Non-high-density lipoprotein cholesterol levels as a risk factor for short-term mortality in elderly Chinese: a large-scale, population-based cohort study.

OBJECTIVES: To explore the association between non-high-density lipoprotein (non-HDL) and mortality risk, both short-term and long-term, in Chinese people. DESIGN: A prospective cohort study. SETTING: The National Basic Public Health Service (BPHS) in China. PARTICIPANTS: Including 621 164 elderly individuals around Hunan Province who underwent healthcare management receiving check-ups in China BPHS from 2010 to 2020. EXCLUSION CRITERIA: (1) missing information on gender; (2) missing records of lipid screening; (3) missing information on key covariates; and (4) missing records of comorbidities (cardiovascular disease, hypertension, diabetes, cancer.) PRIMARY AND SECONDARY OUTCOME MEASURES: The study's primary endpoint was all-cause and cause-specific mortality, sourced from Hunan's CDC(Center for Disease Control and Prevention)-operated National Mortality Surveillance System, tracking participants until 24 February 2021. RESULTS: 26 758 (4.3%) deaths were recorded, with a median follow-up of 0.83 years. Association between non-HDL and mortality was non-linear after multivariable adjustment, with the optimum concentration (OC) being 3.29 and 4.85 mmol/L. Compared with OC, the risk increased by 1.12-fold for non-HDL <3.29 mmol/L (HR: 1.12 (1.09 to 1.15)) and 1.08-fold for non-HDL ≥4.85 mmol/L (HR: 1.08 (1.02 to 1.13)) for all-cause mortality. Furthermore, there is also an increased risk of cardiovascular mortality (HR for non-HDL <3.29: 1.10 (1.06 to 1.32) and HR for non-HDL ≥4.85: 1.07 (1.01 to 1.14)). However, cancer mortality risk was significantly increased only for non-HDL <3.29 mmol/L (HR: 1.11 (1.04 to 1.18)). Non-optimum concentration of non-HDL had significant effects on both the long-term and the short-term risk of mortality, especially for risks of mortality for all-cause (log HR:0 .086 (0.038 to 0.134)), cardiovascular (log HR:0 .082 (0.021 to 0.144)), and cancer (log HR:0 .187 (0.058 to 0.315)) within 3 months. A two-sided value of p <0.05 was considered to be statistically significant. CONCLUSIONS: Non-HDL was non-linearly associated with the risk of mortality, and non-optimal concentrations of non-HDL significantly increased short-term mortality in elderly Chinese, which needs more attention for cardiovascular disease prevention.

Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes.

AIMS/HYPOTHESIS: This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. METHODS: We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. RESULTS: MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes.

Global burden of type 2 diabetes attributable to non-high body mass index from 1990 to 2019.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) currently was increased in some countries of the world like China. However, the epidemiological trends of T2DM attributable to non-high body mass index (BMI) remain unclear. Thus, we aimed to describe the burden of T2DM attributable to non-high BMI. METHODS: To estimate the burden of T2DM attributable to non-high BMI, data from the Global Burden of Disease Study 2019 were used to calculate the deaths and disability-adjusted life years (DALYs) by age, sex, year, and location. The estimated annual percentage change (EAPC) was applied in the analysis of temporal trends in T2DM from 1990 to 2019. RESULTS: Globally in 2019, the number of death cases and DALYs of T2DM attributable to non-high BMI accounted for 57.9% and 48.1% of T2DM-death from all risks, respectively. Asia accounted for 59.5% and 63.6% of the global non-high-BMI-related death cases and DALYs of T2DM in 2019, respectively. From 1990 to 2019, regions in the low-income experienced a rise in DALYs attributable to non-high BMI. As compared to other age groups, older participants had higher deaths and DALYs of T2DM attributable to non-high BMI. The death and DALY rates of T2DM due to non-high BMI were higher in males and people in regions with low socio-demographic index (SDI) countries. CONCLUSIONS: The burden of T2DM attributable to non-high BMI is higher in the elderly and in people in regions with low- and middle-SDI, resulting in a substantial burden on human health and the social cost of healthcare.

