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

Background Inflammatory 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.

We 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.

MR 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).

These 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. Competing Interest Statement The authors have declared that no competing interests exist. Clinical Trial Not applicable. Funding Statement The author(s) received no specific funding for this work. Author Declarations 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: Not applicable. 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 Data Availability If the data are all contained within the manuscript and/or Supporting Information files, enter the following: All relevant data are within the manuscript and its Supporting Information files. Abbreviations - SSc - Systemic sclerosis - MR - Mendelian Randomization - IL-6 - Interleukin-6 - SNPs - Single nucleotide polymorphisms - IVs - Instrumental variables - GWAS - Genome-wide association studies - IVW - Inverse variance weighted - LD - Linkage disequilibrium - OR - Odds ratio - CI - Confidence interval - MRPRESSO - MR pleiotropy residual and outlier - FDR - False discovery rate - MVMR - Multivariable Mendelian randomization - SCF - Stem cell factor - HGF - Hepatocyte growth factor - PAH - Pulmonary arterial hypertension - MMP-1 - Matrix Metalloproteinase-1 - CTGF - Connective tissue growth factor - MSCs - Modified mesenchymal stem cells - MCP-1 - Monocyte chemoattractant protein-1 - OSM - Oncostatin-M - EC - Endothelial cell - STAT3 - Signal transducer and activator of transcription 3 - CXCL12 - C-X-C motif chemokine ligand 12 - TGF-β - Transforming growth factor-beta - LN - Lupus nephritis - dcSSc - Diffuse cutaneous systemic sclerosis - Myh9 - Myosin heavy chain 9 - 5-HIAA - 5-Hydroxyindole Sulfate - RA - Rheumatoid arthritis - 5-HT - 5-Hydroxytryptamine