Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.

The pathogenesis of all forms of psoriasis remains obscure. Segregation analysis and twin studies together with ethnic differences in disease frequency all point to an underlying genetic susceptibility to psoriasis, which is both complex and likely to reflect the action of a number of genes. We performed a genome wide analysis using a total of 271 polymorphic autosomal markers on 284 sib relative pairs identified within 158 independent families. We detected evidence for linkage at 6p21 (PSORS1) with a non-parametric linkage score (NPL)=4.7, p=2 x 10(-6) and at chromosome 1p (NPL=3.6, p=1.9 x 10(-4)) in all families studied. Significant excess (p=0. 004) paternal allele sharing was detected for markers spanning the PSORS1 locus. A further three regions reached NPL scores of 2 or greater, including a region at chromosome 7 (NPL 2.1), for which linkage for a number of autoimmune disorders has been reported. Partitioning of the data set according to allele sharing at 6p21 (PSORS1) favoured linkage to chromosomes 2p (NPL 2.09) and 14q (NPL 2.0), both regions implicated in previous independent genome scans, and suggests evidence for epistasis between PSORS1 and genes at other genomic locations. This study has provided linkage evidence in favour of a novel susceptibility locus for psoriasis and provides evidence of the complex mechanisms underlying the genetic predisposition to this common skin disease.

Double blind randomized trial of sucralfate vs placebo during radical radiotherapy for head and neck cancers.

BACKGROUND: This study sought to determine whether sucralfate prophylaxis during a course of high dose radiation therapy (RT) for head and neck cancer decreases acute side effects. METHODS: Patients receiving curative intent RT for advanced head and neck cancers participated in a single institution double-blind randomized trial comparing sucralfate to placebo. Patients were stratified according to fractionation, use of concurrent chemotherapy, Karnofsky performance status (KPS), age, and pretreatment presence of a feeding gastrostomy. Patients were prospectively evaluated during weekly treatment checks, and analyzed with regard to time (measured in terms of dose) until development of the following: weight loss, mucositis, pain, nutritional intake, and need for a treatment break. After completion of RT, time until healing was similarly compared. RESULTS: Fifty-two patients received sucralfate and 50 received placebo. The mean (+/-SD) prescribed dose was 69 +/- 7 Gy. Sixty-nine patients received BID fractionation and 27 received concurrent chemotherapy. No difference was detected in any outcome measure in the direct comparison between the two groups. On multivariate analysis, weight loss >5% or >10% occurred more frequently in patients receiving chemotherapy (p < 0.01 and p = 0.05, respectively). Grade 3 mucositis was more common in patients receiving chemotherapy (p = 0.05) or BID fractionation (p = 0.04) or having a poor KPS (p = 0.02). Interval to healing was not associated with any of the pretreatment- or treatment-related factors. Sucralfate did not result in any additional toxicity. CONCLUSIONS: Prophylactic treatment with sucralfate during high-dose head and neck RT did not decrease acute treatment side effects. Other modalities should be investigated.

Characterization of the major susceptibility region for psoriasis at chromosome 6p21.3.

Psoriasis is a common inflammatory skin condition caused by genetic and environmental factors. Recent genome-wide linkage analyses have identified a locus encoding susceptibility to psoriasis and placed this gene in the 12 cM interval between markers D6S426 and D6S276 on chromosome 6p21.3. This is a broad region and encompasses the human major histocompatibility complex. We have sought to localize the susceptibility gene more precisely by exploiting the linkage, haplotype, and linkage disequilibrium information available through genotyping 118 affected sib pairs, their parents and other affected family members. A total of 14 highly polymorphic markers were genotyped, combining anonymous loci with the class I genes HLA-B and -C distributed across a genetic interval of approximately 14 cM including the entire major histocompatibility complex. Through the application of higher density mapping within the major histocompatibility complex, we identified those regions most commonly shared identical by descent in patients with psoriasis. Using the transmission-disequilibrium test, we found significant evidence of linkage and allelic association across an interval defined by the markers tn62 (p = 1.0 x 10(-7)), HLA-B (p = 4.0 x 10(-7)), and HLA-C (p = 2.7 x 10(-9)), a region encompassed within a 285 kb genomic DNA fragment. Hence these studies contribute to the refinement of the localization of a major psoriasis susceptibility gene and place the critical region near to HLA-C.

Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.

Psoriasis is a common chronic inflammatory disorder of the skin. To further understand the pathogenesis of psoriasis we have chosen to investigate the molecular genetic basis of the disorder. We have used a two-stage approach to search the human genome for the location of genes conferring susceptibility to psoriasis, using a total of 106 affected sibling pairs identified from 68 independent families. As over a third of the extended kindreds included affected relatives besides siblings, in addition to an analysis of allele sharing between affected sibling pairs, a novel linkage strategy was applied that extracts full non-parametric information. Four principal regions of possible linkage were identified on chromosomes 2, 8, 20 (p <0.005) and markers from the MHC region at 6p21 (p <0.0000006) for which significant evidence of linkage disequilibrium was also observed (p <0.00002). Whilst data from limited case control associations exist to implicate the MHC, the results of this genome wide analysis demonstrate that, at least in the population studied, a gene or genes located within the MHC and close to the class 1 HLA loci, represent the major determinant of the genetic basis of psoriasis.