Search PubMed⌕ Search

Biomedical subjects

T Henseler

Publications and source records attributed to T Henseler.

At least 19 recordsLinked to original sources
PubMed2001

The genetics of psoriasis 2001: the odyssey continues.

Accumulating evidence indicates that psoriasis is a multifactorial disorder caused by the concerted action of multiple disease genes in a single individual, triggered by environmental factors. Some of these genes control the severity of multiple diseases by regulating inflammation and immunity (severity genes), whereas others are unique to psoriasis. Various combinations of these genes can occur even within a single family, accounting in large measure for the many clinical manifestations of psoriasis. The disease-causing variants (alleles) of these genes probably arose early in the history of modern humans. As a result, psoriasis disease alleles are common in the general population, have a worldwide distribution, and often share the same ancestral chromosome with neutral alleles at adjacent loci. This phenomenon, called linkage disequilibrium, explains why psoriasis is strongly associated with HLA-Cw6 worldwide, although HLA-Cw6 is unlikely to be the disease allele. Many unaffected individuals carry 1 or more disease alleles, but lack other genetic and/or environmental factors necessary to produce disease. This explains why psoriasis develops in only about 10% of HLA-Cw6-positive individuals, and why genome-wide linkage scans for psoriasis and other multifactorial genetic disorders have not been uniformly successful. The Human Genome Project is rapidly generating a catalog of human DNA sequence variations. This resource has already allowed precise linkage disequilibrium mapping of the major histocompatibility complex psoriasis gene to just beyond HLA-C, toward HLA-A. This gene is likely to be identified soon. Further development and use of linkage disequilibrium resources will provide a powerful tool for the identification of the remaining psoriasis genes.

Genetic Heterogeneity↗
PubMed2001

S100A2 coding sequence polymorphism: characterization and lack of association with psoriasis.

Psoriasis is a chronic inflammatory skin disease with a strong genetic component. Linkage studies have identified several susceptibility loci for psoriasis including a region on chromosome 1q21 termed the 'epidermal differentiation complex'. At least 20 genes involved in epidermal differentiation and proliferation have been mapped to this region including S100A2, a gene known to be over-expressed in psoriasis lesions. In the course of cloning and sequencing several S100A2 cDNAs, we identified an A/G (Asn62Ser) polymorphism at nucleotide 185 of the S100A2 coding region. To determine whether this polymorphism is associated with psoriasis, we tested DNA from 38 unrelated normal and 40 unrelated psoriatic individuals. The 185G allele was present in 148 of the 156 chromosomes analysed, giving an allele frequency of 94.9%. All of the remaining chromosomes carried 185A. There was no significant difference in the allele distribution between normal and psoriatic individuals (normals 72G, 4A; psoriatics 76G, 4A; P = 1.00 by Fisher's exact test). Our data explain conflicting results in the literature regarding the sequence of S100A2 but provide no support for a direct causal role for S100A2 in psoriasis.

Adolescent↗
PubMed2001

Patch testing of nickel sulfate and potassium dichromate with a standardized ready-to-use test system gives highly reproducible results: a double-blind multicentre study.

There is still some doubt about the reproducibility of patch tests. A sound assessment needs optimized and unbiased studies. This study analysed the results of a double-blind multicentre study with nickel sulfate and potassium dichromate patch tests attached synchronously to both sides of the back of patients with a history of nickel allergy, conducted with a highly standardized randomized test system (TRUE-test). Out of 589 patients tested, a total of 388 had responded with allergic reactions to nickel sulfate and 130 to potassium dichromate. The reproducibility of positive nickel (dichromate) patch tests was 99.2% (90.8%). The reaction index was also calculated, which relates the number of allergic reactions obtained with a test preparation to the number of questionable and irritant reactions; the reaction index can range from -1 (questionable and irritant reactions only occur) to 1 (allergic reactions only occur). For nickel sulfate the reaction index was 0.91, but it was only 0.23 for potassium dichromate, as a result of considerably more questionable reactions. In conclusion, a highly synchronous reproducibility of results can be achieved by using a well-standardized patch-test system, especially with nickel sulfate. However, distinct allergens and test systems need to be evaluated separately.

Adult↗
PubMed2000

Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.

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 approximately 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 approximately 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.

