S Gene (Corneodesmosin) Diversity and its Relationship to Psoriasis; High Content of cSNP in the HLA-Linked S Gene

Psoriasis is a heterogeneous disease in which several reports suggest the presence of a susceptibility gene in or in the proximity of the human leukocyte antigen complex in chromosome 6p. There is an association between HLA-Cw6 and young onset of the disease. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes. We have studied this gene in a large Swedish psoriasis population and we report a strikingly high degree of polymorphism in the coding parts of the gene, 1 every 100 base pairs. We used a stratified approach to compare the polymorphic variants in patients and controls. A single nucleotide polymorphism in the coding region leading to an amino acid exchange (Ser→Phe) that differed significantly between patients and controls was identified (position 619). Owing to a high allele frequency in a larger control group, however, and an insignificant influence of the variant on the age at onset distribution curve based on a large psoriasis population, we could not confirm that this coding single nucleotide polymorphism was involved in disease etiology. We also examined the single nucleotide polymorphism in position 1243, recently proposed to have an influence on the pathogenesis of the disease. This polymorphism showed less association to the disease as compared with the single nucleotide polymorphism at positions 619 and 722. Such a high degree of variation present also in an HLA gene which is not involved in immune response indicates the difficulty involved in assessing the role of a specific allele in the pathogenesis of a complex disease in this region. A strong association effect due to linkage disequilibrium in an extended region in the HLA complex is also a complicating factor

Collecting a set of psoriasis family material through a patient organisation; clinical characterisation and presence of additional disorders

BACKGROUND: The aim of the present study was to describe the clinical characteristics of a population of psoriatics sampled from a patient organisation and not from hospitals or out-patient clinics. Furthermore, we wanted to compare siblings with and without psoriasis regarding the occurrence of other diseases. METHODS: At the end of 1991, we initiated a project which aimed to study genetic factors leading to psoriasis. Firstly, we sent questionnaires to all the members of the Swedish Psoriasis Association. We then examined 1,217 individuals (570 with psoriasis) from 310 families, in their homes in the southern part of Sweden. All the available family members were examined clinically and asked about the course of the skin disease and the occurrence of other diseases. The eight hundred members of the proband generation were divided into two groups, with or without psoriasis, and their clinical features were compared. RESULTS: Most individuals in this study population had a mild form of psoriasis. The siblings with psoriasis had joint complaints significantly more frequently than their siblings without the skin disease and those with joint complaints had more widespread skin disease. Among the other studied concomitant diseases (iritis, heart or hypertension disease, endocrine disease, inflammatory bowel disease and neurological disease), we were not able to find any difference. Seventy-seven of 570 persons were found to be in remission (13.5%). Females had a mean onset 2.5 years earlier than males. We were not able to find any correlation between the extent of the skin disease and age at onset. Twice as many persons with joint complaints were found among those with psoriasis than among those without, 28% versus 13%. Almost half (48%) the psoriatics who also had joint complaints had psoriasis lesions on their nails. Endocrine disorders were found in 9% of those without any allele for Cw6, but only in 1% of those who had Cw6. In fact, none of 183 Cw6 carriers had diabetes, as compared to the population prevalence of 3–5% in Sweden. CONCLUSION: With the exception of joint complaints, persons with psoriasis, collected from a patient organisation, did not have an increased frequency of (studied) co-existing diseases

Population genetic studies of psoriasis

Psoriasis is a genetically determined, common skin disease affecting about 3 % of the population. The inheritance pattern has earlier been unclear. In collaboration with the Swedish Psoriasis Association, we have collected information on the occurrence of psoriasis in the families of 11,366 members of the Association.Analysis of the answers to a questionnaire showed that 64% of all probands had no parents with psoriasis. The distribution of psoriasis in the parents, the siblings and among the children of probands was compatible with an autosomal recessive inheritance. The cumulative incidence of psoriasis in the elderly can be estimated to 5% and the gene frequency in the population to 25%.Analysis of the ages of onset shows that there is a peak of onset in puberty and that women develop the disease earlier than men. There was a correlation of the onset ages between siblings. Assuming a recessive inheritance, we have calculated the gene frequencies for different onset ages. The earliest onset age, in puberty, is found to have the highest gene frequency, 25%.The risk of acquiring psoriasis depending on the occurrence of psoriasis in the family has been determined empirically. The life-time risk varies from 24%, which is the risk if one sibling already has the disease, to 83%, which is the risk if both parents and one sibling are affected. The risk of getting psoriasis at a certain age is dependent on the age at onset of psoriasis in the affected parent.Family members from 310 families have been examined, altogether 1217 individuals. The body location and extent of psoriasis have been recorded. Remission of the skin disease was found in 13.5% at examination. The accuracy of diagnosis of psoriasis given by the proband was high. We compared concomitant diseases, in the cardiovascular, neurological and endocrine systems, and in joints, as well as iritis and inflammatory bowel disease, in the sibling generation. We found a strong association with joint complaints in persons with psoriasis. For the rest of the disorders studied, we could not find any significant difference. Presence of HLA-Cw6 seemed to protect against diabetes mellitus

Patch testing with own cosmetics-a prospective study of testing and reporting of adverse effects to the Swedish Medical Products Agency.