Association of joint exposure to various ambient air pollutants during adolescence with blood pressure in young adulthood.

The association of various air pollutants exposure during adolescence with blood pressure (BP) in young adulthood is uncertain. We intended to evaluate the long-term association of individual and joint air pollutants exposure during adolescence with BP in young adulthood. This cross-sectional study of incoming students was conducted in five geographically disperse universities in China during September and October 2018. Mean concentrations of particulate matter with diameters ≤2.5 µm (PM2.5 ), ≤10 µm (PM10 ), nitrogen dioxides (NO2 ), carbon monoxide (CO), sulfur dioxide (SO2 ), and ozone (O3 ) at participants' residential addresses during 2013-2018 were collected from the Chinese Air Quality Reanalysis dataset. Generalized linear mixed models (GLM) and quantile g-computation (QgC) models were utilized to estimate the association between individual and joint air pollutants exposure and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). A total of 16,242 participants were included in the analysis. The GLM analyses showed that PM2.5 , PM10 , NO2 , CO, and SO2 were significantly positively associated with SBP and PP, while O3 was positively associated with DBP. The QgC analyses indicated that long-term exposure to a mixture of the six air pollutants had a significant positive joint association with SBP and PP. In conclusion, air pollutant co-exposure during adolescence may influence BP in young adulthood. The findings of this study emphasized the impacts of multiple air pollutants interactions on potential health and the need of minimizing pollution exposures in the environment.

Association of long-term ambient fine particulate matter (PM2.5) and incident non-alcoholic fatty liver disease in Chinese adults.

Air pollution is increasingly recognized as an important environmental risk factor for non-alcoholic fatty liver disease (NAFLD). However, epidemiologic evidence on long-term exposure to high air pollution concentrations with incident NAFLD is still very limited. Here, we constructed a population-based dynamic cohort involving 17,106 subjects who were enrolled between 2005 and 2013 and subsequently followed until 2017, combined with a high-resolution ambient fine particulate matter ≤2.5 µm (PM2.5) dataset, to investigate the association of long-term PM2.5 exposure (cumulative annual average levels ranged from 36.67 to 111.16 µg/m3) with NAFLD incidence (N = 4,640). We estimated the adjusted hazard ratio (HR) for incident NAFLD among those exposed to the highest quartile of PM2.5 was 2.04 [95% confidence interval (CI), 1.80-2.30] compared with individuals exposed to the lowest quartile of PM2.5. The dose-response relationships for PM2.5 are non-linear for NAFLD across the exposure distribution. Further stratified analyses revealed that lean (<23 kg/m2), younger (<40-year-old), and women individuals appeared more vulnerable to the harmful effects of PM2.5 exposure. Our study suggests a greater long-term high ambient PM2.5 exposure is associated with an increased risk of NAFLD in Chinese adults, particularly in specific groups, including lean, women, and younger people.

Sepsis as an independent risk factor in atrial fibrillation and cardioembolic stroke.

Background: Electrolyte balance is an important factor to sustain the homeostasis of human body environment and in sepsis pathogenesis. Many current cohort-based studies have already revealed that electrolyte disorder may intensify sepsis and induce stroke. However, the corresponding randomized controlled trials did not show that electrolyte disorder in sepsis has a harmful effect on stroke. Objectives: The aim of this study was to examine the association of genetically sepsis-derived electrolyte disorder with stroke risk using meta-analysis and Mendelian randomization. Results: In four studies (182,980 patients), electrolyte disorders were compared with stroke incidence in patients with sepsis. The pooled odds ratio (OR) of stroke is 1.79 [95% confidence interval (CI): 1.23-3.06; p < 0.05], which shows a significant association between electrolyte disorder and stroke in sepsis patients. Furthermore, in order to evaluate the causal association between stroke risk and sepsis-derived electrolyte disorder, a two-sample Mendelian randomization (MR) study was conducted. The genetic variants extracted from a genome-wide association study (GWAS) of exposure data that are strongly associated with frequently used sepsis were used as instrumental variables (IVs). Based on the IVs' corresponding effect estimates, we estimated overall stroke risk, cardioembolic stroke risk, and stroke induced by large/small vessels from a GWAS meta-analysis with 10,307 cases and 19,326 controls. As a final step to verify the preliminary MR results, we performed sensitivity analysis using multiple types of Mendelian randomization analysis. Conclusion: Our study revealed the association between electrolyte disorder and stroke in sepsis patients, and the correlation between genetic susceptibility to sepsis and increased risk of cardioembolic stroke, hinting that cardiogenic diseases and accompanying electrolyte disorder interference in due course could help sepsis patients get more benefits in stroke prevention.

