Genetic and geographic influence on phenotypic variation in European sarcoidosis patients

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

doi:https://doi.org/10.3389/fmed.2023.1218106

Genetic and geographic influence on phenotypic variation in European sarcoidosis patients

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

Research output: Contribution to journal › Article › Academic › peer-review

1 Citation (Scopus)

Abstract

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.

Original language	English
Article number	1218106
Journal	Frontiers in Medicine
Volume	10
DOIs	https://doi.org/10.3389/fmed.2023.1218106
Publication status	Published - 2023

Keywords

genetic polymorphism
genetic risk factors
genotype–phenotype-relationship
region-specific genetic links
sarcoidosis

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https://doi.org/10.3389/fmed.2023.1218106

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Freitag-Wolf, S., Schupp, J. C., Frye, B. C., 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, K. I., Dubaniewicz, A., Marshall, B. G., Günther, A., ... Müller-Quernheim, J. (2023). Genetic and geographic influence on phenotypic variation in European sarcoidosis patients. Frontiers in Medicine, 10, Article 1218106. https://doi.org/10.3389/fmed.2023.1218106

@article{f604919d4bb349f58670d4cf055eb313,

title = "Genetic and geographic influence on phenotypic variation in European sarcoidosis patients",

abstract = "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.",

keywords = "genetic polymorphism, genetic risk factors, genotype–phenotype-relationship, region-specific genetic links, sarcoidosis",

author = "Sandra Freitag-Wolf and Schupp, {Jonas C.} and Frye, {Bj{\"o}rn C.} and Annegret Fischer and Raihanatul Anwar and Robert Kieszko and Violeta Mihailovi{\'c}-Vu{\v c}ini{\'c} and Janusz Milanowski and Dragana Jovanovic and Gernot Zissel and Elena Bargagli and Paola Rottoli and Dragos Bumbacea and Ren{\'e} Jonkers and Ling-Pei Ho and Gaede, {Karoline I.} and Anna Dubaniewicz and Marshall, {Ben G.} and Andreas G{\"u}nther and Martin Petrek and Keane, {Michael P.} and Haraldsdottir, {Sigridur O.} and Francesco Bonella and Christian Grah and Tatjana Pero{\v s}-Golubi{\v c}i{\'c} and Zamir Kadija and Stefan Pabst and Christian Groh{\'e} and Strausz, {J. nos} and Martina Safrankova and Ann Millar and Ji{\v r}{\'i} Homolka and Wuyts, {Wim A.} and Spencer, {Lisa G.} and Michael Pfeifer and Dominique Valeyre and Venerino Poletti and Hubertus Wirtz and Antje Prasse and Stefan Schreiber and Astrid Dempfle and Joachim M{\"u}ller-Quernheim",

note = "Funding Information: This study was supported by German Federal Ministry for Education and Research grant 01EY1103 and German Research Foundation grant MU 692/8-1 and FI 1935/1-1, DFG Exzellenzcluster PMI EXC 2/67 and Clusterlab XI EXC 306/2. JCS is supported by the CORE100Pilot Advanced Clinician Scientist Program of Hannover Medical School funded by Else Kr{\"o}ner-Fresenius Foundation (2020_EKSP.78) and the Ministry of Science and Culture of Lower Saxony, and the Fritz Thyssen-Foundation. Publisher Copyright: Copyright {\textcopyright} 2023 Freitag-Wolf, Schupp, Frye, Fischer, Anwar, Kieszko, Mihailovi{\'c}-Vu{\v c}ini{\'c}, Milanowski, Jovanovic, Zissel, Bargagli, Rottoli, Bumbacea, Jonkers, Ho, Gaede, Dubaniewicz, Marshall, G{\"u}nther, Petrek, Keane, Haraldsdottir, Bonella, Grah, Pero{\v s}-Golubi{\v c}i{\'c}, Kadija, Pabst, Groh{\'e}, Strausz, Safrankova, Millar, Homolka, Wuyts, Spencer, Pfeifer, Valeyre, Poletti, Wirtz, Prasse, Schreiber, Dempfle and M{\"u}ller-Quernheim.",

year = "2023",

doi = "https://doi.org/10.3389/fmed.2023.1218106",

language = "English",

volume = "10",

journal = "Frontiers in Medicine",

issn = "2296-858X",

publisher = "Frontiers Media",

}

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, JN, 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 2023, 'Genetic and geographic influence on phenotypic variation in European sarcoidosis patients', Frontiers in Medicine, vol. 10, 1218106. https://doi.org/10.3389/fmed.2023.1218106

