Mendelian Randomization Unveils a Causal Relationship Between Inflammation, Metabolism, and Systemic Sclerosis

BackgroundInflammatory processes and metabolic activity significantly influence the beginning and course of systemic sclerosis (SSc). This study aims to explore the genetic basis for the impact of inflammation and metabolism on susceptibility to SSc. MethodsWe used three types of exposure: 91 inflammatory proteins (14,824 participants), 731 immune cell traits (3,757 Sardinians), 1,400 blood metabolites (8,299 Europeans), with SSc as an outcome (680 cases, 399,355 controls). A two-sample multivariate bivariate Mendelian randomization (MR) was conducted to investigate the causal relationship between inflammation, metabolism, and SSc and explore the interaction of inflammatory proteins, immune cells, and metabolites in SSc. ResultsMR analysis identified potential causal associations of four inflammatory proteins and fourteen metabolites with SSc and a significant causal association of two immune cells with SSc. Among them, HLA DR on CD14- CD16+ monocyte and HLA DR on CD33dim HLA DR+ CD11b+ significantly reduced the risk of SSc. Pleiotropy and heterogeneity were not observed. None showed bidirectional causality in reverse MR analysis. Multivariate MR results showed independent causal effects of two inflammatory proteins, one immune cell, and three metabolites on SSc; three were risk factors (hepatocyte growth factor, stem cell growth factor, and 5-hydroxyindole sulfate levels); three were protective factors (HLA DR on CD14- CD16+ monocyte, Homoarginine levels and Tetradecadienoate (14:2) levels). ConclusionsThese findings reveal causal relationships and interactions between four inflammatory proteins, fifteen immune cell traits, and fourteen metabolites and SSc and its development, offering fresh perspectives on the mechanisms underlying SSc and guiding the choice of treatment approaches.