Causal association of blood lipids with all-cause and cause-specific mortality risk: a Mendelian randomization study.

Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89-0.97], P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01-1.04], P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.

Integrating plasma proteomes with genome-wide association data for causal protein identification in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover novel therapeutic targets. METHODS: First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively. RESULTS: We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR [95% CI]: 1.35 [1.18, 1.55]), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 [1.06, 1.22]), neutrophil cytosol factor 2 (NCF2; 1.27 [1.12, 1.44]), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 [0.86, 0.94]), Fc-gamma receptor III-B (FCGR3B; 0.75 [0.65,0.86]), glypican-1 (GPC1; 0.69 [0.58,0.83]), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): - 0.349), NAMPT (MIP:0.433; MACE: - 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points. CONCLUSIONS: Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development.

Association between antihypertensive drugs and hepatocellular carcinoma: A trans-ancestry and drug-target Mendelian randomization study.

BACKGROUND AND AIMS: Antihypertensive drugs were recently reported to have an oncogenic role in common cancer, however, whether these drugs would affect the risk of hepatocellular carcinoma (HCC) remains unclear. METHODS: A drug-target Mendelian randomization method was adopted to examine the long-term effect of 12 antihypertensive drugs classes on the risk of HCC in Europeans and East Asians. To proxy antihypertensive drugs, we leveraged genetic variants located near or within drug target genes that were associated with systolic blood pressure (SBP). Genetically proxied drugs associated with reduced risk of coronary artery disease were included in primary analysis. Genetic summary statistics of SBP and HCC were derived from publicly available large-scale genome-wide association studies in Europeans and East Asians respectively. Expression quantitative trait loci (eQTLs) of drugs target genes were used to proxy drugs in a sensitivity analysis. RESULTS: Genetically proxied thiazides and related diuretics were associated with decreased risk of HCC in both Europeans (OR [95% CI]: 0.79 [0.73, 0.86] per 1 mmHg reduction in SBP; p < 0.001) and East Asians (0.60 [0.45, 0.82]; p = 0.001). Genetically proxied beta-adrenoceptor blockers (BBs) were strongly associated with increased risk of HCC in Europeans (1.46 [1.12, 1.91]; p = 0.004). These findings were replicated in deCODE genetics study and remained consistent when using eQTLs to proxy antihypertensive drugs. CONCLUSIONS: Our findings suggested that thiazides diuretics may lower the risk of HCC in both Europeans and East Asians, while BBs may increase the risk of HCC specifically in Europeans. Further studies are warranted to explore the potential of repurposing or retargeting antihypertensive drugs for HCC prevention.

Causal relationships between inflammatory factors and multiple myeloma: A bidirectional Mendelian randomization study.

Changes in serum inflammatory factors occur throughout the onset and multiple myeloma (MM) progression, the feedback loops make it harder to distinguish between causes and effects. In the present study, we performed a bidirectional summary-level Mendelian randomization (MR) analysis to elucidate the causal relationships of C-reactive protein (CRP) and inflammatory regulators with MM. Summary-level data of genetic variants associated with inflammation were extracted from two genome-wide association studies (GWASs) on CRP and human cytokines, while data on MM was from large meta-analyses of GWASs among 372 617 UK Biobank participants. The inverse-variance weighted (IVW) method was used as the primary MR analysis and MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were used as the sensitivity analyses. Our results suggested that higher levels of monocyte-specific chemokine-3 (IVW estimate odds ratio [ORIVW ] per SD genetic cytokines change: 1.24; 95% confidence interval [CI]: 1.03-1.49; P = .02), vascular endothelial growth factor (1.14, 1.03-1.27; P = .02), interleukin-10 (1.33, 1.01-1.75; P = .04) and interleukin-7 (1.24, 1.03-1.48; P = .02) were associated with increased risk of MM, while lower levels of tumor necrosis factor-ß (0.84, 0.74-0.92; P < .001) was strongly associated with an increased risk of MM. And conversely, genetically predicted MM was related to increased levels of interleukin-17 (IVW estimate ß: 0.051, 95% CI: 0.018-0.085; P = 2.7 × 10-3 ). Besides, we observed no such significant associations for other inflammatory factors in our study. Overall, our study provides genetic evidence on the relationships of CRP and systemic inflammatory regulators with MM. Targeted interventions of specific inflammatory factors may have implications to alleviate MM cancer risk.