TY - JOUR

T1 - Genetic and geographic influence on phenotypic variation in European sarcoidosis patients

AU - Freitag-Wolf, Sandra

AU - Schupp, Jonas C.

AU - Frye, Björn C.

AU - Fischer, Annegret

AU - Anwar, Raihanatul

AU - Kieszko, Robert

AU - Mihailović-Vučinić, Violeta

AU - Milanowski, Janusz

AU - Jovanovic, Dragana

AU - Zissel, Gernot

AU - Bargagli, Elena

AU - Rottoli, Paola

AU - Bumbacea, Dragos

AU - Jonkers, René

AU - Ho, Ling-Pei

AU - Gaede, Karoline I.

AU - Dubaniewicz, Anna

AU - Marshall, Ben G.

AU - Günther, Andreas

AU - Petrek, Martin

AU - Keane, Michael P.

AU - Haraldsdottir, Sigridur O.

AU - Bonella, Francesco

AU - Grah, Christian

AU - Peroš-Golubičić, Tatjana

AU - Kadija, Zamir

AU - Pabst, Stefan

AU - Grohé, Christian

AU - Strausz, J. nos

AU - Safrankova, Martina

AU - Millar, Ann

AU - Homolka, Jiří

AU - Wuyts, Wim A.

AU - Spencer, Lisa G.

AU - Pfeifer, Michael

AU - Valeyre, Dominique

AU - Poletti, Venerino

AU - Wirtz, Hubertus

AU - Prasse, Antje

AU - Schreiber, Stefan

AU - Dempfle, Astrid

AU - Müller-Quernheim, Joachim

N1 - Funding Information: This study was supported by German Federal Ministry for Education and Research grant 01EY1103 and German Research Foundation grant MU 692/8-1 and FI 1935/1-1, DFG Exzellenzcluster PMI EXC 2/67 and Clusterlab XI EXC 306/2. JCS is supported by the CORE100Pilot Advanced Clinician Scientist Program of Hannover Medical School funded by Else Kröner-Fresenius Foundation (2020_EKSP.78) and the Ministry of Science and Culture of Lower Saxony, and the Fritz Thyssen-Foundation. Publisher Copyright: Copyright © 2023 Freitag-Wolf, Schupp, Frye, Fischer, Anwar, Kieszko, Mihailović-Vučinić, Milanowski, Jovanovic, Zissel, Bargagli, Rottoli, Bumbacea, Jonkers, Ho, Gaede, Dubaniewicz, Marshall, Günther, Petrek, Keane, Haraldsdottir, Bonella, Grah, Peroš-Golubičić, Kadija, Pabst, Grohé, Strausz, Safrankova, Millar, Homolka, Wuyts, Spencer, Pfeifer, Valeyre, Poletti, Wirtz, Prasse, Schreiber, Dempfle and Müller-Quernheim.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - genetic polymorphism

KW - genetic risk factors

KW - genotype–phenotype-relationship

KW - region-specific genetic links

KW - sarcoidosis

UR - http://www.scopus.com/inward/record.url?scp=85168705652&partnerID=8YFLogxK

U2 - https://doi.org/10.3389/fmed.2023.1218106

DO - https://doi.org/10.3389/fmed.2023.1218106

M3 - Article

C2 - 37621457

SN - 2296-858X

VL - 10

JO - Frontiers in Medicine

JF - Frontiers in Medicine

M1 - 1218106

ER -

Genetic and geographic influence on phenotypic variation in European sarcoidosis patients

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Keywords

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