Cysteine cathepsins and autoimmune diseases: A bidirectional Mendelian randomization

Area of Science:

• Biochemistry
• Immunology
• Genetics

Background:

• Cysteine cathepsins are lysosomal proteases involved in physiological and pathological processes, including immune regulation.
• The specific role of cysteine cathepsins in autoimmune diseases is not well understood.

Purpose of the Study:

• To investigate the potential causal relationship between cysteine cathepsins and autoimmune diseases using Mendelian randomization.
• To identify specific cysteine cathepsins associated with increased or decreased risk of autoimmune conditions.

Main Methods:

• Utilized Mendelian randomization (MR) analysis with single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) for cysteine cathepsins (exposure) and 10 GWAS datasets for autoimmune diseases (outcome).
• Employed Wald ratio (WR) and inverse variance weighted (IVW) as primary MR methods, supported by weighted median and MR-Egger analyses.
• Assessed heterogeneity with Cochran Q test and performed sensitivity analysis using MR-PRESSO.

Main Results:

• Elevated cathepsin B showed a potential positive correlation with psoriasis.
• Cathepsin F was potentially linked to increased risk of ulcerative colitis, ankylosing spondylitis, and primary biliary cholangitis (PBC).
• Cathepsin H appeared protective against celiac disease but was associated with increased risk for type 1 diabetes and PBC.
• Cathepsin Z was associated with an increased risk of type 1 diabetes.

Conclusions:

• Mendelian randomization analysis suggests specific causal links between certain cysteine cathepsins and autoimmune diseases.
• Cathepsin F and Z may contribute to the risk of specific autoimmune conditions, while cathepsin H shows a dual role.
• Further research is warranted to elucidate the precise mechanisms underlying these associations.