Differential phase measurement based on synchronous phase shift determination.

Based on synchronous phase shift determination, we propose a differential phase measurement method for differential interference contrast (DIC) microscopy. An on-line phase shift measurement device is used to generate carrier interferograms and determine the phase shift of DIC images. Then the differential phase can be extracted with the least-squares phase-shifting algorithm. In addition to realizing on-line, dynamic, real-time, synchronous and high precision phase shift measurement, the proposed method also can reconstruct the phase of the specimen by using the phase-integral algorithm. The differential phase measurement method reveals obvious advantages in error compensation, anti-interference, and noise suppression. Both simulation analysis and experimental result demonstrate that using the proposed method, the accuracy of phase shift measurement is higher than 0.007 rad. Very accurate phase reconstructions were obtained with both polystyrene microspheres and human vascular endothelial.

Fewer Basins Will Follow Their Budyko Curves Under Global Warming and Fossil-Fueled Development.

The Budyko framework consists of a curvilinear relationship between the evaporative ratio (i.e., actual evaporation over precipitation) and the aridity index (i.e., potential evaporation over precipitation) and defines evaporation's water and energy limits. A basin's movement within the Budyko space illustrates its hydroclimatic change and helps identify the main drivers of change. On the one hand, long-term aridity changes drive evaporative ratio changes, moving basins along their Budyko curves. On the other hand, historical human development can cause river basins to deviate from their curves. The question is if basins will deviate or follow their Budyko curves under the future effects of global warming and related human developments. To answer this, we quantify the movement in the Budyko space of 405 river basins from 1901-1950 to 2051-2100 based on the outputs of seven models from the Coupled Model Intercomparison Project - Phase 6 (CMIP6). We account for the implications of using different potential evaporation models and study low- and high-emissions scenarios. We find considerable differences of movement in Budyko space regarding direction and intensity when using the two estimates of potential evaporation. However, regardless of the potential evaporation estimate and the scenario used, most river basins will not follow their reference Budyko curves (>72%). Furthermore, the number of basins not following their curves increases under high greenhouse gas emissions and fossil-fueled development SP585 and across dry and wet basin groups. We elaborate on the possible explanations for a large number of basins not following their Budyko curves.

Discovery of a Novel Thienopyrimidine Compound as a Urate Transporter 1 and Glucose Transporter 9 Dual Inhibitor with Improved Efficacy and Favorable Druggability.

Gout and hyperuricemia are metabolic diseases characterized with high serum uric acid (SUA) levels that significantly impact human health. Lesinurad, a uricosuric agent, is limited to concurrent use with xanthine oxidase inhibitors (XOIs) in clinical practice due to its restricted efficacy and potential nephrotoxicity. Herein, extensive structural modifications of lesinurad were conducted through scaffold hopping and substituent modification strategies, affording 54 novel derivatives containing pyrimidine-fused cyclic structures. Notably, the thienopyrimidine compound 29 demonstrated a remarkable 2-fold increase in SUA-lowering in vivo activity compared to lesinurad, while exhibiting potent inhibitory activity against the urate transporter 1 (URAT1, IC50 = 2.01 µM) and glucose transporter 9 (GLUT9, IC50 = 18.21 µM). Furthermore, it possessed a lower effective dosage of 0.5 mg/kg, favorable safety profile without any apparent acute toxicity at doses of 1000 mg/kg, and improved pharmacokinetic properties. Overall, we have discovered an efficacious URAT1/GLUT9 dual inhibitor for inhibiting urate reabsorption with favorable pharmacokinetic profiles.

