From Phenotype to Molecules: Unveiling the Genetic and Immunological Bridges Between Autoimmune Diseases and Vitiligo

Abstract

Introduction: Vitiligo is an autoimmune disease characterized by the loss of skin pigmentation. This study aims to explore genetic associations between vitiligo and 21 autoimmune diseases using Mendelian randomization (MR) analysis, with a focus on identifying potential risk and protective factors.

Methods: We performed univariable and multivariable Mendelian randomization analyses to assess the causal associations between 21 autoimmune diseases and vitiligo. Confounding factors, including smoking, alcohol consumption, and Body Mass Index (BMI), were integrated into the multivariable analysis. Strongly associated single nucleotide polymorphisms (SNPs) were mapped to genes, followed by Summary-data-based Mendelian Randomization (SMR) analysis with expression Quantitative Trait Loci (eQTL) and methylation Quantitative Trait Loci (mQTL) data. Risk and protective factors were further identified by evaluating inflammatory mediators and immune cell phenotypes.

Results: The MR analysis identified seven autoimmune diseases with potential causal associations with vitiligo. However, after accounting for confounding factors, only Hashimoto's thyroiditis and type 1 diabetes maintained genetic associations with vitiligo. Gene mapping revealed 25 intersecting genes between these two diseases and vitiligo. SMR analysis confirmed Sulfite Oxidase (SUOX) as a protective gene across multiple tissues. Furthermore, several inflammatory factors were identified as risk factors, including C-X-C motif chemokine ligand 9 (CXCL9), C-X-C motif chemokine ligand 10 (CXCL10), Tumor Necrosis Factor (TNF), and Signaling Lymphocytic Activation Molecule (SLAM). In contrast, Osteoprotegerin (OPG) was identified as a protective factor.

Discussion: This study provides novel insights into the shared molecular mechanisms linking vitiligo with other autoimmune diseases. The identification of SUOX as a common protective gene and the discovery of specific inflammatory and immune-related factors may facilitate future therapeutic strategies.

Keywords: Mendelian randomization; autoimmune diseases; causality; sulfite oxidase; vitiligo.

Figure 1

Study design overview.

Figure 2

The circular diagram illustrates the genetic associations between 21 autoimmune diseases and Vitiligo, with exposures reaching significant levels highlighted in red. The two-sample Mendelian Randomization analysis suggests a genetic associations between vitiligo and the following seven diseases: Celiac Disease, Hashimoto Thyroiditis, Multiple Sclerosis, Primary Sclerosing Cholangitis, Psoriasis, Rheumatoid Arthritis, and Type 1 Diabetes. VD, Validation Dataset.

Figure 3

The circular diagram illustrates the true genetic associations between seven autoimmune diseases with positive Mendelian analysis in two samples, after controlling for confounding factors, and Vitiligo, with exposures reaching significant levels highlighted in red. Multivariable Mendelian Randomization analysis suggests that, after adjusting for potential confounders, there is a significant genetic association between Hashimoto Thyroiditis and Type 1 Diabetes and vitiligo.

Figure 4

The forest plot illustrates the inflammatory factors that have shared pathogenic or protective effects with at least two diseases.

Figure 5

The forest plot illustrates the immune cell phenotypes that have shared pathogenic or protective effects with at least two diseases.

Figure 6

The relationship between SUOX’s eQTL levels in various tissues and Hashimoto Thyroiditis, Type 1 Diabetes, and Vitiligo (with GTEx as the discovery set and CAGE as the validation set). (A) Negative association between SUOX expression and Hashimoto Thyroiditis in the GTEx Whole Blood tissue. (B) Negative association between SUOX expression and Type 1 Diabetes in the GTEx Whole Blood tissue. (C) Negative association between SUOX expression and Vitiligo in the GTEx Whole Blood tissue. (D) Negative association between SUOX expression and Hashimoto Thyroiditis in the GTEx Thyroid tissue. (E) Negative association between SUOX expression and Type 1 Diabetes in the GTEx Pancreas tissue. (F) Negative association between SUOX expression and Vitiligo in the GTEx Skin (Sun-Exposed) tissue. (G) Negative association between SUOX expression and Vitiligo in the GTEx Skin (Not Sun-Exposed) tissue. (H) Negative association between SUOX expression and Hashimoto Thyroiditis in the CAGE Whole Blood tissue. (I) Negative association between SUOX expression and Type 1 Diabetes in the CAGE Whole Blood tissue. (J) Negative association between SUOX expression and Vitiligo in the CAGE Whole Blood tissue.