The effect of circulating cytokines on the risk of systemic lupus erythematosus: Mendelian randomization and observational study.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, the etiology of which involves the alterations in circulating cytokine levels. However, the cause-and-effect relationships and in-depth clinical relevance of them remain to be systematically investigated. We conducted a two-sample Mendelian randomization (MR) study to assess the causality of circulating cytokine levels and SLE and found that genetically determined elevated CTACK and IL-18 were associated with an increased risk of SLE, whereas a higher level of GRO-a was associated with decreased risk. Furthermore, we performed an observational study to further reveal the association between 27 cytokines and the severity measured by SLEDAI score, as well as lupus nephritis (LN), of SLE. We identified six cytokines (MCP1, MIP1β, CTACK, IP10, HGF, IL18, IL13) that were identified as associated with the clinical severity of SLE, and five cytokines, especially IL18, were related with LN and may have good diagnostic value. Moreover, we also predicted four compounds that might have good binding activities with IL18. The evidence supported a potential causal role of circulating cytokines on the risk of SLE. Targeting IL18 might be a meaningful strategy for the prevention or treatment of SLE, especially in LN patients.

Xue D ，Qian Y ，Tu X ，He M ，Xing F ，Ren Y ，Yuan C ... -  《-》

The causal associations of inflammatory cytokines with obesity and systemic lupus erythematosus: A Mendelian randomization study.

Previous studies have partly discussed the roles of inflammatory cytokines in obesity and systemic lupus erythematosus (SLE), but the causal relationship among inflammatory cytokines, obesity, and SLE is unclear. It is challenging to comprehensively evaluate the causal relationship between these variables. This study aimed to investigate the role of cytokines as intermediates between obesity and SLE. The inverse-variance weighted method (IVW) of mendelian randomization (MR) is mainly used to explore the causal relationship between exposure and outcome by using the genetic variation of the open large genome-wide association studies (GWAS), namely single-nucleotide polymorphisms (SNPs) related to obesity (more than 600 000 participants), inflammatory cytokines (8293 healthy participants) and SLE (7219 cases). Methods such as weighted median, MR-Egger are used to evaluate the reliability of causality. Reverse analysis is performed for each MR analysis to avoid reverse causality. Cochran's Q statistic and funnel chart are used to detect heterogeneity, MR-Egger intercept test and leave-one-out sensitivity analyses evaluated pleiotropy. Obesity was associated with 25 cytokines, and 3 cytokines were associated with SLE, including CTACK (OR = 1.19, 95% CI: 1.06, 1.33, p = .002), IL-18 (OR = 1.13, 95% CI: 1.01, 1.26, p = .027), SCGFb (OR = 0.89, 95% CI: 0.79, 0.99, p = .044). In the opposite direction, SLE was associated with 18 cytokines, and 2 cytokines were associated with obesity, including IP-10 (βIVW = -.03, 95% CI: -0.05, -0.01, p = .002), MIP-1B (βIVW = -.03, 95% CI: -0.05, -0.01, p = .004). Our MR study suggested that CTACK, IL-18 and SCGFb may play an intermediary role in obesity to SLE, while IP-10 and MIP-1B may play an intermediary role in SLE to obesity.

Huang AF ，Zhou L ，Xu WD 《-》

Genetically predicted associations between circulating cytokines and autoimmune diseases: a bidirectional two-sample Mendelian randomization.

