Abstract Background: Sarcoidosis represents a complex inflammatory condition of unknown origin, characterized by diverse clinical profiles, particularly identifiable as Lofgren's 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. Methods: To 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. Results: Our 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. Conclusions: This 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.

The authors have declared no competing interest.

Swedish Heart-Lung Foundation awarded to NVR (Grant No. 20200505 and 20200506), SK (Grant No. 20220140 and 20220194); Swedish National Research Council awarded to LP (Grant No. 2018-02884) and SK (Grant No. 2019-01034 and 2022-00870).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committee of the Stockholm Region Review Board gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The genomic data of individuals investigated in the European cohorts are not available due to GPDR regulations.