Gut microbiome and risk of ischaemic stroke: a comprehensive Mendelian randomization study.

AIMS: Increasing evidence implicates the microbiome as a susceptibility factor for ischaemic stroke (IS). Interpretation of this evidence is difficult, for the composition of the microbiome is influenced by various factors and might affect differently in IS subtypes. We aim to determine if the specific gut microbiome is causally associated with IS subtypes and suggest potential approaches for stroke prevention. METHODS AND RESULTS: We conducted a two-sample Mendelian randomization (MR) analysis to test the causal relationship between gut microbiome and IS subtypes. For exposure data, we extracted genetic variants associated with 194 bacterial traits from MiBioGen consortium (n = 18 340). For outcomes, we selected three IS subtypes including cardioembolic stroke (CES, n = 410 484), small vessel stroke (SVS, n = 198 048), and large artery stroke (LAS, n = 198 048). Additionally, we performed a sequence of sensitivity analyses to validate preliminary MR results. There were four, three, and four bacteria showing an increased risk for LAS, SVS, and CES, respectively, and there were five, six, and five bacteria leading a decreasing risk for LAS, SVS, and CES, respectively. Amongst these, the genus_Intestinimonas showed negative associations with LAS [odds ratio (OR) = 0.77, 95% confidence interval (CI) (0.61-0.98)] and SVS (0.85, 0.73-0.98). The genus_LachnospiraceaeNK4A136group was genetically associated with decreased risk of both SVS (0.81, 0.66-0.99) and CES (0.75, 0.60-0.94). CONCLUSION: The study revealed the causal effect of the abundance of specific bacterial features on the risk of IS subtypes. Notably, genus_Intestinimonas and genus_LachnospiraceaeNK4A136group displayed significant protection against more than one IS subtype, further suggesting potential applications of targeted probiotics in IS prevention.

This Mendelian randomization study supports the causal effects of the gut microbiome on ischaemic stroke. Several types of intestinal bacterial traits were detected to potentially increase or decrease the risk of incident ischaemic stroke. These may have prospects for the prevention of different ischaemic stroke subtypes. In addition, the clinical benefits of the gut microbiome should be further evaluated in future large-scale people research.

Age at Menarche Mediating Visceral Adipose Tissue's Influence on Pre-eclampsia: A Mendelian Randomization Study.

CONTEXT: The association between visceral adipose tissue (VAT) and pre-eclampsia (PE) shows inconsistent results and the underlying mediator remains unknown. OBJECTIVE: We aimed to explore the causal effect of VAT on PE risks and the mediation role of age at menarche (AAM) in explaining this relationship. METHODS: Summary data for PE were obtained from the FinnGen genome-wide association study (3556 cases and 114 735 controls). For exposure data, 70 genetic variants associated with the predicted VAT in 161 149 European women from UK Biobank were used as instrumental variables. Inverse variance weighted and multiple sensitivity analyses were applied. We also conducted multivariable Mendelian randomization (MR) analyses to test the association between VAT-associated single-nucleotide variations and PE. Next, mediation analyses were performed to study whether the association between VAT and PE was mediated via AAM. RESULTS: In univariable MR analysis, higher volume of VAT was associated with the advancement of AAM and increased PE risk (beta = -0.33; 95% CI, -0.49 to -0.16 for AAM; odds ratio 1.65, 95% CI, 1.23 to 2.20 for PE). After adjusting for waist circumference, waist to hip ratio, and hip circumference, the multivariable MR results presented the consistent positive causality of VAT on PE. Two-step MR analysis proved an estimated 14.3% of the positive effect of VAT on PE was mediated by AAM. CONCLUSION: Our findings provided evidence of the causal relationship between VAT and PE and proved VAT could accelerate AAM and then contribute to the risk of incident PE.

