Angiotensin-converting enzyme (ACE) gene polymorphisms and familial occurrence of sarcoidosis

Objectives. The aim of this study was to test for genetic linkage and assoc iation between polymorphisms of the angiotensin-converting enzyme (ACE) gen e and familiar occurrence of sarcoidosis. Design, setting and subjects. German families with more than one member suf fering from sarcoidosis were contacted and a DNA bank was established. Sixt y-two families (140 patients, 77 females and 63 males, and 104 unaffected r elatives) were genotyped for the ACE gene insertion/deletion (I/D) polymorp hism 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 m ales) were analysed. ACE allele and genotype frequencies were determined, a nd parametric linkage and affected sib pair analyses and transmission diseq uilibrium tests were performed. Results. There was a striking over-representation of the ACE I/D genotype D D in patients with sarcoidosis and their families as compared with controls of the study and well founded genotype frequencies from the literature. Th e same was evident for the accompanying genotypes CC and 2.2 of the flankin g polymorphisms. Linkage between the segregation of ACE alleles and the dis order 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 disequi librium for any ACE allele or haplotype. Conclusions. ACE is involved in the pathogenesis of sarcoidosis, but the AC E polymorphisms are not an inherited main cause of the disease. They are mo re likely to modify the development of the disorder, and the ACE I/D genoty pe DD might be a promoter to clinical manifestation.