Previous studies have indicated a correlation between cytokines and autoimmune diseases. yet the causality remains uncertain. Through Mendelian Randomization (MR) analysis, we aimed to investigate the causal relationships between genetically predicted levels of 91 cytokines and three autoimmune diseases: Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE), and Hashimoto's Thyroiditis (HT). A bidirectional two-sample MR approach was utilized to assess the causal relationships between cytokines and MS, SLE, and HT. The datasets included 47,429 MS cases and 68,374 controls, 5,201 SLE cases and 9,066 controls, and 16,191 HT cases with 210,612 controls. Data on 91 cytokines comprised 14,824 participants. Causal analyses primarily employed inverse variance weighted, weighted median, and MR-Egger methods, with sensitivity analyses including heterogeneity and pleiotropy assessment. Genetically predicted levels of IL-18 (OR = 0.706; 95% C.I. 0.538-0.925), ADA (OR = 0.808; 95% C.I. 0.673-0.970), and SCF (OR = 0.898; 95% C.I. 0.816-0.987) were associated with a decreased risk of MS. IL-4 (OR = 1.384; 95% C.I. 1.081-1.771), IL-7 (OR = 1.401; 95% C.I. 1.010-1.943), IL-10RA (OR = 1.266; 95% C.I. 1.004-1.596), CXCL5 (OR = 1.170; 95% C.I. 1.021-1.341), NTN (OR = 1.225; 95% C.I. 1.004-1.496), FGF23 (OR = 0.644; 95% C.I. 0.460-0.902), and MCP4 (OR = 0.665; 95% C.I. 0.476-0.929) were associated with SLE risk. CDCP1 (OR = 1.127; 95% C.I. 1.008-1.261), IL-33 (OR = 0.852; 95% C.I. 0.727-0.999), and TRAIL (OR = 0.884; 95% C.I. 0.799-0.979) were associated with HT risk. Bidirectional MR results suggest the involvement of CCL19, IL-13, SLAM, ARTN, Eotaxin, IL-22RA1, ADA, and MMP10 in the downstream development of these diseases. Our findings support causal relationships between certain cytokines and the risks of MS, SLE, and HT, identifying potential biomarkers for diagnosis and prevention. Additionally, several cytokines previously unexplored in these autoimmune disease contexts were discovered, laying new groundwork for the study of disease mechanisms and therapeutic potentials.

Jie J ，Gong Y ，Luo S ，Yang X ，Guo K ... -  《Frontiers in Immunology》

Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization.

Previous studies have reported that a few inflammatory cytokines have associations with systemic lupus erythematosus (SLE)-for example, IL-6, IL-17, and macrophage inflammatory protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 inflammatory cytokines and SLE. The two-sample Mendelian randomization utilized genetic variances of SLE from a large publicly available genome-wide association study (GWAS) (7,219 cases and 15,991 controls of European ancestry) and inflammatory cytokines from a GWAS summary containing 8,293 healthy participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were simultaneously applied to strengthen the final results. The results indicated that cutaneous T cell-attracting chemokine (CTACK) and IL-17 may be suggestively associated with the risk of SLE (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; OR: 1.37, 95%CI: 1.03-1.82, p = 0.029). In addition, cytokines including beta nerve growth factor, basic fibroblast growth factor, IL-4, IL-6, interferon gamma-induced protein 10, monokine induced by interferon-gamma, MIP1b, stromal cell-derived factor-1 alpha, and tumor necrosis factor-alpha are suggested to be the consequences of SLE disease (Beta: 0.035, p = 0.014; Beta: 0.021, p = 0.032; Beta: 0.024, p = 0.013; Beta: 0.019, p = 0.042; Beta: 0.040, p = 0.005; Beta: 0.046, p = 0.001; Beta: 0.021, p = 0.029; Beta: 0.019, p = 0.045; Beta: 0.029, p = 0.048). This study suggested that CTACK and IL-17 are probably the factors correlated with SLE etiology, while a couple of inflammatory cytokines are more likely to be involved in SLE development downstream.

Xiang M ，Wang Y ，Gao Z ，Wang J ，Chen Q ，Sun Z ，Liang J ，Xu J ... -  《Frontiers in Immunology》

Causal Effects of Gut Microbiome on Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Study.

The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10-8) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that Bacilli and Lactobacillales were positively correlated with the risk of SLE and Bacillales, Coprobacter and Lachnospira were negatively correlated with SLE risk. The results of weighted median method supported that Bacilli, Lactobacillales, and Eggerthella were risk factors for SLE and Bacillales and Coprobacter served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted Ruminiclostridium6 was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that Actinobacteria might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of Ruminiclostridium6 and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.

Xiang K ，Wang P ，Xu Z ，Hu YQ ，He YS ，Chen Y ，Feng YT ，Yin KJ ，Huang JX ，Wang J ，Wu ZD ，Yang XK ，Wang DG ，Ye DQ ，Pan HF ... -  《Frontiers in Immunology》