Association of Long-term Ambient Fine Particulate Matter (PM2.5) and Incident CKD: A Prospective Cohort Study in China.

RATIONALE & OBJECTIVE: Increasing evidence has linked ambient fine particulate matter (ie, particulate matter no larger than 2.5 µm [PM2.5]) to chronic kidney disease (CKD), but their association has not been fully elucidated, especially in regions with high levels of PM2.5 pollution. This study aimed to investigate the long-term association of high PM2.5 exposure with incident CKD in mainland China. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 72,425 participants (age ≥18 years) without CKD were recruited from 121 counties in Hunan Province, China. EXPOSURE: Annual mean PM2.5 concentration at the residence of each participant derived from a long-term, full-coverage, high-resolution (1 × 1 km2), high-quality dataset of ground-level air pollutants in China. OUTCOMES: Incident CKD during the interval between the baseline examination of each participant (2005-2017) and the end of follow-up through 2018. ANALYTICAL APPROACH: Cox proportional hazards models were used to estimate the independent association of PM2.5 with incident CKD and the joint association of PM2.5 with temperature or humidity on the development of PM2.5-related CKD. Restricted cubic splines were used to model exposure-response relationships. RESULTS: Over a median follow-up of 3.79 (IQR, 2.03-5.48) years, a total of 2,188 participants with incident CKD were identified. PM2.5 exposure was associated with incident CKD with an adjusted hazard ratio of 1.71 (95% CI, 1.58-1.85) per 10-µg/m3 greater long-term exposure. Multiplicative interactions between PM2.5 and humidity or temperature on incident CKD were detected (all P < 0.001 for interaction), whereas an additive interaction was detected only for humidity (relative risk due to interaction, 3.59 [95% CI, 0.97-6.21]). LIMITATIONS: Lack of information on participants' activity patterns such as time spent outdoors. CONCLUSIONS: Greater long-term ambient PM2.5 pollution is associated with incident CKD in environments with high PM2.5 exposure. Ambient humidity has a potentially synergetic effect on the association of PM2.5 with the development of CKD. PLAIN-LANGUAGE SUMMARY: Exposure to a form of air pollution known as fine particulate matter (ie, particulate matter ≤2.5 µm [PM2.5]) has been linked to an increased risk of chronic kidney disease (CKD), but little is known about how PM2.5 affects CKD in regions with extremely high levels of PM2.5 pollution. This longitudinal cohort study in China investigates the effect of PM2.5 on the incidence of CKD and whether temperature or humidity interact with PM2.5. Our findings suggest that long-term exposure to high levels of ambient PM2.5 significantly increased the risk of CKD in mainland China, especially in terms of cumulative average PM2.5. The associations of PM2.5 and incident CKD were greater in high-humidity environments. These findings support the recommendation that reducing PM2.5 pollution should be a priority to decrease the burden of associated health risks, including CKD.

Management of BMI Is a Potential New Approach for the Prevention of Idiopathic Pulmonary Fibrosis.

