Unraveling genetic mysteries: phenotype-shaping profiles in chronic sarcoidosis

Abstract

BackgroundSarcoidosis represents a complex inflammatory condition of unknown origin, characterized by diverse clinical profiles, particularly identifiable as Lofgrens syndrome (LS) and non-LS cases. Delving into the genetic underpinnings of chronic sarcoidosis phenotypes is essential for advancing our understanding and treatment of this disease. MethodsTo classify chronicity, pulmonologists evaluated sarcoidosis phenotypes over a follow-up period of two years, distinguishing between chronic and nonchronic classifications. We assessed the genetics of these chronicity phenotypes in a Swedish cohort of 1,515 sarcoidosis cases (679 nonchronic and 836 chronic) alongside 3,085 controls using the Immunochip array. To confirm our findings, replication analysis was conducted in a German cohort of 1,216 sarcoidosis cases (485 nonchronic and 731 chronic) and 3,042 controls. A comprehensive meta-analysis of significant SNPs (p < 5e-8) was carried out using inverse variance weighting. Additionally, we employed gene-based analysis, enrichment mapping, and pathway analysis to gain deeper functional insights. ResultsOur meta-analysis uncovered significant genetic associations with chronic sarcoidosis phenotypes, including LS nonchronic (rs3135356; OR = 3.13, 95% CI: 2.38 - 4.12), non-LS nonchronic (rs2395162; OR = 2.34, 95% CI: 1.96 - 2.85), and non-LS chronic cases (rs1049550; OR = 0.68, 95% CI: 0.59 - 0.76). Specifically, gene-based analysis revealed that CLIC1 is associated with nonchronic forms, while ANXA11 is linked to the chronic phenotype. Our enrichment analysis highlighted the expression of quantitative trait loci (eQTLs) in immune cells, whole blood, and lung tissues. The pathway analysis pinpointed the antigen presentation pathway as vital to understanding chronicity phenotypes. ConclusionsThis study illuminates the distinct genomic features that differentiate chronic sarcoidosis phenotypes, underscoring the critical involvement of immune-related genes and regulatory networks. By advancing the knowledge of sarcoidosis chronicity, these findings pave the way for targeted therapeutic interventions and personalized treatment strategies that can significantly improve patient outcomes.