Estimating causal effects of atherogenic lipid-related traits on COVID-19 susceptibility and severity using a two-sample Mendelian randomization approach.

As the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach. We used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant. This MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001-1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04-1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08-1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely. Our MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.

Yoshikawa M ，Asaba K ，Nakayama T 《BMC Medical Genomics》

Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis.

Richardson TG ，Sanderson E ，Palmer TM ，Ala-Korpela M ，Ference BA ，Davey Smith G ，Holmes MV ... -  《-》

Using genetic variants to evaluate the causal effect of serum vitamin D concentration on COVID-19 susceptibility, severity and hospitalization traits: a Mendelian randomization study.

The coronavirus disease 2019 (COVID-19) pandemic has struck globally and is exerting a devastating toll on humans. The pandemic has led to calls for widespread vitamin D supplementation in public. However, evidence supporting the role of vitamin D in the COVID-19 pandemic remains controversial. We performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effect of the 25-hydroxyvitamin D [25(OH)D] concentration on COVID-19 susceptibility, severity and hospitalization traits by using summary-level GWAS data. The causal associations were estimated with inverse variance weighted (IVW) with fixed effects (IVW-fixed) and random effects (IVW-random), MR-Egger, weighted edian and MR Robust Adjusted Profile Score (MR.RAPS) methods. We further applied the MR Steiger filtering method, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test and PhenoScanner tool to check and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. We found no evidence to support the causal associations between the serum 25(OH)D concentration and the risk of COVID-19 susceptibility [IVW-fixed: odds ratio (OR) = 0.9049, 95% confidence interval (CI) 0.8197-0.9988, p = 0.0473], severity (IVW-fixed: OR = 1.0298, 95% CI 0.7699-1.3775, p = 0.8432) and hospitalized traits (IVW-fixed: OR = 1.0713, 95% CI 0.8819-1.3013, p = 0.4878) using outlier removed sets at a Bonferroni-corrected p threshold of 0.0167. Sensitivity analyses did not reveal any sign of horizontal pleiotropy. Our MR analysis provided precise evidence that genetically lowered serum 25(OH)D concentrations were not causally associated with COVID-19 susceptibility, severity or hospitalized traits. Our study did not provide evidence assessing the role of vitamin D supplementation during the COVID-19 pandemic. High-quality randomized controlled trials are necessary to explore and define the role of vitamin D supplementation in the prevention and treatment of COVID-19.

Cui Z ，Tian Y 《Journal of Translational Medicine》

The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study.

Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β = 1.1 (95% CI [0.411-1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β = 1.619 (95% CI [0.412-2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C β = -0.164, (95% CI = [-1.329 to 1.00]; p = 0.782), and TG β = -0.934 (CI = [-2.815 to 0.947]; p = 0.33) were not significantly causally associated with the risk of eGFR. In the multivariable analysis inverse-variance weighted (MVIVW) method, there was evidence for a causal association between LDL and eGFR β = 1.228 (CI = [0.477-1.979]; p = 0.001). A significant causal effect of Triglycerides (TG) on eGFR in the MVIVW analysis β = -1.3 ([-2.533 to -0.067]; p = 0.039) was observed as well. All the causal estimates reported reflect a unit change in the outcome per a 1 SD increase in the exposure. HDL showed no evidence of a significant causal association with eGFR in the MVIVW method (β = -0.117 (95% CI [-1.252 to 0.018]; p = 0.840)). We found no evidence of a reverse causal impact of eGFR on serum lipids. All our sensitivity analyses indicated no strong evidence of pleiotropy or heterogeneity between our instrumental variables for both the forward and reverse MR analysis. In this African ancestry population, genetically predicted higher LDL-C and TC are causally associated with higher eGFR levels, which may suggest that the relationship between LDL, TC and kidney function may be U-shaped. And as such, lowering LDL_C does not necessarily improve risk of kidney disease. This may also imply the reason why LDL_C is seen to be a poorer predictor of kidney function compared to HDL. In addition, this further supports that more work is warranted to confirm the potential association between lipid traits and risk of kidney disease in individuals of African Ancestry. Wellcome (220740/Z/20/Z).

Kintu C ，Soremekun O ，Kamiza AB ，Kalungi A ，Mayanja R ，Kalyesubula R ，Bagaya S B ，Jjingo D ，Fabian J ，Gill D ，Nyirenda M ，Nitsch D ，Chikowore T ，Fatumo S ... -  《EBioMedicine》

The Relationship between Blood Lipids and Risk of Atrial Fibrillation: Univariable and Multivariable Mendelian Randomization Analysis.

Yang S ，Pudasaini R ，Zhi H ，Wang L ... -  《Nutrients》