Women's reproductive traits and cerebral small-vessel disease: A two-sample Mendelian randomization study.

Background: Observational studies have suggested that women's reproductive factors (age at menarche (AAM), age at first birth (AFB), age at first sexual intercourse (AFS), age at natural menopause (ANM), and pregnancy loss) may influence the risk of cerebral small-vessel disease (CSVD) although the causality remains unclear. Methods: We conducted two-sample univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) to simultaneously investigate the causal relationships between five women's reproductive traits and CSVD clinical [intracerebral hemorrhage (ICH) by location or small-vessel ischemic stroke (SVS)] and subclinical measures [white matter hyperintensities (WMH), fractional anisotropy (FA), and mean diffusivity (MD)], utilizing data from large-scale genome-wide association studies of European ancestry. For both UVMR and MVMR, the inverse-variance-weighted (IVW) estimates were reported as the main results. The MR-Egger, weighted median, generalized summary-data-based MR (GSMR), and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods for UVMR and MVMR-Egger, and the MVMR-robust methods for MVMR were used as sensitivity analyses. Sex-combined instruments for AFS and AFB were used to assess the impact of sex instrumental heterogeneity. Positive control analysis was implemented to measure the efficacy of selected genetic instruments. Results: We found no evidence to support causal associations between genetic liability for women's reproductive factors and the risk of CSVD in UVMR (all P-values > 0.05). Using MVMR, the results were consistent with the findings of UVMR after accounting for body mass index and educational attainment (all P-values > 0.05). Sensitivity analyses also provided consistent results. The putative positive causality was observed between AAM, ANM, and ovarian cancer, ensuring the efficacy of selected genetic instruments. Conclusion: Our findings do not convincingly support a causal effect of women's reproductive factors on CSVD. Future studies are warranted to investigate specific estrogen-related physiological changes in women, which may inform current researchers on the causal mechanisms involved in cerebral small-vessel disease progression.

Protective effects of Althaea officinalis L. extract against N-diethylnitrosamine-induced hepatocellular carcinoma in male Wistar rats through antioxidative, anti-inflammatory, mitochondrial apoptosis and PI3K/Akt/mTOR signaling pathways.

Hepatocellular carcinoma is the fourth cause of death due to cancer and includes 90% of liver tumors. Therefore, in this study, it was tried to show that Althaea officinalis L. flower extract (ALOF) can protect hepatocytes against N-diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Totally, 70 Wistar rats were divided into seven groups (n = 10/group) of sham, DEN, treatment with silymarin (SIL; DEN + SIL), treatment with ALOF (DEN + 250 and 500 ALOF), and cotreatment with SIL and ALOF (DEN + SIL + 250 and 500 ALOF). At the end of the study, the serum levels of liver indices (albumin, total protein, bilirubin, C-reactive protein, ALT, AST, and ALP), inflammatory cytokines (IL-6, IL-1ß, IL-10, and TNF-α), and oxidants parameters (glutathione peroxidase [GPx], superoxide dismutase [SOD], catalase [CAT] activity along with nitric oxide [NO] levels) were evaluated. The level of Bax, Bcl-2, Caspase-3, p53, PI3K, mTOR, and AKT genes were measured. ALOF in cotreatment with SIL was able to regulate liver biochemical parameters, improve serum antioxidant indices, and decrease the level of proinflammatory cytokines significantly (p < .05). ALOF extract in both doses of 250 and 500 mg/kg in cotreatment with SIL caused a significant (p < .05) decrease in the p53-positive cells and a significant (p < .05) increase in Bcl-2-positive cells. Therefore, ALOF was able to modulate the proliferation of cancer cells and protect normal cells through the regulation of Bax/Bcl-2/p53 and PI3K/Akt/mTOR signaling pathways. It seems that ALOF can be used as a prodrug or complementary treatment in the protection of hepatocytes in induced damages caused by carcinogens.

Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study.

