High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences

Am J Respir Crit Care Med. 2016 May 1;193(9):1008-22. doi: 10.1164/rccm.201507-1372OC.


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.

Keywords: Immunochip; Löfgren’s syndrome; genetic epidemiology of sarcoidosis; genome-wide associations; non-Löfgren’s syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Czech Republic
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genomics / methods*
  • Genotype*
  • Germany
  • Humans
  • Male
  • Middle Aged
  • Netherlands
  • Phenotype*
  • Sarcoidosis, Pulmonary / genetics*
  • Sweden
  • United States