Sarcoidosis is a systemic disease of granulomatous inflammation and unknown etiology. An inherited predisposition is involved, and many candidate susceptibility genes have been tested in association studies. We have applied the more general strategy of genome-wide microsatellite linkage analysis to identify chromosomal regions that contribute to the risk of sarcoidosis. On the basis of 225 microsatellite markers tested in 63 families with affected siblings (138 patients) and multipoint nonparametric linkage (NPL) analysis, we found the most prominent peak (six adjacent markers including D6S1666; NPL score = 2.99; p = 0.001) at the major histocompatibility complex (MHC). Six minor peaks (p < 0.05) were found on chromosomes 1 (D1S1665 ), 3 (D3S1766 ), 7 (D7S821 and D7S3070), 9 (D9S934), and the X chromosome (DXS6789). A subset of nine families with more than two affected siblings (30 patients) contributed little to the peak at the MHC (D6S1666; NPL score = 0.79; p = 0.21). Our results point to locus heterogeneity of susceptibility to sarcoidosis, with a major effect of the MHC.

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.