Abstract
Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10−8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.
Highlights
Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs
Of the human leukocyte antigen (HLA) alleles, only HLA-DRB1*0803 showed genome-wide significance as a risk factor for sarcoidosis (PGC = 4.1 × 10−8, OR = 1.82, 95% CI = 1.46–2.26); HLA-DQB1*0601 showed the highest significance as a risk allele for sarcoidosis (PGC = 1.5 × 10−7, OR = 1.32, 95% CI = 1.12–1.56)
We identified three loci (CCL24, STYXL1-SRRM3, and C1orf141-IL23R) that showed a genome-wide significant association with sarcoidosis in the metaanalysis of the Genome-wide association studies (GWASs) cohort and the two replication cohorts
Summary
Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. Genome-wide association studies (GWASs) in populations of European descent and/or African-Americans have reported several genetic loci/genes that confer susceptibility to sarcoidosis, including C10orf[67], ANXA11, RAB23, OS9, CCDC88B, NOTCH4, and XAF18,9. An Immunochip study identified four other loci associated with susceptibility to sarcoidosis in populations of European descent, but not African-Americans: SH2B3ATXN2, IL12B, NFKB1-MANBA, and FAM117B10. Those findings could lead to a more precise understanding of the etiology and pathophysiology of sarcoidosis at the molecular level. Our analysis identifies three non-HLA susceptibility loci (CCL24, STYXL1-SRRM3, and C1orf141-IL23R) for sarcoidosis and demonstrates the importance of genetic control of CCL24, POR, and IL23R, through genetic polymorphisms, in the pathogenesis of sarcoidosis
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