Alleles↗
PubMed2000

Positive nickel patch tests do not intensify positive reactions to adjacent patch tests with dichromate. Results from a double-blind multicentre study of the German Contact Dermatitis Research Group (Deutsche Kontaktallergie-Gruppe, DKG).

The possible interference of neighbouring allergic patch-test reactions is still an open question. In this study, we investigated whether there is a distance-related mutual modification of neighbouring allergic patch-test reactions to nickel sulfate and potassium dichromate. We used a double-blind multicentre study design with randomized attachment of special TRUE Tests with 1, 3 and 7 cm distance between nickel sulfate and potassium dichromate patches. 589 patients with a history of nickel allergy (523 female, 66 male) were tested, with a mean age of 35 years. A log-linear modelling approach was used for statistical assessment of the relation between the distance separating neighbouring patch tests with nickel and dichromate and the reactions to the allergens. Non-reproducibility coefficients were compared by the generalized version of Fisher's exact test for arbitrary 2-dimensional contingency tables. For the left side of the back, virtually no differences (p=0.70) were found in the reaction patterns obtained for the 3 distances separating nickel and dichromate patch tests. On the right side of the back, the number of reactions to dichromate patches with only 1 cm distance from moderate/strong nickel reactions was lower than the number of positive dichromate tests at larger distances from nickel tests (on the border of statistical significance: p= 0.05). Corresponding side-related results were obtained for subgroups of patients with and without a history of atopic dermatitis. The non-reproducibility of reactions to dichromate was not significantly related to the distance between neighbouring tests. Our data argue against a "spillover" effect of strong/moderate nickel reactions, but indicate that such reactions may, under certain conditions, attenuate adjacent reactions to an unrelated allergen. In the case of future verification, this will have implications for the interpretation of patch tests.

Adolescent↗
PubMed1999

Linkage disequilibrium analysis of familial psoriasis: identification of multiple disease-associated MHC haplotypes.

Although psoriasis vulgaris (PsV) is strongly associated with certain human leukocyte antigens, the pathogenetic nature of these associations remains elusive. The objectives of this study were: (i) to determine whether HLA loci directly determine susceptibility or merely serve as markers for the susceptibility allele; and (ii) to identify additional disease-associated haplotypes. By applying maximum likelihood linkage disequilibrium analysis (LDA) in cases vs. controls, we found the susceptibility gene to be more strongly associated with specific HLA haplotypes than with their component alleles. Stronger linkage disequilibrium between PsV and HLA alleles was detected at HLA-C and HLA-B than at DRB1 and DQB1. Parametric linkage analysis accounting for marker-trait disequilibrium in psoriasis vulgaris pedigrees yielded most significant results for a locus close to HLA-B and -C. Furthermore, we found that susceptibility is linked to at least three different ancestral HLA haplotypes; among them, HLA-Cw7-B8-DRB1*0301-DQB1*02 is linked to PsV for the first time. These results identify a major PsV susceptibility locus in the immediate vicinity of, but distinct from HLA-B or HLA-C, and suggest that multiple disease alleles have arisen during human evolution.

Alleles↗
PubMed1999

Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with HLA and association with psoriasis vulgaris.

Corneodesmosin (CD) is thought to play a key role in corneocyte cohesion, and its proteolysis appears to be a major event in the process of desquamation. Recently it was shown that CD is encoded by the S-gene, which is located approximately 160 kb telomeric of HLA-C. In the present study, the role of CD in the genetics of psoriasis vulgaris was studied in greater detail. The second exon of the CD gene was sequenced in 86 HLA-typed individuals from 13 psoriasis multiplex families. A total of 11 silent dimorphisms and 7 variants resulting in amino acid substitutions were found. Pedigree analysis showed that these variants could be grouped into 7 alleles, encoding 6 different amino acid sequences. These alleles are in strong linkage disequilibrium with HLA-B and -C, indicating that the polymorphism of the CD gene is ancient and well conserved rather than sporadic. One allele at the CD locus, designated CD2, displayed strong linkage disequilibrium with HLA-Cw6, the HLA allele most prominently associated with psoriasis. CD2 demonstrated a greater relative risk than Cw6 (3.4 vs. 2.5, not significant) and higher significant transmission disequilibrium with psoriasis than any of the investigated HLA-alleles. Due to its biologic function, cellular location and disease association, the CD gene appears to be an excellent candidate gene for PSORS1, the HLA-linked determinant of psoriasis vulgaris.

