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 《-》

No evidence of genetic causal association between sex hormone-related traits and systemic lupus erythematosus: A two-sample Mendelian randomization study.

Previous studies have demonstrated an association between sex hormone-related traits and systemic lupus erythematosus (SLE). However, because of the difficulties in determining sequential temporality, the causal association remains elusive. In this study, we used two-sample Mendelian randomization (MR) to explore the genetic causal associations between sex hormone-related traits and SLE. We used a two-sample MR to explore the causal association between sex hormone-related traits and SLE. The summarized data for sex hormone-related traits (including testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), and bioavailable testosterone (BT)) originated from large genome-wide association studies (GWASs) of European descent. Aggregated data for SLE were derived from the FinnGen consortium (835 cases and 300,162 controls). Random-effects inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods were used for the MR analysis. Random-effects IVW was the primary method used to analyze the genetic causal association between sex hormone-related traits and SLE. Heterogeneity of the MR results was detected using the IVW Cochran's Q estimates. The pleiotropy of MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, leave-one-out analysis was performed to determine whether MR results were affected by a single single-nucleotide polymorphism (SNP). Random-effects IVW as the primary method showed that testosterone (odds ratio (OR), 0.87; 95% confidence interval (CI), 0.41-1.82; P = 0.705), E2 (OR, 0.95; 95% CI, 0.73-1.23; P = 0.693), SHBG (OR, 1.25; 95% CI, 0.74-2.13; P = 0.400), and BT (OR, 0.99; 95% CI, 0.67-1.47; P = 0.959) had no potential causal association with SLE. The MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods all indicated consistent results. The results of the MR-Egger regression showed that there was no pleiotropy in our MR analysis (P > 0.05). The IVW Cochran's Q estimates showed that the MR analysis results of E2, SHBG, and BT on SLE had no heterogeneity (P > 0.05), but testosterone and SLE had heterogeneity (P < 0.05). The leave-one-out analysis confirmed that a single SNP did not affect the MR results. Our MR analysis demonstrated that genetically predicted testosterone, E2, SHBG, and BT levels were not associated with SLE risk, but the roles of other non-genetic pathways cannot be ruled out. Key Points • This is the first MR study to explore the causal association of sex hormone-related traits with SLE. • No evidence to support causal associations between sex hormone-related traits and SLE. • Our MR analysis may provide novel insights into the causal association between sex hormone-related traits and SLE risk.

Yuan G ，Yang M ，Xie J ，Xu K ，Zhang F ... -  《-》

Systemic lupus erythematosus is causally associated with hypothyroidism, but not hyperthyroidism: A Mendelian randomization study.

The relationship between systemic lupus erythematosus (SLE) and thyroid diseases is still controversial. Due to confounders and reverse causation, previous studies were not convincing. We aimed to investigate the relationship between SLE and hyperthyroidism or hypothyroidism by Mendelian randomization (MR) analysis. We performed a two-step analysis using bidirectional two-sample univariable and multivariable MR (MVMR) to explore the causality of SLE and hyperthyroidism or hypothyroidism in three genome-wide association studies (GWAS) datasets, including 402,195 samples and 39,831,813 single-nucleotide polymorphisms (SNPs). In the first step analysis, with SLE as exposure and thyroid diseases as outcomes, 38 and 37 independent SNPs strongly (P < 5*10-8) associated with SLE on hyperthyroidism or SLE on hypothyroidism were extracted as valid instrumental variables (IVs). In the second step analysis, with thyroid diseases as exposures and SLE as outcome, 5 and 37 independent SNPs strongly associated with hyperthyroidism on SLE or hypothyroidism on SLE were extracted as valid IVs. In addition, MVMR analysis was performed in the second step analysis to eliminate the interference of SNPs that were strongly associated with both hyperthyroidism and hypothyroidism. 2 and 35 valid IVs for hyperthyroidism on SLE and hypothyroidism on SLE were obtained in MVMR analysis. MR results of two steps analysis were estimated respectively by multiplicative random effects-inverse variance weighted (MRE-IVW), simple mode (SM), weighted median (WME) and MR-Egger regression methods. Sensitivity analysis and visualization of MR results were performed by heterogeneity test, pleiotropy test, leave-one-out test, scatter plots, forest plots and funnel plots. The MRE-IVW method in the first step of MR analysis revealed that SLE was causally associated with hypothyroidism (OR = 1.049, 95% CI = 1.020-1.079, P < 0.001), but not causally associated with hyperthyroidism (OR = 1.045, 95% CI = 0.987-1.107, P = 0.130). In the inverse MR analysis, the MRE-IVW method revealed that both hyperthyroidism (OR = 1.920, 95% CI = 1.310-2.814, P < 0.001) and hypothyroidism (OR = 1.630, 95% CI = 1.125-2.362, P = 0.010) were causally associated with SLE. Results from other MR methods were consistent with MRE-IVW. However, when MVMR analysis was performed, there was no longer a causal relationship of hyperthyroidism on SLE (OR = 1.395, 95% CI = 0.984-1.978, P = 0.061), nor was there a causal relationship of hypothyroidism on SLE (OR = 1.290, 95% CI = 0.823-2.022, P = 0.266). The stability and reliability of the results were confirmed by sensitivity analysis and visualization. Our univariable and multivariable MR analysis revealed that systemic lupus erythematosus was causally associated with hypothyroidism, but did not provided evidence to support a causal relationship of hypothyroidism on SLE or between SLE and hyperthyroidism.

