Sarcoidosis is likely to result from exposure of genetically susceptible hosts to environmental agents. Erythrocyte (E) complement receptor 1 (CR1) is a membrane protein mediating the transport of immune complexes (ICs) to phagocytes, and at least three polymorphisms on the CR1 gene are related to erythrocyte surface density of CR1 molecules, in turn related to the rate of IC clearance from circulation. We hypothesized that sarcoidosis could be associated with increased frequency of the CR1 gene alleles coding for reduced CR1/E ratio. We studied 91 sarcoid patients and two control groups: 94 healthy volunteers and 71 patients with chronic obstructive pulmonary disease (COPD). Three polymorphic sites of CR1 gene, His1208Arg, intron 27 HindIII/RFLP, and Pro1827Arg, were analyzed. The three polymorphisms were in linkage disequilibrium. The GG genotype for the Pro1827Arg (C(5507)G) polymorphism was significantly associated with sarcoidosis in comparison to both control groups (odds ratio [OR] = 3.13; 95% confidence interval [CI] 1.49-6.69 versus healthy control subjects, and OR= 2.82, 95% CI 1.27-6.39 versus COPD control subjects). The same genotype was particularly associated to disease in females (OR = 7.05; 95% CI 3.10-16.61 versus healthy control subjects). These findings agree with speculations on the role of CR1 gene as a possible susceptibility factor.

Sarcoidosis is an immune-mediated, multiorgan, granulomatous disorder thought to be triggered by an intricate combination of environmental and genetic factors. Two robust lines of evidence support the hypothesis of a genetic component in the pathogenesis of sarcoidosis: racial variation in its epidemiology and familial clustering of cases. The relationship between epidemiology and environmental factors affecting variations in sarcoidosis incidence/prevalence and presentation are reviewed, as well as strategies to be pursued in the search for susceptibility genes for the disorder.Pathogenic processes leading to sarcoid granuloma formation and maintenance have prompted investigators interested in the genetics of sarcoidosis to focus mainly on major histocompatibility complex genes, and indeed a remarkable amount of data has been accumulated during the last two decades. Whilst in contrast with some autoimmune disorders a clear association between human leukocyte antigen (HLA) and sarcoidosis is still a controversial issue, there is, however, a general agreement that some HLA genes are related to phenotypic variations of the disease. Some genetic investigators have focused on T-cell receptor genes, immunoglobulin genes, angiotensin converting enzyme gene, chemokine genes and others.From a review of studies performed in different racial and ethnic groups, a reasonable suggestion arises that genetic factors are the major determinant in the racial variations in the epidemiology of the disorder. This assumption is, however, so far limited by lack of studies considering both genetic and environmental factors simultaneously. Eur Respir J 2000; 16: 768±780.

A complete screening of the CFTR gene by DGGE and DNA sequencing was performed in patients with sarcoidosis. In 8/26 cases, missense and splicing CFTR gene mutations were found, a significant difference over controls (9/89) from the same population (P = 0.014). The odds ratio for a person with a CFTR gene mutation to develop the disease is 3.95 (1.18 < OR < 13.26). Seven different CFTR gene mutations were observed: R75Q, R347P, 621 + 3 A/G, 1898 + 3 A/G, L997F, G1069R, and a novel mutation which was detected in this study, I991V. R75Q mutation was present in 3/26 patients, a significant increase (P = 0.01) in cases over controls, indicating its preferential association with sarcoidosis. A trend towards disease progression was observed in patients with CFTR gene mutations compared to patients without mutations. These data suggest that CFTR gene mutations predispose to the development of sarcoidosis. European Journal of Human Genetics (2000) 8, 717-720.