Journal Article

Genetic and geographic influence on phenotypic variation in European sarcoidosis patients

Zamir Kadija, Wim A. Wuyts, Tatjana Peroš-Golubičić, Michael P. Keane, Dominique Valeyre, Lisa G. Spencer, Björn C. Frye, Gernot Zissel, Dragos Bumbacea, Hubertus Wirtz, Antje Prasse, Ann Millar, Astrid Dempfle, Violeta Mihailović-Vučinić, René Jonkers, Stefan Schreiber, Martin Petrek, Annegret Fischer, Raihanatul Anwar, Jonas C. Schupp, Sigridur O. Haraldsdottir, Stefan Pabst, János Strausz, Dragana Jovanovic, Ling-Pei Ho, Janusz Milanowski, Robert Kieszko, Anna Dubaniewicz, Elena Bargagli, Francesco Bonella, Joachim Müller-Quernheim, Jiří Homolka, Karoline I. Gaede, Andreas Günther, Christian Grohé, Michael Pfeifer, Ben G. Marshall, Christian Grah, Venerino Poletti, Martina Safrankova, Paola Rottoli, Sandra Freitag-Wolf

2023

Overview

IntroductionSarcoidosis 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.MethodsAfter 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.ResultsIn 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.DiscussionThe 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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: ANXA11 / DISEASE / General & Internal Medicine / genetic polymorphism / genetic risk factors / Genetic testing / GENOME-WIDE ASSOCIATION / Genomes / Genotype & phenotype / genotype-phenotype-relationship / Health risk assessment / Life Sciences & Biomedicine / Medicine / Medicine (General) / Medicine, General & Internal / Medizin / Meta-analysis / Pathogenesis / Patients / POLYMORPHISMS / R5-920 / region-specific genetic links / Regions / Regression analysis / RISK / Sample size / Sarcoidosis / Science & Technology / SUSCEPTIBILITY LOCI / Variables