Alleles↗
PubMed1998

Genetics of psoriasis.

Non-pustular psoriasis consists of two disease subtypes, type I and type II, which demonstrate distinct characteristics. Firstly the disease presents in different decades of life, in type I before the age of 40 years and later in type II. Secondly, contrasting frequencies of HLA alleles are found: type I patients express predominantly HLA-Cw6, -B57, and -DR7, whereas in type II patients HLA-Cw2 is overrepresented. Finally, familial inheritance is found in type I but not in type II psoriasis. The study of concomitant diseases in psoriasis contributes to deciphering the distinct patterns of the disease. Defence against invading microorganisms seems better developed in psoriatics than in controls. This evolutionary benefit may have caused the overall high incidence of psoriasis of 2%. Psoriasis is a multifactorial and heterogenetically inherited disease. The heterogeneity is evident by the diversity of genetically linked markers. The multifactorial component results from the observation of external trigger mechanisms, such as the Koebner phenomenon, stress and the intake of certain drugs. Twin studies have shown that environmental factors contribute to the onset of the disease. In type I psoriasis, special extended haplotypes such as EH57.1 (HLA-Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303) and EH65.1 (HLA-Cw8-B65-DRB1*0102-DQB1*0501) have been found to be increased. The application of microsatellite techniques has identified distinct positions on several chromosomes at which putative psoriasis genes may be located. Disease susceptibility genes are thought to be present on chromosomes 4q, 6p, 16q, 17q and 20p. Moreover, on chromosome 1q, genes regulating epidermal differentiation have been identified. Linkage to this area has been proposed. Furthermore, psoriasis gene loci on chromosomes 2, 8 and 20 have been suggested.

HLA Antigens↗
PubMed1998

Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region.

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.

Adult↗
PubMed1997

Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.

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.

Adult↗
PubMed1997

[Mycoses in patients with psoriasis or atopic dermatitis].

Both, psoriasis and atopic dermatitis are multifactorial diseases with an unknown pathogenesis. To elucidate the influence of fungal infections in the onset or recurrence of those inflammatory skin disease we determined the frequencies of Candida and dermatophyte infections of the skin and orointestinal tract concomitantly seen in patients with psoriasis or atopic dermatitis. We analyzed the files of more than 40,000 in-patients of the Department of Dermatology, Kiel. Sex- and age-adjusted relative risk were calculated. The results demonstrate that patients with psoriasis (N = 3006) presented with a decreased rate of tinea. This was significant for tinea corporis (RR = 0.13, p < 0.01). Candida infections of the skin were seen more often in psoriasis patients compared to controls. Differentiating between Type I (early onset) and Type II (late onset) psoriasis only Type I psoriasis patients presented with decreased dermatophyte infections and increased Candida colonization of the intestinum. However, patients with Type II psoriasis demonstrated an increased rate of candidosis cutis and candidosis oris as compared to controls. Patients with atopic dermatitis (N = 1808) displayed a decreased overall incidence of tinea and Candida infections. Furthermore, in patients with atopic dermatitis a Candida colonization of the orointestinal tract was found elevated (RR = 1.51, p < 0.01), whereas tinea corporis (RR = 0.24, p < 0.01) and candidosis cutis (RR = 0.30, p < 0.001) was found decreased compared to controls. Our results show that the influence of fungal infections on the two skin diseases investigated is not as strong as often considered. The increased relative risk in patients with atopic dermatitis to present with Candida colonization in the digestive tract or vice versa may contribute to the pathogenesis of atopic dermatitis.

Candidiasis↗
PubMed1997

The genetics of psoriasis.

