The causal relationship between sarcoidosis and autoimmune diseases: a bidirectional Mendelian randomization study in FinnGen

Abstract

Background: Sarcoidosis has been considered to be associated with many autoimmune diseases (ADs), but the cause-and-effect relationship between these two diseases has not been fully explored. Therefore, the objective of this study is to explore the possible genetic association between sarcoidosis and ADs.

Methods: We conducted a bidirectional Mendelian randomization (MR) study using genetic variants associated with ADs and sarcoidosis (4,041 cases and 371,255 controls) from the FinnGen study. The ADs dataset comprised 96,150 cases and 281,127 controls, encompassing 44 distinct types of autoimmune-related diseases. Subsequently, we identified seven diseases within the ADs dataset with a case size exceeding 3,500 and performed subgroup analyses on these specific diseases.

Results: The MR evidence supported the causal association of genetic predictors of ADs with an increased risk of sarcoidosis (OR = 1.79, 95% CI = 1.59 to 2.02, P _IVW-FE = 1.01 × 10^-21), and no reverse causation (OR = 1.05, 95% CI 0.99 to 1.12, P _IVW-MRE = 9.88 × 10^-2). Furthermore, subgroup analyses indicated that genetic predictors of type 1 diabetes mellitus (T1DM), celiac disease, and inflammatory bowel disease (IBD) were causally linked to an elevated risk of sarcoidosis (All P < 6.25 × 10^-3). Conversely, genetic predictors of sarcoidosis showed causal associations with a higher risk of type 1 diabetes mellitus (P < 6.25 × 10^-3).

Conclusion: The present study established a positive causal relationship between genetic predictors of ADs (e.g. T1DM, celiac disease, and IBD) and the risk of sarcoidosis, with no evidence of reverse causation.

Keywords: FinnGen; Mendelian randomization; autoimmune diseases; causality; sarcoidosis.

Figure 1

Three assumptions for IVs in MR study. IVs, Instrumental variables; SNPs, Single nucleotide polymorphisms; MR, Mendelian randomization.

Figure 2

Relationship between exposures and outcomes. The MR analyses were conducted separately with sarcoidosis as both the outcome (A) and the exposure (B). The dataset of autoimmune diseases analyzed in this study comprised a total of 44 different types of autoimmune-related diseases. SNPs, Single nucleotide polymorphisms; OR, Odds ratio; CI, Confidence intervals; IVW-MRE, Multiplicative random-effect inverse variance weighted; IVW-FE, Fixed-effect inverse variance weighted; MR, Mendelian randomization.

Figure 3

Scatter plots of associations between exposures-associated SNPs and sarcoidosis. The MR analyses were conducted with various exposures, including autoimmune diseases: autoimmune diseases (A), rheumatoid arthritis (B), autoimmune hypothyroidism (C), type 1 diabetes mellitus (D), coeliac disease (E), inflammatory bowel disease (F), psoriasis (G), and anterior iridocyclitis (H). The dataset of autoimmune diseases analyzed in this study comprised a total of 44 different types of autoimmune-related diseases. SNP, Single nucleotide polymorphism; MR, Mendelian randomization.

Figure 4

Scatter plots of associations between sarcoidosis-associated SNPs and outcomes. The MR analyses were conducted with the following outcomes: autoimmune diseases (A), rheumatoid arthritis (B), autoimmune hypothyroidism (C), type 1 diabetes mellitus (D), coeliac disease (E), inflammatory bowel disease (F), psoriasis (G), and anterior iridocyclitis (H). The dataset of autoimmune diseases analyzed in this study comprised a total of 44 different types of autoimmune-related diseases. SNP, Single nucleotide polymorphism; MR, Mendelian randomization.