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While numerous observational studies have indicated an association between lipids and Sudden Sensorineural Hearing Loss (SSNHL), it remains uncertain whether dyslipidemia serves as a causal risk factor for SSNHL. Our objective is to elucidate the potential causal relationship between lipid levels and SSNHL through Mendelian randomization analysis. The primary and secondary lipid data used in this study were sourced from the UK Biobank (UKBB) and the Global Lipid Genetics Consortium results (GLGC), respectively. These datasets were obtained from large, publicly available genome-wide association studies (GWAS). The outcome data for sudden sensorineural hearing loss (SSNHL) were acquired from the Finnegan Biobank, consisting of 1491 cases and 196,592 controls. Subsequently, both single-variable Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) methods were employed to evaluate the causal relationship between lipids and the occurrence of SSNHL. Among the primary lipid data, SVMR analysis showed a significant correlation between high density lipoprotein cholesterol (HDL-C) (OR: 0.822, 95 %CI: 0.694–0.974, p = 0.023) and SSNHL, and triglycerides (TG) (OR: 0.997, 95 %CI: 0.836–1.188, p = 0.975), low density lipoprotein cholesterol (LDL-C) (OR: 1.067, 95 %CI: 0.861–1.322, p = 0.552) did not correlate with SSNHL. In the secondary lipid data, SVMR analysis showed that HDL-C (OR: 0.987, 95 %CI: 0.805–1.210, p = 0.903), TG (OR: 0.991, 95 %CI: 0.787–1.246, p = 0.937) and LDL-C (OR: 1.092, 95 % CI: 0.926–1.287, p = 0.294) did not correlate with SSNHL. MVMR analysis of the primary lipid data showed that HDL-cholesterol (OR: 0.755, 95 % CI: 0.596–0.956, p = 0.019) was significantly associated with SSNHL, while TG (OR: 0.808, 95 %CI: 0.611–1.068, p = 0.134) and LDL-C (OR: 1.146, 95 %CI: 0.869–1.511, p = 0.333) did not correlate with SSNHL, consistent with the results of SVMR. Inverse MR results showed that SSNHL did not correlate with TG (OR: 0.999, 95 %CI: 0.997–1.001, p = 0.835), HDL-C (OR: 1.001, 95 %CI: 0.998–1.003), LDL-C (OR: 0.999, 95 %CI: 0.997–1.002, p = 0.863). Mendelian randomization (MR) results suggest that decreased serum HDL-C levels are an independent risk factor for SSNHL. Monitoring and focusing on lipid levels may be of value in the prevention and treatment of SSNHL. [ABSTRACT FROM AUTHOR]

Background: This study aims to comprehensively investigate the phenotypic and genetic relationships between four common lipids (high-density lipoprotein cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; total cholesterol, TC; and triglycerides, TG), chronic kidney disease (CKD), and estimated glomerular filtration rate (eGFR). Methods: We first investigated the observational association of lipids (exposures) with CKD (primary outcome) and eGFR (secondary outcome) using data from UK Biobank. We then explored the genetic relationship using summary statistics from the largest genome-wide association study of four lipids (N = 1,320,016), CKD (Ncase = 41,395, Ncontrol = 439,303), and eGFR(N = 567,460). Results: There were significant phenotypic associations (HDL-C: hazard ratio (HR) = 0.76, 95%CI = 0.60–0.95; TG: HR = 1.08, 95%CI = 1.02–1.13) and global genetic correlations (HDL-C: r g = − 0.132, P = 1.00 × 10–4; TG: r g = 0.176; P = 2.66 × 10–5) between HDL-C, TG, and CKD risk. Partitioning the whole genome into 2353 LD-independent regions, twelve significant regions were observed for four lipids and CKD. The shared genetic basis was largely explained by 29 pleiotropic loci and 36 shared gene-tissue pairs. Mendelian randomization revealed an independent causal relationship of genetically predicted HDL-C (odds ratio = 0.91, 95%CI = 0.85–0.98), but not for LDL-C, TC, or TG, with the risk of CKD. Regarding eGFR, a similar pattern of correlation and pleiotropy was observed. Conclusions: Our work demonstrates a putative causal role of HDL-C in CKD and a significant biological pleiotropy underlying lipids and CKD in populations of European ancestry. Management of low HDL-C levels could potentially benefit in reducing the long-term risk of CKD. [ABSTRACT FROM AUTHOR]