Background: Increasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses. Methods: We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis. Results: Our results showed that genetically predicted higher stem cell growth factor-ß (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra). Conclusions: Our MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.

Women's reproductive traits and major depressive disorder: A two-sample Mendelian randomization study.

BACKGROUND: Evidence suggested strong associations between women's reproductive factors and major depressive disorder (MDD), but their causalities are unclear. METHODS: Using female-specific SNPs as genetic instruments obtained from large-scale genome-wide association studies for women's reproductive traits, we designed two-sample univariable and multivariable Mendelian randomization (MR) analysis to evaluate the causal effects of women's reproductive traits on MDD. For both univariable MR (UVMR) and multivariable MR (MVMR), the inverse variance weighting estimates were reported as main results. MR-Egger, weighted median, and generalized summary-data-based MR (GSMR) methods for UVMR, and MVMR-Egger and MVMR-robust methods for MVMR were used as sensitivity analyses. Negative control analyses, MVMR of age at first birth (AFB) and age at first sexual intercourse (AFS) on MDD, and sex-combined genetic variants for AFB and AFS were performed to enhance the robustness of our study. RESULTS: There was substantial evidence for associations of genetically predicted later age at menarche (AAM) (odds ratio (OR) = 0.97, 95 % confidence interval (CI) = 0.94-0.99, P = 0.007), AFB (OR = 0.91, 95 % CI = 0.86-0.97, P = 0.002) and AFS (OR = 0.70, 95 % CI = 0.60-0.80, P < 0.001) with lower MDD risk in UVMR. After adjustment of BMI and educational attainment using MVMR, we found consistently significant causal effects of AAM (OR = 0.95, 95 % CI = 0.92-0.99, P = 0.006), AFB (OR = 0.88, 95 % CI = 0.84-0.91, P < 0.001) and AFS (OR = 0.71, 95 % CI = 0.64-0.79, P < 0.001) on MDD. CONCLUSIONS: Our results provide compelling evidence that early AAM, AFB, and AFS are risk factors for MDD. Promoting the cognition of reproductive health care for women may reduce the risk of MDD.

Women's reproductive traits and ischemic stroke: a two-sample Mendelian randomization study.

OBJECTIVE: We conducted a Mendelian randomization (MR) study to disentangle causal associations between women's reproductive behaviors and ischemic stroke (IS) and investigate the roles of two modifiable risk factors (body mass index (BMI) and educational attainment (EA)) in these associations. METHODS: Using summary-level data from large-scale genome-wide association studies, we performed univariable MR to examine whether there is genetic evidence that women's reproductive traits are causally associated with IS and its subtypes. Multivariable MR and MR mediation analysis were used to investigate whether BMI and EA are common mechanisms or mediators for these associations. A set of sensitivity analyses were conducted to test valid MR assumptions. RESULTS: We observed consistent and statistically significant associations across female and sex-combined analyses for earlier age at first birth (AFB) and age at first sexual intercourse (AFS) with a higher risk of IS and large-artery atherosclerotic stroke (LAS) risk in the primary analysis. The odds ratios of IS per 1 SD increase in genetically predicted early AFB and AFS were 0.93 (95% CI, 0.86-0.99; p = 0.046) and 0.83 (95% CI, 0.70-0.97, p = 0.020), respectively. Further analyses indicated that BMI played a shared role in AFS and IS/LAS while EA played a shared role in AFS/AFB and IS/LAS as well as a mediator in the path from AFS to IS/LAS. INTERPRETATION: These findings may inform prevention strategies and interventions directed toward relative women's reproductive behaviors and IS. Future studies are warranted to explore other factors related to EA which are responsible for these causalities.

Experimental and Numerical Investigation on the Aerosol Micro-Jet 3D Printing of Flexible Electronic Devices.

