Sarcoidosis is a systemic granulomatous disorder associated with high CD4+ cell activity, but no pathogen is detectable. Clustering in families occurs, and the existence of a genetic predisposition to sarcoidosis is widely accepted. The major histocompatibility complex (MHC) is believed to contribute to this susceptibility. Many studies testing this hypothesis have produced conflicting results. We have genotyped 122 affected siblings from 55 families for seven DNA polymorphisms that flank and cover the MHC region on chromosome 6, and for HLA-DPB1, a candidate gene for granulomatous disorders. Multipoint nonparametric linkage (NPL) analysis showed linkage (NPL score > 2.5; p < 0.006) for the entire MHC region with a maximum NPL score of 3.2 (p = 0.0008) at marker locus D6S1666 in the Class III gene cluster. There was a significant excess of marker haplotype sharing among affected siblings. However, the frequency of HLA-DPB1 alleles on 104 shared chromosomes did not differ from that of a control group of founders from the family panel. Transmission disequilibrium was found for allele DPB1*0201, but only nine families contributed to this result. We conclude that genes of the MHC are involved in the genetic predisposition to sarcoidosis, but HLA-DPB1 alone does not sufficiently explain this fact.

Objectives. The aim of this study was to test for genetic linkage and association between polymorphisms of the angiotensin-converting enzyme (ACE) gene and familial occurrence of sarcoidosis. Design, setting and subjects. German families with more than one member suffering from sarcoidosis were contacted and a DNA bank was established. Sixty-two families (140 patients, 77 females and 63 males, and 104 unaffected relatives) were genotyped for the ACE gene insertion/deletion (I/D) polymorphism and for two flanking variable sites (ACE A-5466C and ACE 4656(CT)2/3). As controls, 100 DNAs from unrelated resident Caucasians (50 females, 50 males) were analysed. ACE allele and genotype frequencies were determined, and parametric linkage and affected sib pair analyses and transmission disequilibrium tests were performed.Results. There was a striking over-representation of the ACE I/D genotype DD in patients with sarcoidosis and their families as compared with controls of the study and well founded genotype frequencies from the literature. The same was evident for the accompanying genotypes CC and 2,2 of the flanking polymorphisms. Linkage between the segregation of ACE alleles and the disorder within families was clearly excluded for simple models of inheritance. However, there was a suggestive but not significant (P = 0.06) excess of allele sharing amongst affected siblings. There was no transmission disequilibrium for any ACE allele or haplotype. Conclusions. ACE is involved in the pathogenesis of sarcoidosis, but the ACE polymorphisms are not an inherited main cause of the disease. They are more likely to modify the development of the disorder, and the ACE I/D genotype DD might be a promoter to clinical manifestation.

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Die intrathorakalen Manifestationen der Sarkoidose haben von uns (1, 2, 3, 4) eine neue Stadieneinteilung erfahren. Sie bringt die Dynamik des Krankheitsgesdiehens, die Ausbreitungsweise und den zeitlichen Ablauf zum Ausdruck und ist weiterhin durch eine Reihe besonderer Merkmale charakterisiert. Ihre Grundlage Ist die im Röntgenbild erkennbare formale Pathogenese. Dadurch unterscheidet sie sich von der rein deskriptiven Einteilung anderer Autoren (5, 6, 7, 8, 9). Als Stadium I bezeichnen wir die viszerale Lymphknotenschwellung, welche fast immer mediastinal, ganz selten Abb. 1. Schematische Darstellung des Stadienverlaufes der Sarkoidose

We have followed up a patient with 8q24.2 --> qter and 15q14 --> pter duplication due to a maternal reciprocal translocation, a condition related to Prader-Willi Syndrome. Apart from dysmorphic features, the patient suffered from recurring episodes of bipolar psychosis. Interestingly, PET scanning revealed revealed prominent bilateral hypometabolism in the frontal, temporal, and parietal lobes as well as in the cerebellum. Possible implications of this rare chromosomal abnormality with regards to psychiatric disorders are discussed, with emphasis on recent evidence suggesting chromosome 15q13-15 as a susceptibility locus for psychosis.

M Mi ic cr ro oh he et te er ro og ge en ne ei it ty y o of f a ac cu ut te e--p ph ha as se e g gl ly yc co op pr ro ot te ei in ns s i in n p pa at ti ie en nt ts s w wi it th h p pu ul lm mo on na ar ry y s sa ar rc co oi id do os si is s The glycosylation profile of AGP and ACT was studied using affinity immunoelectrophoresis with the lectin concanavalin A (conA). Serum concentration of soluble receptor for interleukin-2 (sIL-2R) and activity of serum angiotensin converting enzyme (ACE) were measured by specific enzyme-linked immunosorbent assay (ELISA) and enzyme kinetic assay, respectively. Rocket immunoelectrophoresis and nephelometric assay were used to determine serum concentration of AGP, ACT and C-reactive protein (CRP).In 11 patients with active disease, a decreased reactivity of AGP with conA was found as compared with controls (n=44) and patients with nonactive sarcoidosis (n=26). A similar tendency was seen with ACT. In the same group, increased concentrations of serum AGP and higher levels of sIL-2R were detected compared with patients with nonactive sarcoidosis. In the entire sarcoidosis group, there was a negative correlation between ACE activity and AGP and ACT affinity for conA (r= -0.6358, and r=-0.5019, respectively) and a positive correlation with sIL-2R level (r=0.8241). In nine patients with elevated concentrations of serum CRP, no differences were found in disease activity and glycosylation profile of AGP and ACT when compared to patients with normal serum CRP.The results suggest that in active pulmonary sarcoidosis changes in the glycosylation pattern of acute-phase glycoproteins exist, which are similar in trend and magnitude to those found in other chronic inflammatory diseases. The synthesis and glycosylation of acute-phase proteins in pulmonary sarcoidosis are probably regulated independently. Eur Respir J., 1996, 9, 313-318

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