High-density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences

Natalia V. Rivera*, Marcus Ronninger, Klementy Shchetynsky, Andre Franke, Markus M. Nöthen, Joachim Müller-Quernheim, Stefan Schreiber, Indra Adrianto, Bekir Karakaya, Coline H.M. Van Moorsel, Zdenka Navratilova, Vitezslav Kolek, Benjamin A. Rybicki, Michael C. Iannuzzi, Martin Petrek, Jan C. Grutters, Courtney Montgomery, Annegret Fischer, Anders Eklund, Leonid PadyukovJohan Grunewald

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

42 Citations (Scopus)

Abstract

Rationale: Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. Objectives: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. Methods: An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. Measurements and Main Results: A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. Conclusions: Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.

Original languageEnglish
Pages (from-to)1008-1022
Number of pages15
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume193
Issue number9
DOIs
Publication statusPublished - 1 May 2016

Keywords

  • Genetic epidemiology of sarcoidosis
  • Genome-wide associations
  • Immunochip
  • Löfgren's syndrome
  • Non-Löfgren's syndrome

Fingerprint

Dive into the research topics of 'High-density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences'. Together they form a unique fingerprint.

Cite this