Genetic and geographic influence on phenotypic variation in European sarcoidosis patients.
Freitag-Wolf S., Schupp JC., Frye BC., Fischer A., Anwar R., Kieszko R., Mihailović-Vučinić V., Milanowski J., Jovanovic D., Zissel G., Bargagli E., Rottoli P., Bumbacea D., Jonkers R., Ho L-P., Gaede KI., Dubaniewicz A., Marshall BG., Günther A., Petrek M., Keane MP., Haraldsdottir SO., Bonella F., Grah C., Peroš-Golubičić T., Kadija Z., Pabst S., Grohé C., Strausz J., Safrankova M., Millar A., Homolka J., Wuyts WA., Spencer LG., Pfeifer M., Valeyre D., Poletti V., Wirtz H., Prasse A., Schreiber S., Dempfle A., Müller-Quernheim J.
INTRODUCTION: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. METHODS: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. RESULTS: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. DISCUSSION: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.