In this study, the optimal forming parameters for printing flexible circuits using aerosol jet printing technology are explored through numerical simulation and experiments. The printhead during the deposition process is numerically simulated. By employing the controlled variable method, the process parameters such as gas flow rate, working distance, nozzle diameter, and printing speed are selected to investigate their effects on the morphology of the printed lines. Accordingly, single-factor experiments are designed to validate the printing of flexible circuits on both planar and curved substrates. Laser micro-sintering is utilized to improve the conductivity of the printed lines and ultimately fabricate flexible strain sensors. Under the sheath gas flow rate of 400 sccm, carrier gas flow rate of 100 sccm, working distance of 3 mm, nozzle diameter of 500 µm, and printing speed of 10 mm/s, the optimal morphology of the printed lines is achieved with low linewidth characteristics. The variations in the focal ratio, working distance, nozzle diameter, and printing speed significantly affect the minimum feature line width and morphology of the printed lines.

Mendelian randomization and colocalization analyses reveal an association between short sleep duration or morning chronotype and altered leukocyte telomere length.

Observational studies suggest certain sleep traits are associated with telomere length, but the causal nature of these associations is unclear. The study aimed to determine the causal associations between 11 sleep-related traits and leukocyte telomere length (LTL) through two-sample Mendelian randomization and colocalization analyses using the summary statistics from large-scale genome-wide association studies. Univariable Mendelian randomization indicates that genetically determined short sleep is associated with decreased LTL, while morning chronotype is associated with increased LTL. Multivariable Mendelian randomization further supports the findings and colocalization analysis identifies shared common genetic variants for these two associations. No genetic evidence is observed for associations between other sleep-related traits and LTL. Sensitivity MR methods, reverse MR and re-running MR after removing potential pleiotropic genetic variants enhance the robustness of the results. These findings indicate that prioritizing morning chronotype and avoiding short sleep is beneficial for attenuating telomere attrition. Consequently, addressing sleep duration and chronotype could serve as practical intervention strategies.

Discriminating the impacts of vegetation greening and climate change on the changes in evapotranspiration and transpiration fraction over the Yellow River Basin.

Evapotranspiration (ET) is a vital parameter in terrestrial water-energy cycles. The transpiration fraction (TF) is defined as the ratio of transpiration (T) to evapotranspiration (ET), representing the contribution rate of vegetation transpiration to ecosystem ET. Quantifying the relative contributions of vegetation and climate change on the ET and TF dynamic is of great significance to better understand the water budget between the land and atmosphere. Here, we chose Yellow River Basin (YRB) as the study area and analyzed the spatiotemporal changes of ET, T, and TF from 1982 to 2015 using the Priestley-Taylor Jet Propulsion Laboratory (PT-JPL) model. Meanwhile, the relative contributions of vegetation and climate change to ET, T and TF change were quantified. Model evaluation showed that the PT-JPL model performs well in the simulation of ET and T. During 1982-2015, the average annual ET, T, and TF increased at a rate of 3.20 mm/a, 0.77 mm/a and 0.003/a over the YRB during 1982-2015, respectively. The regions with significant increases in ET, T and TF almost covered the whole study area except for the upper reaches of the YRB. Vegetation greening was the main factor for the increase of ET and TF in the YRB and enhanced ET and TF at a rate of 0.72 mm/a and 0.57/a, respectively, which mainly observed in the entire Loess Plateau region (over 50 % of the study area). Precipitation (PRE) was also the dominated factor contributing to the increase in ET and TF, and temperature (TEM) showed a positive correlation with the changes in ET and TF in the most areas of YRB, which jointly dominated ET changes in the upper reaches of the YRB and TF changes in the southern part of the basin. Except for the total effects, leaf area index (LAI) also indirectly promoted ET changes by affecting PRE, TEM and relative humidity (RH). While wind speed (WS) and radiation (RAD) had a relatively weak regulatory effect on the changes in ET and TF. These findings were helpful for regional water resources management and formulating water resources-sustainable vegetation restoration strategies for local government.

Effects of metabolic factors in mediating the relationship between Type 2 diabetes and depression in East Asian populations: A two-step, two-sample Mendelian randomization study.

