Bidirectional Mendelian randomization exploring the causal relationship between immune cell dynamics and adult-onset Still’s disease

Abstract

Aim: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder marked by fever, rash, joint pain, and hyperferritinemia. While immune dysregulation is implicated in AOSD, the exact causal mechanisms remain unclear. This study aimed to investigate the genetic causal relationship between 731 immune cell phenotypes and AOSD, and to identify protective or risk-associated profiles.

Methods: Using a two-sample Mendelian randomization (TSMR) approach, we applied inverse variance weighted (IVW) as the primary method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods for robustness. Genetic instrumental variables for immune traits were sourced from recent genome-wide association studies (GWAS), and AOSD genetic predispositions were derived from the finn-b-STILL_ADULT cohort, comprising 201,947 individuals of European ancestry (3,403 AOSD cases and 198,544 controls).

Results: We identified 49 immune cell-related traits showing nominally significant associations with AOSD (all adjusted P > 0.05 after FDR correction). Among these, 34 traits showed nominally protective trends, while 15 showed nominally risk-associated trends. Reciprocally, AOSD showed nominally suggestive effects on 40 immune cell traits, with 25 exhibiting a trend toward decreased levels and 15 toward increased levels. Additionally, we conducted multiple sensitivity analyses to explore potential heterogeneity and pleiotropy, though the primary findings did not survive FDR correction.

Conclusions: These nominally significant associations between immune cell traits and AOSD, though not surviving FDR correction, may offer hypothesis-generating insights for future therapeutic research. The observed directional trends-with certain traits showing nominally protective or risk-associated patterns-suggest potential avenues for further exploration in the development of targeted treatment approaches for AOSD.

Keywords

adult-onset Still’s disease / Mendelian randomization / genome-wide association study / immune cell / causal relationship

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