Genetically Predicted Serum Iron Status Is Associated with Altered Risk of Systemic Lupus Erythematosus among European Populations.

Observational epidemiological studies have reported an inconsistent relation between iron status and risk of systemic lupus erythematosus (SLE). Moreover, it remains uncertain whether the observed association is causal or due to confounding or reverse causality. We aimed to investigate the association between serum iron status and risk of SLE using a 2-sample Mendelian randomization (MR) approach. Genetic instruments for iron status including serum iron, log-transformed ferritin, transferrin saturation, and transferrin were identified from a large-scale genome-wide association study (GWAS) performed by the Genetics of Iron Status Consortium among 48,972 individuals of European ancestry (55% female). Three independent single nucleotide polymorphisms (rs1800562, rs1799945, and rs855791) concordantly related with 4 iron status biomarkers were selected as instrumental variables. Summary statistics of SLE were obtained from a publicly available GWAS of 4036 patients with SLE and 6959 controls of European descent. The MR study was conducted using the inverse-variance weighted (IVW) method, supplemented with MR-Egger regression and simple- and weighted-median methods. Leave-one-out analysis was further performed to test the robustness of our findings. ORs with 95% CIs were calculated. Genetically predicted iron status was associated with altered risk of SLE, with ORs of 0.79 (95% CI: 0.66, 0.94), 0.54 (95% CI: 0.34, 0.85), 0.82 (95% CI: 0.71, 0.94), and 1.36 (95% CI: 1.06, 1.76) per 1-SD increase in iron, log-transformed ferritin, transferrin saturation, and transferrin using the IVW method, respectively. MR-Egger regression did not indicate potential pleiotropic bias. Sensitivity analyses produced similar findings, suggesting the robustness of the association. Our study suggested that high iron status may be associated with a reduced risk of SLE among European populations. Further studies are warranted to elucidate the mechanism underlying the protective role of iron against susceptibility to SLE.

Ye D ，Zhu Z ，Huang H ，Sun X ，Liu B ，Xu X ，He Z ，Li S ，Wen C ，Mao Y ... -  《-》

Genetically predicted iron status was associated with the risk of prostate cancer.

Observational studies have reported a relationship between iron status and the risk of prostate cancer. However, it remains uncertain whether the association is causal or due to confounding or reverse causality. To further clarify the underlying causal relationship, we conducted a Mendelian randomization (MR) analysis. We selected three genetic variants (rs1800562, rs1799945, and rs855791) closely correlated with four iron status biomarkers (serum iron, log-transformed ferritin, transferrin saturation, and transferrin) as instrumental variables. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium including 79,148 cases and 61,106 controls of European ancestry. The inverse-variance weighted (IVW) method was conducted primarily to estimate the association of genetically predicted iron status and the risk of prostate cancer, supplemented with simple-median, weighted-median and maximum-likelihood methods as sensitivity analysis. MR-Egger regression was used to detect directional pleiotropy. We also conducted a meta-analysis of observational studies to assess the associations between iron status and the risk of prostate cancer. Genetically predicted increased iron status was associated with the decreased risk of prostate cancer, with odds ratio of 0.91 [95% confidence interval (CI): 0.84, 0.99; P = 0.035] for serum iron, 0.81 (95% CI: 0.65, 1.00; P = 0.046) for log- transformed ferritin, 0.94 (95% CI: 0.88, 0.99; P = 0.029) for transferrin saturation, and 1.15 (95% CI: 0.98, 1.35; P = 0.084) for transferrin (with higher transferrin levels representing lower systemic iron status), using the inverse-variance weighted method. Sensitivity analyses produced consistent associations, and MR-Egger regression indicated no potential pleiotropy. Our replication analysis based on FinnGen research project showed compatible results with our main analysis. Results from our meta-analysis similarly showed that serum ferritin [standardized mean difference (SMD): -1.25; 95% CI: -2.34, -0.16; P = 0.024] and transferrin saturation (SMD: -1.19; 95% CI: -2.34, -0.05; P = 0.042) were lower in patients with prostate cancer compared with that in controls. Our study suggests a protective role of iron in the risk of prostate cancer, further investigations are required to clarify the underlying mechanisms.

Ying J ，Wang B ，Han S ，Song J ，Liu K ，Chen W ，Sun X ，Mao Y ，Ye D ... -  《Frontiers in Oncology》

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 ... -  《-》

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 《-》

Alcohol intake and risk of systemic lupus erythematosus: a Mendelian randomization study.

Bae SC ，Lee YH 《-》