Background: The Swedish Medical Products Agency (MPA) provides a voluntary reporting system for adverse reactions to cosmetics. However, the reporting is sparse, and the products involved are sometimes difficult to identify. Objectives: To investigate how often patients referred for patch testing were tested with the cosmetic products that they had been using themselves, and to improve the reporting to the MPA by the use of photographic documentation of product labels. Patients and methods: Consecutive patients at five dermatology departments who were patch tested with their own cosmetics were included. Reports including protocols of positive patch test results for the patients' own cosmetics and photographs/photocopies of product labels were sent to the MPA. Results: Three hundred and sixteen of 948 patients (33%) were tested with their own cosmetics, and 15% of these tested positive with one or more products. The number of reports was more than three times higher than in corresponding periods in earlier years. For 79% of the products, photographs/photocopies of the containers were submitted, and for 30%, batch numbers were submitted. Conclusions: For a substantial number of patients, their own cosmetics were suspected of causing adverse reactions and were therefore tested. During the study, the number of reports to the MPA tripled, and the relevant products were easier to identify

Analysis of chromosome 5q31-32 and psoriasis: confirmation of a susceptibility locus but no association with SNPs within SLC22A4 and SLC22A5

We have previously reported a region on chromosome 5q as a possible susceptibility region for psoriasis. This cytokine cluster-rich region has also been suggested as a susceptibility locus in other autoimmune or inflammatory diseases including Crohn's disease (CD) and rheumatoid arthritis (RA). Three specific single-nucleotide polymorphisms (SNPs) have been reported to associate with RA and CD and to change the functional activity of two organic cation transporters, solute carrier family 22 member 4/5 (SLC22A4) and (SLC22A5). In this study, we have analyzed these SNPs for an association with psoriasis. We have also performed a denser linkage analysis of this region with an additional 31 microsatellite markers. We were not able to detect any association with any of the three SNPs analyzed. However, our linkage result supports the involvement of this region in the etiology of psoriasis. We obtained a peak non-parametric linkage value of 3.1 for marker D5S436 in a subgroup of patients with joint complaints. This result supports the findings in another study of psoriasis patients originating from Iceland in which the authors obtained a peak logarithm of the odds score of 2.6 for marker D5S2090, only 2Mb from D5S436. This suggests a psoriasis susceptibility locus on chromosome 5q32 that is involved in the arthritic phenotype of the disease

Stronger association with HLA-Cw6 than with corneodesmosin (S-gene) polymorphisms in Swedish psoriasis patients.

Psoriasis vulgaris is strongly associated with certain human leukocyte antigens, especially in early onset. The purpose of this study was to study the HLA-Cw6 allele and its contribution to disease susceptibility in a set of 104 families with at least two affected siblings. A sequencing method was utilized to examine the two exons that build up the antigen binding site of the C locus receptor. DNA from patients homozygous for Cw6 based on haplotype information were sequenced. The results confirmed the identity of the Cw6 allele in affected individuals with the consensus sequence for Cw*0602. We screened the set of families for psoriasis patients homozygous for Cw6 and found 11 individuals with a mean age at onset of 16.1 years. The corresponding figure for the Cw6 heterozygotes was 18.45 years and for the Cw6-negatives 22.36 years. This is indicative of a gene dose effect. We performed a transmission disequilibrium test (TDT) on the Cw6 allele per se, used as a biallelic marker. The analysis resulted in a P-value of 5.3 x 10(-17) (t167/nt45). This greatly exceeds our previous results of a TDT in the region, including microsatellite markers and single nucleotide polymorphisms (SNPs) in the coding part of the S gene (corneodesmosin), which is a suggested candidate gene in the region. The maximum nonparametric linkage (NPL) value was also reached using HLA-C as a marker. We conclude that Cw6 is the allele which shows the highest degree of association with psoriasis in our set of families and we propose that it directly influences the age at onset of the disease rather than increasing the genetic load in accordance with a polygenic theory

The HCR Gene on 6p21 is Unlikely to be a Psoriasis Susceptibility Gene

The PSORS1 locus in the human major histocompatibility complex on 6p21 has been consistently associated with psoriasis in populations of diverse ethnicity. The HLA-C allele Cw*0602, located therein, has been found in up to 67% of psoriasis patients but is no longer considered a candidate gene in itself. The α-helix coiled-coil rod homolog gene (HCR, previously Pg8) is located 110 kb from the HLA-C gene, positioned between the CDSN and SC1 genes, within a region thought to harbor a psoriasis gene (PSORS1). We investigated the HCR gene for disease association by direct sequencing of nine polymerase chain reaction products amplified from a series of Swedish psoriasis patients and controls. We found that HCR is a very polymorphic gene with 25 polymorphisms in the open reading frame alone, of which 10 demonstrated disease association; however, the relationship between HCR polymorphisms and HLA-Cw*0602 indicates that HCR cannot truly be considered a likely candidate gene. We investigated Cw*0602 association while stratifying for HCR single nucleotide polymorphisms. We also investigated HCR single nucleotide polymorphism association with the disease while stratifying for the presence of Cw*0602. We found that whichever single nucleotide polymorphism that was stratified for, there was still a strongly significant Cw*0602 association with psoriasis; however, when we stratified for Cw*0602 presence, only one silent polymorphism showed significant association. In a recent similar study this polymorphism was actually found to be decreased in psoriasis individuals. Thus we conclude that HCR polymorphisms display association with psoriasis due to linkage disequilibrium with Cw*0602 and is, therefore, unlikely to be directly involved in the development of psoriasis