* Correspondence:
Zhang Hui and Zhirong Yao, Institute of Dermatology, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China,
E-mail: c_zhanghui@sina.comandyaozhirong@xinhuamed.com.cn
Author Contributions: Zhenquan Xuan, Hui Zhang and Zhirong Yao conceived the project. Zhenquan Xuan and Jiawen Chen was responsible for the data analysis. Zhenquan Xuan, Zhen Zhang, Yifeng Guo, Hui Zhang and Zhirong Yao wrote and revised the manuscript. Hui Zhang and Zhirong Yao were responsible for the study concept and design, study supervision and funding. All authors reviewed and approved the manuscript.
To the Editor,
Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both common inflammatory skin diseases, having an immune pathogenesis. There has been substantial interest about their inter-relationships with respect to altered susceptibility. Some studies have indicated that patients with AD were more likely to suffer from ACD, especially caused by nickel, preservatives and cosmetics, probably due to the compromised skin barrier abnormality of AD [1-3]. However, there is compelling evidence in favor of reduced risk of ACD in patients with AD, especially severe patients. A systematic review showed that the prevalence of ACD was significantly lower among children with AD, compared with controls [4]. Additionally, in patients with AD, severe ones were less sensitive to dinitrochlorobenzene than mild or moderate ones [5, 6]. A register-based clinical study also found that patients with severe AD have an overall lower prevalence of ACD when compared with controls, whereas mild-to-moderate AD does not suppress ACD [7]. Since severe cases may have a higher genetic load for the disease-causing mutations and help reduce the interference of confounding factors [8]. Therefore, we presumed that there might be a negative causal effect from AD to ACD at the genetic level.
Mendelian randomization (MR) is a genetic epidemiological tool which uses single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to infer the potential causality of exposure and outcome. The MR tool could conquer confounders and reverse causation bias, which is due to the fact that an individual’s genotype is determined at conception and cannot be altered. Considering this, we performed a two-sample MR analysis for the association of AD with ACD using large-scale genome-wide association study (GWAS) data sheets of Europeans. For AD, the instrumental variables (IVs) were generated from the wide summary statistics from a GWAS of 10788 cases and 30047 controls from 20 studies of European ancestry, excluding the 23andMe study [9]. For ACD, we used the summary statistics (finn-b-L12_ALLERGICCONTACT) from FinnGen biobank analysis including 2,204 cases and 198,740 controls of European ancestry. The participants of AD and ACD data sheets, to our knowledge, did not overlap. The “TwoSampleMR” package of the R software (version 4.1.2) was used to performed two-sample MR analysis. SNPs associated (P < 5e-08) with AD were selected, and the clumping process (r 2 < 0.001, clumping distance = 10,000 kb) was carried out to eliminate the linkage disequilibrium between the included SNPs, also the palindromic SNP rs10790275 with intermediate allele frequencies was excluded. Eventually, 11 SNPs were chosen as IVs (Table S1). Inverse variance weighting (IVW) was used as the main analysis, and the MR Egger, weighted median, simple mode, and weighted mode as supplementary methods. And the effect of each SNP locus on ACD was shown in Figure 1A and 1B. Analysis based on IVW suggested a significant casual effect of AD on ACD (OR 95% confidence interval [CI] = 0.73 [0.63-0.89]; P = 3.02e-05) (Figure 1A; Table S2). Moreover, weighted median analysis also showed a remarkable casual effect of AD on ACD (OR 95% CI = 0.75 [0.64-0.89]; P = 8.76e-04) (Figure 1A, Table S2), while the results of analysis based on simple mode (OR 95% CI = 0.75 [0.57-1.00]; P = 0.08) (Figure 1A, Table S2) and weighted mode (OR 95% CI = 0.77 [0.62-0.97]; P = 0.05) (Figure 1A, Table S2) were slightly significant. Leave-one-out analysis further revealed that there was no fundamental impact on ACD (all lines were on the left side of 0), regardless of which SNP was removed, suggesting that the MR result was robust (Figure 2). MR Egger regression was used to detect the horizontal pleiotropy of our analysis, and no significant pleiotropy was determined (P = 0.53) (Table S3), indicating the basic assumption of MR analysis was satisfied. The P -values for heterogeneity tests using the MR-Egger and IVW methods were 0.15 and 0.12, respectively, which suggests that there is no heterogeneity (Table S3).
To our knowledge, this study is the first to analyze the causal relationship between AD and ACD based on two-sample MR. Surprisingly, the present results found that AD had negative causal relationships with overall ACD with respect to genetic effects. The altered risk of ACD in AD patients is a controversial topic in the field as mentioned above [1-7], and indeed, some showed the decreased risk of ACD in patients with AD, in especial, severe cases [4-7]. However, these observational studies could not draw a causal link between the two conditions, therefore, we utilized MR to detect it. The present study extends prior research by showing a causal relationship between AD and ACD, although the pathophysiological mechanisms underlying this relationship are not entirely clear. One possible explanation for this relationship is, under genetic control, the relative weak Th1-mediated cellular immunity in AD inhibit the onset of ACD [10]. The data used for this study were limited to participants of European ancestry, therefore, a comprehensive and clear database is required for further research. Furthermore, it is of importance to explore the causal effect between AD and diverse allergen-specific-ACD subtypes in the future. Finally, the exposure factors in this study were the effects of mutated genes, which may differ from the actual exposure in terms of time and dose.