Aims: Current idiopathic pulmonary fibrosis (IPF) therapies usually show a poor outcome or treatment efficacy. The search for new risk factors has significant implications in preventing, delaying, and treating IPF. The association between obesity and the risk of IPF is not clear. This study aimed to investigate the role of different obesity types in IPF risk, which provides the possibility of weight loss as a new approach for IPF prevention. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect of obesity on IPF risk. We collected summary data of genetically determined obesity-related traits, including body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) from large-scale consortia (the sample size ranging from 232,101 to 681,275), and genetic association with IPF from one of the largest meta-analyses including 2,668 cases. A total of 35-469 single nucleotide polymorphisms were selected as instrumental variables for obesity-related traits. We further performed multivariable MR to estimate the independent effect of BMI and WC on the risk of IPF. Results: Increased BMI and WC were associated with higher risk of IPF [odds ratio (OR) = 1.51, 95% confidence interval (CI) (1.22-1.87), p = 1.27 × 10-4, and OR = 1.71, 95% CI (1.08-2.72), p = 2.33 × 10-2, respectively]. Similar results for the BMI and WC were obtained in the replicated analysis. Subsequently, only the result for BMI survived following the multiple testing correction and showed good consistency with the weighted median estimator. Sensitivity analyses indicated that there was no heterogeneity or horizontal pleiotropy for MR estimations. Further multivariable MR suggested that the BMI showed the same direction and similar magnitude with that in the univariable MR analysis. There was little evidence to support the causal role of WHR on the risk of IPF in this study. Conclusion: Genetically determined BMI demonstrates a causal risk for IPF, which offers a novel insight into probing potential mechanisms. Meanwhile, these results also suggest that weight loss may be beneficial to IPF prevention.

Assessment of causal effects of visceral adipose tissue on risk of cancers: a Mendelian randomization study.

BACKGROUND: Despite the established association between obesity and cancer risk, it remains unclear whether visceral obesity is causally related to cancer risk and whether it is more pro-oncogenic than total body fat. METHODS: We conducted two-sample Mendelian randomization (MR) analysis to assess the causal effects of visceral adipose tissue (VAT) on six common cancers. For exposure data, 221 genetic variants associated with the predicted volume of VAT in 325 153 Europeans from UK Biobank were used as instrumental variables. Genetic association data of six common cancers (breast, lung, colorectal, ovarian, pancreatic and prostate cancers) were obtained from large-scale consortia with an average of 19 576 cases and 43 272 controls. We performed univariable MR with five MR methods [inverse-variance weighted (IVW), MR-Egger regression, weighted median, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR] and multivariable MR to estimate the effect of VAT independent of body mass index (BMI). Finally, we performed a series of sensitivity analyses as validation of primary MR results. RESULTS: Two associations survived the false discovery rate correction for multiple testing (q-value < 0.05): in IVW, the odds ratios (95% CIs) per unit increase in genetically determined VAT were 1.65 (1.03 to 2.62) for pancreatic cancer and 1.47 (1.20 to 1.82) for lung squamous-cell carcinoma, respectively, which showed the same directions and overlapped confidence intervals with MR-Egger regression and weighted median results. There were no outlier variants identified by MR-PRESSO and no evidence supporting the presence of heterogeneity and pleiotropy in sensitivity analyses, although with wider confidence intervals that included the null, multivariable MR results for these two cancers showed the same directions and similar effect sizes as in IVW, which were independent of the effect from BMI. There was no evidence for a causal effect of VAT on the risk of other types of cancer. CONCLUSION: Our findings suggest that lifelong exposure to elevated volumes of VAT might increase the risk of pancreatic cancer and lung squamous-cell carcinoma, highlighting the importance of revealing the underlying mechanisms for intervention targets.

Assessment of the Causal Effects of Obstructive Sleep Apnea on Atrial Fibrillation: A Mendelian Randomization Study.

BACKGROUND: Obstructive sleep apnea (OSA) and atrial fibrillation (AF) are epidemiologically correlated, but the causal relationship between them remains elusive. We aimed to explore the causal relationships between OSA and AF. METHOD: Using both the Finnish biobank and publicly available genome-wide association study data (GWAS), we conducted a two-sample Mendelian randomization (MR) analysis to estimate the causal effect of OSA on AF, both in the primary analysis and replicated analysis. The inverse variance weighted MR was selected as the main method. To further test the independent causal effect of OSA on AF, we also performed multivariable MR (MVMR), adjusting for body mass index (BMI), hypertension, and coronary artery disease (CAD), respectively. RESULTS: In the primary analysis, OSA was significantly associated with the increased risk of AF (OR 1.21, 95% CI 1.11-1.32) and the replicated analysis showed consistent results (OR 1.17, 95% CI 1.05-1.30). Besides, there was no heterogeneity and horizontal pleiotropy observed both in the primary and replicated analysis. Further multivariable MR suggested that the causal relationships between OSA and AF exist independently of BMI and CAD. The MVMR result after the adjustment for hypertension is similar in magnitude and direction to the univariable MR. But it did not support a causal relationship between OSA and AF. CONCLUSION: Our study found that genetically driven OSA causally promotes AF. This causal relationship sheds new light on taking effective measures to prevent and treat OSA to reduce the risk of AF.