Background and purpose: We used two‐sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid‐modifying drugs on intracranial aneurysm (IA). Methods: Genetic variants for the effects of high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein A1, low‐density lipoprotein cholesterol (LDL‐C), apolipoprotein B, and triglycerides and targets for lipid‐modifying drugs were selected from the genome‐wide discovery analyses of the UK Biobank. Summary‐level data on IAs were obtained from the International Stroke Genetics Consortium. Univariate and multivariate MR analyses were performed. Results: Univariate MR analyses showed that the HDL‐C was negatively correlated with IA (odds ratio [OR] = 0.816, 95% confidence interval [CI] = 0.715–0.932, p = 0.003) and ruptured IA (rIA; OR = 0.775, 95% CI = 0.663–0.906, p = 0.001). The multivariate MR–inverse variance weighted analysis showed that the HDL‐C was negatively correlated with IA (OR = 0.655, 95% CI = 0.434–0.988, p = 0.043) and rIA (OR = 0.563, 95% CI = 0.347–0.913, p = 0.02), and the LDL‐C was negatively correlated with IA (OR = 0.402, 95% CI = 0.191–0.848, p = 0.017) and rIA (OR = 0.376, 95% CI = 0.160–0.883, p = 0.025). Using genetic proxies of known lipid‐modifying drugs, we found that the increased HDL‐C with cholesterol ester transfer protein proxies was associated with a decreased risk of rIA (OR = 0.852, 95% CI = 0.747–0.973, p = 0.018), and the decreased LDL‐C with 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase proxies was associated with increased risk of IA (OR = 1.772, 95% CI = 1.080–2.908, p = 0.024) and rIA (OR = 1.856, 95% CI = 1.022–3.371, p = 0.042). Conclusions: Genetically determined HDL‐C and LDL‐C reduce the risk of IA and rIA. The effects of different lipid‐modifying drugs on IA need to be further investigated. [ABSTRACT FROM AUTHOR]

Fat mass and fat-free mass are found to be associated with different health outcomes in observational studies, but the underlying causality remains unclear. We aimed to investigate the causal relationships between body composition and cardiometabolic traits using a two-sample Mendelian randomization (MR) approach. Independent genetic variants associated with body fat mass, fat-free mass, and fat percentage in UK Biobank population were used as genetic instrumental variables, and their causal effects on circulatory diseases, type 2 diabetes, glycemic traits, and lipid fractions were estimated from large-scale genome-wide association studies (GWAS) in European populations. Univariable, multivariable, and bidirectional MR analyses were performed. Genetically predicted high fat mass and fat percentage significantly increased risks of most cardiometabolic diseases, and high fat-free mass had protective effects on most cardiometabolic diseases after accounting for fat mass. Fat mass, fat-free mass, and fat percentage were all positively associated with higher risks of atrial fibrillation and flutter, varicose veins, and deep vein thrombosis and pulmonary embolism. High fat mass increased fasting glucose, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, decreased high-density lipoprotein cholesterol, and high fat-free mass reduced HOMA-IR, triglycerides, and low-density lipoprotein cholesterol. Genetically predicted fat-free mass was bidirectionally negatively associated with 2-h glucose and total cholesterol. The findings may be helpful in risk stratification and tailoring management of body composition in patients with different cardiometabolic statuses. [ABSTRACT FROM AUTHOR]

Background: The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear.Methods: Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies.Results: There were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels.Conclusion: Our MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels. [ABSTRACT FROM AUTHOR]

The lipid profile is consistently associated with coronary artery disease (CAD) and ischemic stroke (IS). However, the lipoprotein subfractions have not been deeply explored in stroke subtypes, especially in IS outcome. We performed two-sample Mendelian randomization (MR) analysis using 92 lipid traits measured by nuclear magnetic resonance in 115,000 subjects from the UK Biobank. Data for genetic associations with IS, its subtypes, and long-term outcome (LTO) were obtained from three cohorts of European ancestry: GIGASTROKE (73,652 cases, 1,234,808 controls), GODS (n = 1791) and GISCOME (n = 6165). Results obtained using CARDIoGRAMPlusC4D were used to identify differences with CAD. Genetically determined low concentration of medium high-density lipoprotein (HDL) particles (odds ratio (OR) = 0.92, 95% CI 0.88–0.96; p = 3.6 × 10−4) and its cholesterol content (OR = 0.92, 95% CI 0.88–0.96; p = 1.9 × 10−4) showed causal associations with an increased risk of stroke. Genetic predisposition to high apolipoprotein (apo)B to apoA-I ratio was causally associated with an increased risk of IS (OR = 1.12, 95% CI 1.06–1.18, p = 1.1 × 10−4), and a highly suggestive association was found between non-esterified cholesterol in low-density lipoprotein (LDL) and increased risk of atherothrombotic stroke (LAS) (OR = 1.35, 95% CI 1.10–1.66; p = 4.0 × 10−3). Low cholesterol in small and medium LDL was suggestively associated with poor LTO. Our results support that low medium HDL concentration was causally associated with an increased stroke risk, while high levels of non-esterified cholesterol in LDL were suggestively associated with an increased risk of LAS and with a better LTO. [Display omitted] • Causal association of low HDL-C with stroke risk is due to the medium subfraction. • Free cholesterol content is implicated in the association of high LDL with stroke risk. • The association of triglyceride-rich lipoproteins with stroke remains inconclusive. • ApoB-lipoproteins play a more important role in CAD risk than in stroke risk. • The association of low LDL-C with a poor long-term outcome needs further studies. [ABSTRACT FROM AUTHOR]