The causal relationship and potential mediators between plasma lipids and atopic dermatitis: a bidirectional two-sample, two-step mendelian randomization

Abstract

Background: Observational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway.

Methods: We utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran's Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings.

Results: The Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929-0.972, p = 6.65 × 10^{- 6}), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906-0.971, p = 2.79 × 10^{- 4}), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906-0.969, p = 1.48 × 10^{- 4}) and TAG (56:8) (OR: 0.918, 95% CI: 0.876-0.961, p = 2.72 × 10^{- 4}) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028-1.079, p = 2.11 × 10^{- 5}) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039-1.135, p = 2.47 × 10^{- 4}) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%.

Conclusion: Our research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach.

Keywords: Atopic dermatitis; Inflammatory protein; Mendelian randomization; Plasma lipids.

Fig. 1

Overview of the study design. Mediation effect = β2 × β3. Mediation proportion = β2 × β3/β1

Fig. 2

Two-sample MR results of the causal effects of plasma lipids on AD risk. nSNP, number of single-nucleotide polymorphisms; OR, odds ratio; CI, confidence interval

Fig. 3

Two-sample MR results of the causal effects of plasma lipids on circulating inflammatory proteins. nSNP, number of single-nucleotide polymorphisms; Beta, estimated effect size of the IVs on the outcome; CI, confidence interval

Fig. 4

Two-sample MR results of the causal effects of circulating inflammatory proteins on AD risk. nSNP, number of single-nucleotide polymorphisms; OR, odds ratio; CI, confidence interval

Fig. 5

The mediation effect of IL-18R1 in the causal effect of PC (18:1_20:2) on AD risk