age of the patient (P = 0.009) and the disease-free interval between primary and stage II disease (P = 0.01). The following features were not significantly related to survival: sex, site, histogenetic type of primary tumour, tumour thickness and level of invasion. The number of malignant lymph-nodes was confirmed on multivariate analysis as the single most useful and significant predictor of survival, with the patients age providing an additional significant contribution. In future adjuvant trials in stage II melanoma after therapeutic lymphadenectomy, patients should be stratified for both age and number of malignant nodes.