Qin Q ，Zhao L ，Ren A ，Li W ，Ma R ，Peng Q ，Luo S ... -  《Frontiers in Immunology》

Investigating the causal association between systemic lupus erythematosus and migraine using Mendelian randomization analysis.

To assess whether systemic lupus erythematosus (SLE) may be genetically causally associated with migraine, including the two primary subtypes: migraine with aura (MWA) and migraine without aura (MWoA). The association between SLE and migraine has been investigated extensively. Previous studies have shown a higher prevalence of migraine in patients with SLE, although the exact relationship remains unclear. This study investigated the potential causal association between SLE and migraine using the powerful analytical tool of Mendelian randomization (MR). We performed two-sample MR analysis of publicly available summary statistic datasets using inverse variance-weighted (IVW), weighted median, and MR-Egger methods based on an SLE genome-wide association study (GWAS; 5201 cases; 9066 controls; the exposure frequency is 36.5%) as an exposure and migraine GWAS (15,905 cases; 264,662 controls) in individuals with European ancestry as outcomes, focusing on the two migraine subtypes MWA (6780 cases; 264,662 controls) and MWoA (5787 cases; 264,662 controls). Thepleiotropy and heterogeneity were performed. We selected 42 single-nucleotide polymorphisms from SLE GWAS as instrumental variables (IVs) for SLE on migraine, and 41 SNP IVs for SLE on MWA or MWoA. The IVW (odds ratio [OR] = 1.01, 95% confidence interval [CI] = [0.99, 1.03], p = 0.271), weighted median (OR = 1.00, 95% CI = [0.97, 1.03], p = 0.914), and MR-Egger (OR = 1.04, 95% CI = [0.99, 1.09], p = 0.153) methods showed no causal effect of SLE on migraine. A causal effect of SLE was observed on MWA (IVW: OR = 1.05, 95% CI = [1.02, 1.08], p = 0.001; weighted median: OR = 1.05, 95% CI = [1.01, 1.10], p = 0.018; MR-Egger: OR = 1.07, 95% CI = [1.01, 1.14], p = 0.035 and pIVW < 0.017 [Bonferroni correction]) but not MWoA (IVW: OR = 0.99, 95% CI = [0.96, 1.02], p = 0.331; weighted median: OR = 0.98, 95% CI = [0.94, 1.03], p = 0.496; MR-Egger: OR = 1.02, 95% CI = [0.95, 1.09], p = 0.652). The results showed no significant pleiotropy or heterogeneity. Our MR analysis demonstrated the complex relationship between SLE and migraine, suggesting a potential effect of SLE on the risk of MWA but not MWoA. These findings can aid in the development of improved subtype-specific management of migraine in patients with SLE.

Xu D ，Wu B 《-》

Causal association between systemic lupus erythematosus and the risk of dementia: A Mendelian randomization study.

It is well-documented that systemic lupus erythematosus (SLE) is associated with dementia. However, the genetic causality of this association remains unclear. Mendelian randomization (MR) was used to investigate the potential causal relationship between SLE and dementia risk in the current study. We selected 45 single nucleotide polymorphisms (SNPs) associated with SLE from publicly available genome-wide association studies (GWAS). Summary level statistics were obtained from the dementia GWAS database. MR estimates were performed using the inverse variance weighted (IVW) method, MR-Egger method and weighted median (WM) method. Cochran's Q test, the intercept of MR-Egger, MR-Pleiotropy Residual Sum and Outlier method, leave-one-out analysis and funnel plot were applied for sensitivity analyses. No significant causal association was found between SLE and any type of dementia, including Alzheimer's disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. These findings were robust across several sensitivity analyses. Overall, our findings do not support a causal association between SLE and dementia risk.

Jin T ，Huang W ，Cao F ，Yu X ，Guo S ，Ying Z ，Xu C ... -  《Frontiers in Immunology》