Iron status and obesity-related traits: A two-sample bidirectional Mendelian randomization study.

The association between iron status and obesity-related traits is well established by observational studies, but the causality is uncertain. In this study, we performed a two-sample bidirectional Mendelian randomization analysis to investigate the causal link between iron status and obesity-related traits. The genetic instruments strongly associated with body mass index (BMI), waist-hip ratio (WHR), serum ferritin, serum iron, transferrin saturation (TSAT), and total iron-binding capacity (TIBC) were obtained through a series of screening processes from summary data of genome-wide association studies (GWAS) of European individuals. We used numerous MR analytical methods, such as inverse-variance weighting (IVW), MR-Egger, weighted median, and maximum likelihood to make the conclusions more robust and credible, and alternate methods, including the MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis to evaluate the horizontal pleiotropy and heterogeneities. In addition, the MR-PRESSO and RadialMR methods were utilized to identify and remove outliers, eventually achieving reduced heterogeneity and horizontal pleiotropy. The results of IVW analysis indicated that genetically predicted BMI was associated with increased levels of serum ferritin (β: 0.077, 95% CI: 0.038, 0.116, P=1.18E-04) and decreased levels of serum iron (β: -0.066, 95% CI: -0.106, -0.026, P=0.001) and TSAT (β: -0.080, 95% CI: -0.124, -0.037, P=3.08E-04), but not associated with the levels of TIBC. However, the genetically predicted WHR was not associated with iron status. Genetically predicted iron status were not associated with BMI and WHR. In European individuals, BMI may be the causative factor of serum ferritin, serum iron, and TSAT, but the iron status does not cause changes in BMI or WHR.

Zhou Z ，Zhang H ，Chen K ，Liu C ... -  《Frontiers in Endocrinology》

Iron Status and NAFLD among European Populations: A Bidirectional Two-Sample Mendelian Randomization Study.

Liu C ，Chen Y ，Zhang Z ，Xie J ，Yu C ，Xu L ，Li Y ... -  《Nutrients》

Evidence for genetic causality between iron homeostasis and Parkinson's disease: A two-sample Mendelian randomization study.

Parkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence. We used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors. By coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ β = - 0.524; 95%cl=-0.046 to -0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (β=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (β=-0.387; 95%Cl=-1.179-0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (β=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (β=-0.101; 95%Cl=--0.987 to -0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test. Our study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.

Chen H ，Wang X ，Chang Z ，Zhang J ，Xie D ... -  《-》

Genetic Causal Association between Iron Status and Osteoarthritis: A Two-Sample Mendelian Randomization.

Xu J ，Zhang S ，Tian Y ，Si H ，Zeng Y ，Wu Y ，Liu Y ，Li M ，Sun K ，Wu L ，Shen B ... -  《Nutrients》

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 ... -  《-》