Cystic Fibrosis Conductance Regulator, Tumor Necrosis Factor, Interferon Alpha-10, Interferon Alpha-17, and Interferon Gamma Genotyping as Potential Risk Markers in Pulmonary Sarcoidosis Pathogenesis in Greek Patients Periklis Makrythanasis, 1, * Maria Tzetis, 1 Aggeliki Rapti, 2 Athanasios Papatheodorou, 1 Maria Tsipi, 1 Sophia Kitsiou, 1 Alexia Tsiamouri, 1 Myrto Poulou, 1 Charis Roussos, 3 and Emmanouel Kanavakis 1 Sarcoidosis is a complex disease with autoimmune basis and still unknown etiology. We have screened for mutations in the cystic fibrosis conductance regulator (CFTR) gene and genotyped single-nucleotide polymor- phisms in the tumor necrosis factor (TNF), interferon alpha-10 (IFNA10), IFNA17, and interferon gamma (IFNG) genes in 89 Greek patients with sarcoidosis and 212 control subjects to detect possible association between them and the risk for developing sarcoidosis. We have found a statistically significant increase ( p ¼ 6.110 8 ) of CFTR mutation carriers in the population of patients with sarcoidosis versus the control population. A difference was also noted within the group of patients with sarcoidosis where the ones with CFTR mutations suffered more frequently from dyspnea than those without ( p ¼ 510 6 ). Our study did not reproduce the associations pre- viously noted with the TNF, IFNA10, IFNA17, and IFNG genes, which highlights the genetic complexity of the disorder and is in agreement with previous studies showing that CFTR might be an important factor in the clinical course of the disease. Introduction S arcoidosis is a systemic granulomatous disease of un- known etiology (Costabel and Hunninghake, 1999; Hun- ninghake et al., 1999; ATS, ERS, WASOG, 1999) that was first described as a separate medical condition in 1877. The hall- mark of the disease is the formation of noncaseating granu- lomas (Rosen, 2007). It has a worldwide incidence and it mainly affects individuals from 25 to 40 years of age, while later onset of the disease is not an unusual finding (Nunes et al., 2007). Higher incidence is found in women and people of African origin. The clinical course of the disease usually in- volves the lungs (86%–92%) (Lynch et al., 2007) alone or in combination to an extra pulmonary site, with the skin, eyes, liver (Rose et al., 2008), and central nervous system ( Joseph and Scolding, 2007) most frequently affected. The severity of the extrapulmonary disease depends on the location and size of the granulomas and can occasionally cause severe symp- toms (ATS, ERS, WASOG, 1999). The natural course of the disease is usually mild with the majority of patients being asymptomatic (sarcoidosis diagnosed as a random radiologic finding) (Vagal et al., 2007) or with symptoms responding well to treatment. Around 5% of the patients will have hard-to- control disease resulting in lung fibrosis and leading ulti- mately to respiratory insufficiency and in some cases death from pulmonary or cardiac complications (Nunes et al., 2007). The etiology of the disease remains unknown, yet the cur- rent working hypothesis supports the idea that an exogenous agent acts in genetically susceptible individuals, triggering an immune response and leading to the formation of the patho- gnomonic granulomas (Baughman et al., 2003; Iannuzzi et al., 2007). The ACCESS study (ACCESS Research Group, 1999) attempted to identify those occupational or environmental factors without success, but some positive associations were made. The stronger ones were connected to insecticides, ag- ricultural employment or similar exposures in rural commu- nities, and bioaerosols. Evidence was also produced that bacteria such as propionobacteria could also play a role at the 1 Department of Medical Genetics, Medical School, University of Athens, Athens, Greece. 2 6th Department of Respiratory Medicine, Sotiria Chest Disease Hospital, Athens, Greece. 3 Critical Care Department, Evangelismos Hospital, Medical School, Athens University, Athens, Greece. *Present address: Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 14, Number 4, 2010 ª Mary Ann Liebert, Inc. Pp. 577–584 DOI: 10.1089/gtmb.2009.0198 577