Diet-Derived Circulating Antioxidants and Risk of Stroke: A Mendelian Randomization Study.

BACKGROUND: Oxidative stress is crucial in stroke pathogenesis. Many cohort-based studies suggested that the intake of exogenous antioxidants originated from food may prevent stroke. However, the corresponding randomized controlled trials did not show diet-derived antioxidants have a protective effect on stroke. OBJECTIVES: To examine the association of genetically proxied diet-derived antioxidants with stroke risk using Mendelian randomization. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of diet-derived antioxidants on stroke risk. For exposure data, we extracted genetic variants as instrumental variables (IVs) that are strongly associated with frequently used diet-derived antioxidants, including vitamin C, vitamin E (α-tocopherol, γ-tocopherol), carotene, retinol, zinc, and selenium, from a large-scale genome-wide association study (GWAS). We obtained IVs' corresponding effect estimates on the risk of total stroke and ischemic stroke from a GWAS meta-analysis with 40,585 cases and 406,111 controls. Finally, we applied five types of Mendelian randomization analysis to obtain preliminary MR results and performed four three kinds of sensitivity analysis to verify them. RESULTS: According to the primary MR estimations and further sensitivity analyses, we established two robust associations after Bonferroni correction: genetically proxied circulating γ-tocopherol was causally associated with total stroke [odds ratio (OR) = 0.68, 95% confidence interval (CI) (0.52-0.88), p = 3.78E - 03] and ischemic stroke [OR = 0.66, 95% CI (0.51-0.86), p = 2.34E - 03]. There was no evidence to support the causal effect of other diet-derived antioxidants on the risk of total stroke and ischemic stroke. CONCLUSION: Our study revealed a protective impact of genetic susceptibility to high circulating γ-tocopherol levels on stroke risk, providing new information on the potential therapeutic targets for primary stroke prevention.

A Mendelian randomization study to assess the genetic liability of type 1 diabetes mellitus for IgA nephropathy.

Background: The prevalence of immunoglobulin A nephropathy (IgAN) seems to be higher in patients with type 1 diabetes mellitus (T1DM) than that in the general population. However, whether there exists a causal relationship between T1DM and IgAN remains unknown. Methods: This study conducted a standard two-sample Mendelian randomization (MR) analysis to assess the causal inference by four MR methods, and the inverse variance-weighted (IVW) approach was selected as the primary method. To further test the independent causal effect of T1DM on IgAN, multivariable MR (MVMR) analysis was undertaken. Sensitivity analyses incorporating multiple complementary MR methods were applied to evaluate how strong the association was and identify potential pleiotropy. Results: MR analyses utilized 81 single-nucleotide polymorphisms (SNPs) for T1DM. The evidence supports a significant causal relationship between T1DM and increased risk of IgAN [odds ratio (OR): 1.39, 95% confidence interval (CI): 1.10-1.74 for IVW, p < 0.05]. The association still exists after adjusting for triglyceride (TG), fasting insulin (FI), fasting blood glucose (FBG), homeostasis model assessment of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycated hemoglobin (HbA1c). MVMR analysis indicated that the effect of T1DM on IgAN vanished upon accounting for low-density lipoprotein cholesterol (LDL-c; OR: 0.97, 95% CI: 0.90-1.05, p > 0.05). Conclusions: This MR study provided evidence that T1DM may be a risk factor for the onset of IgAN, which might be driven by LDL-c. Lipid-lowering strategies targeting LDL-c should be enhanced in patients with T1DM to prevent IgAN.

Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study.

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results. Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89-0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88-0.99, unadjusted p < 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke. Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.