The analysis of population-specific human leukocyte antigen (HLA) haplotypes has provided evidence that susceptibility to psoriasis is linked to the class I and II major histo-compatibility complex on human chromosome 6. In addition, these studies show that psoriasis consists of two distinct disease subtypes (type I and type II), which differ in age of onset and in the frequency of HLA. In type I (early-onset) psoriasis, Cw6, B57, and DR7 are strongly increased, whereas in type II (late-onset) psoriasis, HLA-Cw2 is overrepresented. It has also been proposed that HLA haplotypes extended by class III play a role in the genetics of this disease. Moreover, studies of affected families indicate that other disease susceptibility loci may also be involved. Likely candidates for additional susceptibility genes are located at chromosomes 1, 6, and 17, and microsatellite markers over the whole genome have been used to identify susceptibility genes. Two years ago linkage to the distal part of chromosome 17 was published. However, this linkage could not be confirmed by other groups with comparable or enlarged numbers of psoriatic family members investigated. Recently, an investigation presenting an area of chromosome 4 as a susceptibility locus for psoriasis was published. According to our knowledge today, psoriasis is a polygenetically inherited disease. Furthermore from twin studies it is known that environmental factors play a significant role in the onset or recurrence of the disease.

Chromosomes, Human, Pair 1↗
PubMed1995

Disease concomitance in psoriasis.

BACKGROUND: Psoriasis is a multifactorial disease of unknown origin. OBJECTIVE: Our purpose was to determine the frequency of skin disorders concomitantly seen in patients with psoriasis. METHODS: We analyzed data from more than 40,000 patients and calculated sex- and age-adjusted ratios of expected and observed incidence rates of associated disorders. RESULTS: The results demonstrate that, compared with age-matched control patients without psoriasis, cutaneous immune disorders such as allergic contact dermatitis, atopic dermatitis, and urticaria are underrepresented in patients with psoriasis. In contrast, certain systemic disorders such as diabetes, heart insufficiency, and obesity occur significantly more often in patients with psoriasis than in control subjects. Increased resistance to cutaneous bacterial infections was noted only in patients with early-onset psoriasis. CONCLUSION: Our observations show that a distinct pattern of associated diseases exists in patients with psoriasis. Although systemic disorders such as obesity, diabetes, and heart disease may be related to dietary habits and nutritional status, the relative resistance to cutaneous infections together with decreased immune responsiveness suggest a genetically determined selection.

Adult↗
PubMed1995

[Mucocutaneous candidiasis in patients with skin diseases].

We investigated skin diseases associated with mucocutaneous Candida infection by analyzing the clinical records of 44695 in-patients of the department of dermatology of Kiel. For more than eighty skin diseases the relative risk (RR) was calculated by age-and sex-adjusting methods. 1996 patients demonstrated a mucocutaneous candidosis, 14.8% of them being hospitalized because of extensive Candida infection. In patients with dermatomyositis, bullous pemphigus, tinea inguinalis, and condylomata acuminata a Candida infection was observed more than threefold than expected. Furthermore, patients with urticaria, folliculitis, and bullous pemphigoid demonstrated candidosis more than twice as often as control patients. In addition, patients with erysipelas, acne, psoriasis, and atopic dermatitis showed a candidosis significantly more often (RR between 1.3 and 1.6). Some internistic maladies were investigated, too. In patients presenting with diabetes mellitus, heart-insufficiency, hypertension, chronic tonsillitis, and urinary tract infection a mucocutaneous Candida infection was significantly increased.

Age Factors↗
PubMed1995

Evaluation of patch test results by use of the reaction index. An analysis of data recorded by the Information Network of Departments of Dermatology (IVDK).

Results of patch tests performed in 15,553 patients by 18 dermatological departments (members of the German Contact Dermatitis Research Group) and recorded by the Information Network of Departments of Dermatology (IVDK) were analysed by comparing recently defined reaction indices (RIs). The RIs studied were calculated from the numbers of allergic (a), questionable (q), and irritant (i) reactions (RI = (a-q-i/(a + q + i)), which were obtained using 13 European standard allergens. RIs were calculated for all patients and for separate subgroups defined by age, sex, history of atopic dermatitis, time of allergen exposure (1 versus 2 days), and time of patch test reading (2 or 3 days after allergen application). Higher RIs were consistently obtained when patch tests were applied for 1 day, as compared to 2 days. Readings at 3 days after allergen application resulted in higher RIs than readings after 2 days. In contrast, sex, age, and history of atopic dermatitis of patients were not found to have a consistent influence on the RIs. We suggest that reading after 3 days should be obligatory, and that allergen exposure for 1 day instead of 2 days might make patch test evaluation easier. These suggestions need to be substantiated by data on clinical relevance.

Adult↗