1. FUNCTIONAL VARIANT OF THE ANXA11 GENE: TRUE MARKER OF PROTECTION AND CANDIDATE DISEASE MODIFIER IN SARCOIDOSIS Stahelova A 1, Mrazek F 1, Kriegova E 1, Hutyrova B 2, Kubistova Z 1, Kolek V 2, Petrek M 1 1 Laboratory of Immunogenomics and Proteomics, Dept of Immunology & 2 Dept. of Respiratory Medicine; Medical Faculty of Palacky University and University Hospital, Olomouc, Czech Republic. Grant support: MSM6198959205 and PU project SV LF_2010_008 Patients and Methods 1)The study population Czech patients with sarcoidosis: N = 245 The diagnosis of sarcoidosis was established according to international recommendations ("ATS / ERS / WASOG statement on sarcoidosis"). Subgroups defined according to the chest X-ray (CXR) stage (I-IV) of pulmonary sarcoidosis and the presence/absence of Löfgren´s syndrome. Healthy control subjects (control population): N = 254 All individuals included in the study were unrelated of Czech nationality. 2)Genetic analysis Genotyping for ANXA11 rs1049550 C / T (R230C) polymorphism was made using qRT-PCR with "TaqMan" probes (Fig. 1) 3)Statistical analysis Consistency of distribution of ANXA11 genotypes with Hardy-Weinberg expectation was verified by the "χ2 goodness-of-fit" test, comparisons of the frequencies of ANXA11 variants in the studied groups was performed by χ2 test. The frequency of ANXA11 rs1049550 *T allele was significantly lower in patients with sarcoidosis (35%) compared with the control group (42%, p = 0.04, OR = 0.77, Fig. 2). "Protective" effect of ANXA11*T allele was related to the number of its copies in the genotype (gene-dose effect, Fig. 3). In the subanalysis, ANXA11*T allele was less numerous in patients with affection of the lung parenchyma (CXR stages II-IV) compared to patients with isolated hilar lymphadenopathy (CXR stage I, p = 0.01, Fig. 4). "Protective" effect of ANXA11*T allele was also apparent in the subanalysis by Löfgren´s syndrome (LS): TT homozygotes were more frequent among the patients with LS (21%) compared to patients without LS (7%, p = 0.02, OR = 0.31, 95% CI = 0.11-0.84). Introduction Results The genome-wide association study (GWAS) in the German population has recently revealed an association of variants in the ANXA11 (Annexin A11) gene with susceptibility to sarcoidosis (1) The aim of this work was to replicate the association of ANXA11 functional variant rs1049550 with sarcoidosis in Czechs. We wondered also whether this ANXA11 variant might be related to the clinical manifestation of sarcoidosis. (1) S. Hofmann et al., Nature Genetics 40, 1103-1106, 2008. Sarcoidosis is a systemic granulomatous disease with unknown etiology. Sarcoidosis most commonly affects the lungs. Pulmonary disease is classified according to the chest X-ray findings. Löfgren´s syndrome (LS) is an acute form of sarcoidosis with favourable prognosis in most cases. Epidemiological studies and direct evidence from recent reports strongly support the genetic component of the disease. Conclusion Our data confirmed the findings from the whole-genome study in the German population that ANXA11 rs1049550 *T allele reduces the risk of sarcoidosis. Protective effect of this ANXA11 variant was characterised by the „gene-dose effect". Based on our subanalysis we also conclude that ANXA11 rs1049550 *T variant may protect from more severe manifestations of sarcoidosis. The mechanism by which ANXA11 and its gene variants implicate in the pathogenesis of sarcoidosis, will undoubtedly be in the scope of further research. Rationale and Aim