The HLA-Cw6 antigen has been associated with psoriasis vulgaris despite racial and ethnic differences. However, it remains unclear whether it is the HLA-Cw6 antigen itself or a closely linked, hitherto unidentified, locus that predisposes to the disease. Here, in order to map the susceptibility locus for psoriasis vulgaris precisely within the HLA class I region, 11 polymorphic microsatellite markers distributed throughout a 1060 kb segment surrounding the HLA-C locus were subjected to association analysis in Japanese psoriasis vulgaris patients. Statistical analyses of the distribution and deviation from Hardy-Weinberg equilibrium of the allelic frequency at each micro-satellite locus revealed that the pathogenic gene for psoriasis vulgaris is located within a reduced interval of 111 kb spanning 89-200 kb telomeric of the HLA-C gene. In addition to three known genes, POU5F1, TCF19 and S, this 111 kb fragment contains four new, expressed genes identified in the course of our genomic sequencing of the entire HLA class I region. Therefore, these seven genes are the potential candidates for susceptibility to psoriasis vulgaris.

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HLA alleles in generalized pustular psoriasis (GPP) were investigated to clarify the etiology and/or pathogenesis of this disease. Not only serological typing of HLA class I and II antigens but also genotyping of HLA class II alleles were carried out in twenty-six unrelated Japanese patients with GPP. These patients were classified according to their history of psoriasis vulgaris (PV). Serological typing revealed a significantly high incidence of HLA-Cw1 (Pc = 0.04) in the patients as compared with Japanese healthy controls. The frequency of HLA-B46 was particularly high in the patients with GPP and a previous history of PV. Genotyping of HLA class II alleles showed a highly significant increase in HLA-DQB1*0303 (Pc = 0.01) in the patients vs. the healthy controls. In particular, HLA-DQB1*0303 was significantly more frequent in the patients with no prior history of PV than in those with a history of PV. Analysis on linkage disequilibrium showed remarkably different patterns for HLA class II haplotypes between the patients and the healthy controls. Based on the comparative analysis among the amino acid sequences of the beta 1-domain of the HLA-DQB1*03 alleles, proline at residue 55 was suggested to be important as a common amino acid for determination of the susceptibility to GPP. These results revealed not only an association between the etiology and/or pathogenesis of GPP and HLA, but also different mechanisms of the immune response between the patients with GPP and PV.

We investigated whether patients with contact allergy differed from non-contact-allergic, non-atopic controls with regard to genotype and phenotype of the polymorphic enzyme N-acetyltransferase 2 (NAT2). 55 contact-allergic patients recruited from the Information Network of Departments of Dermatology (IVDK) were compared to 85 controls from among local health care personnel. NAT2 activity was calculated from HPLC analysis of the ratio of the caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine (1MX) in the urine. NAT2 genotype was determined by polymerase chain reaction (PCR). A statistically significantly increased proportion of rapid acetylators was found in contact-allergic patients. This may have 2 possible implications: acetylation may enhance contact sensitization; or NAT2 status may be a genetic marker for contact sensitizability.

HLA class I and class II alleles of 32 Japanese patients with postherpetic neuralgia (PHN) and 136 healthy controls were analyzed by serological (class I) and DNA (class II) typing for any significance in the susceptibility to varicella-zoster virus (VZV). We recognized positive associations of the development of PHN with the HLA class I antigens HLA-A33 and -B44, and the HLA-A33-B44 haplotype. This haplotype is tightly linked to DRB1*1302 in a Japanese healthy population. However, no significant association between PHN and HLA class II alleles was observed with no linkage of the HLA haplotype HLA-A33-B44 to HLA-DRB1*1302 in the patients with PHN. These findings suggest that HLA class I gene may genetically control the immune response against VZV in the pathogenesis of PHN.

Low constitutive N-acetylating capacity has been implicated as a predisposing factor for the development of adverse reactions to certain drugs. This prompted us to investigate whether the N-acetylating capacity of patients with serious cutaneous adverse reactions, i.e., Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) differed from that of healthy control subjects. N-acetylating activity was measured in hair root cells by preparing a homogenate from freshly extracted hair roots and assessing acetyl-CoA-dependent N-acetylation by RP-HPLC using 2-aminofluorene as a substrate. Samples were obtained from hospitalized patients suffering from acute SJS and TEN or from healthy controls. All patients with SJS and TEN were found to have a low N-acetylating capacity (0.85 nmol/mg/min compared to 2.21 nmol/mg/min in controls, p < 0.05). Based on these findings, a low constitutive N-acetylating capacity may be one of the predisposing factors for the development of serious cutaneous adverse reactions to drugs that require N-acetylation in these patients.

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. SummaryBackground Para-phenylenediamine (PPD) is a common contact sensitizer causing allergic contact dermatitis, a major skin problem. As PPD may need activation to become immunogenic, the balance between activation and ⁄or detoxification processes may influence an individual's susceptibility. PPD is acetylated and the metabolites do not activate dendritic-like cells and T cells of PPD-sensitized individuals.Objectives To investigate whether PPD can be acetylated in vitro by the two N-acetyltransferases 1 (NAT1) and 2 (NAT2). Based on the assumption that N-acetylation by NAT1 or NAT2 is a detoxification reaction with respect to sensitization, we examined whether NAT1 and NAT2 genotypes are different between PPDsensitized individuals and matched controls. Methods Genotyping for NAT1 and NAT2 polymorphisms was performed in 147 PPD-sensitized individuals and 200 age-and gender-matched controls.Results Both PPD and monoacetyl-PPD were N-acetylated in vitro by recombinant human NAT1 and to a lesser extent by NAT2. Genotyping for NAT1*3, NAT1*4, NAT1*10, NAT1*11 and NAT1*14 showed that genotypes containing the rapid acetylator NAT1*10 allele were under-represented in PPD-sensitized cases (adjusted odds ratio 0AE72, 95% confidence interval 0AE45-1AE16). For NAT2, NAT2*4, NAT2*5AB, NAT2*5C, NAT2*6A and NAT2*7B alleles were genotyped. Individuals homozygous for the rapid acetylator allele NAT2*4 were under-represented in cases compared with controls (4AE3% vs. 9AE4%), but this trend was not significant. Conclusions With respect to data indicating that NAT1 but not NAT2 is present in human skin, we conclude that NAT1 genotypes containing the rapid acetylator NAT1*10 allele are potentially associated with reduced susceptibility to PPD sensitization.

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