BACKGROUND: Observational studies suggested a close link between type 2 diabetes (T2D), metabolic factors and depression, while the causal relationships remained poorly understood. OBJECTIVE: To determine the causality between T2D and depression, and to investigate the roles of metabolic factors in mediating the relationship between T2D and depression in East Asians. METHODS: Using summary statistics from the largest and most up-to-date genome-wide association studies of depression (12,588 cases and 85,914 controls) and T2D (36,614 cases and 155,150 controls) among East Asians, two-step and two-sample MR analyses were performed to estimate the causal mediation effects of metabolic factors including lipid profiles, blood pressure (BP) and fasting insulin (FI) on the relationship between T2D and depression. RESULTS: Genetically predicted T2D was significantly associated with depression (OR [95 % CI]:1.06 [1.01, 1.11], P = 0.043), but not vice versa. T2D was causally associated with lower levels of HDL-C and higher levels of LDL-C, triglycerides (TG), BP and FI. Furthermore, the causal effects of T2D on depression were significantly mediated by LDL-C (ß [95 % CI]: -0.003 [-0.005, -0.001], P = 0.007), and suggestively mediated by TG (0.001 [0.001, 0.003], P = 0.049) and FI (0.006 [0.001, 0.012], P = 0.049). LIMITATIONS: First, depression was defined by several methods, like symptom questionnaires or self-completed surveys. Second, two-sample MR approach is unable to detect the non-linear causal relationships. Third, independent data sets were not available for replication of our findings. CONCLUSION: T2D was causally associated with the risk of depression, and LDL-C, TG, and FI were potential causal mediators of the effect of T2D on depression. Understanding the causality among T2D, metabolic factors and depression is crucial for identifying potential targets for early intervention.

Investigating linear and nonlinear associations of LDL cholesterol with incident chronic kidney disease, atherosclerotic cardiovascular disease and all-cause mortality: A prospective and Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies suggest potential nonlinear associations of low-density lipoprotein cholesterol (LDL-C) with cardio-renal diseases and mortality, but the causal nature of these associations is unclear. We aimed to determine the shape of causal relationships of LDL-C with incident chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality, and to evaluate the absolute risk of adverse outcomes contributed by LDL-C itself. METHODS: Observational analysis and one-sample Mendelian randomization (MR) with linear and nonlinear assumptions were performed using the UK Biobank of >0.3 million participants with no reported prescription of lipid-lowering drugs. Two-sample MR on summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen (N = 625,219) was employed to replicate the relationship for kidney traits. The 10-year probabilities of the outcomes was estimated by integrating the MR and Cox models. RESULTS: Observationally, participants with low LDL-C were significantly associated with a decreased risk of ASCVD, but an increased risk of CKD and all-cause mortality. Univariable MR showed an inverse total effect of LDL-C on incident CKD (HR [95% CI]:0.84 [0.73-0.96]; p = 0.011), a positive effect on ASCVD (1.41 [1.29-1.53]; p<0.001), and no significant causal effect on all-cause mortality. Multivariable MR, controlling for high-density lipoprotein cholesterol (HDL-C) and triglycerides, identified a positive direct effect on ASCVD (1.32 [1.18-1.47]; p<0.001), but not on CKD and all-cause mortality. These results indicated that genetically predicted low LDL-C had an inverse indirect effect on CKD mediated by HDL-C and triglycerides, which was validated by a two-sample MR analysis using summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen consortium (N = 625,219). Suggestive evidence of a nonlinear causal association between LDL-C and CKD was found. The 10-year probability curve showed that LDL-C concentrations below 3.5 mmol/L were associated with an increased risk of CKD. CONCLUSIONS: In the general population, lower LDL-C was causally associated with lower risk of ASCVD, but appeared to have a trade-off for an increased risk of CKD, with not much effect on all-cause mortality. LDL-C concentration below 3.5 mmol/L may increase the risk of CKD.