scholarly journals Genetically-predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: A Mendelian randomization study in UK biobank

EBioMedicine ◽  
2019 ◽  
Vol 45 ◽  
pp. 487-494 ◽  
Author(s):  
Qi Wang ◽  
Yunzhang Wang ◽  
Kelli Lehto ◽  
Nancy L. Pedersen ◽  
Dylan M. Williams ◽  
...  
Keyword(s):  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Uk Biobank ◽  
Low Density Lipoprotein Cholesterol

scholarly journals A novel Mendelian randomization method identifies causal relationships between gene expression and low-density lipoprotein cholesterol levels

2019 ◽  
Author(s):  
Adriaan van der Graaf ◽  
Annique Claringbould ◽  
Antoine Rimbert ◽  
Harm-Jan Westra ◽  
Yang Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Causal Relationships ◽  
Low Density Lipoprotein Cholesterol ◽  
Individual Level

AbstractRobust inference of causal relationships between gene expression and complex traits using Mendelian Randomization (MR) approaches is confounded by pleiotropy and linkage disequilibrium (LD) between gene expression quantitative loci (eQTLs). Here we propose a new MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data. In simulations, MR-link shows false positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other MR methods we tested, even when only one eQTL variant is present. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals and eQTLs summary statistics from whole blood and liver identified 19 genes causally linked to LDL-C. These include the previously functionally validatedSORT1gene, and thePVRL2gene, located in theAPOElocus, for which a causal role in liver was yet unknown. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.

scholarly journals Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia

2020 ◽  
Vol 13 (5) ◽  
pp. 515-523
Author(s):  
Mark Trinder ◽  
Martine Paquette ◽  
Lubomira Cermakova ◽  
Matthew R. Ban ◽  
Robert A. Hegele ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Meta Analysis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Uk Biobank ◽  
Low Density Lipoprotein Cholesterol ◽  
Polygenic Score ◽  
Ascvd Risk

Background: Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence of an LDL-C polygenic score on levels of LDL-C and risk of ASCVD for individuals with monogenic FH. Methods: We constructed a weighted LDL-C polygenic score, composed of 28 single-nucleotide variants, for individuals with monogenic FH from the British Columbia FH (n=262); Nutrition, Metabolism and Atherosclerosis Clinic (n=552); and UK Biobank cohorts (n=306). We assessed the association between LDL-C polygenic score with LDL-C levels and ASCVD risk using linear regression and Cox-proportional hazard models, respectively. ASCVD was defined as myocardial infarction, coronary or carotid revascularization, transient ischemic attack, or stroke. The results from individual cohorts were combined in fixed-effect meta-analyses. Results: Levels of LDL-C were significantly associated with LDL-C polygenic score in the Nutrition, Metabolism and Atherosclerosis Clinic cohort, UK Biobank cohort, and in the meta-analysis (β [95% CI]=0.13 [0.072–0.19] per a 20% increase in LDL-C polygenic score percentile, P <0.0001). Additionally, an elevated LDL-C polygenic score (≥80th percentile) was associated with a trend towards increased ASCVD risk in all 3 cohorts individually. This association was statistically significant in the meta-analysis (hazard ratio [95% CI]=1.48 [1.02–2.14], P =0.04). Conclusions: Polygenic contributions to LDL-C explain some of the heterogeneity in clinical presentation and ASCVD risk for individuals with FH.

Low-density lipoprotein cholesterol and risk of gallstone disease: A Mendelian randomization study and meta-analyses

2013 ◽  
Vol 58 (1) ◽  
pp. 126-133 ◽  
Author(s):  
Stefan Stender ◽  
Ruth Frikke-Schmidt ◽  
Marianne Benn ◽  
Børge G. Nordestgaard ◽  
Anne Tybjærg-Hansen
Keyword(s):  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Gallstone Disease ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Meta Analyses

scholarly journals Low-Density Lipoprotein Cholesterol and the Risk of Cancer: A Mendelian Randomization Study

2011 ◽  
Vol 103 (6) ◽  
pp. 508-519 ◽  
Author(s):  
Marianne Benn ◽  
Anne Tybjærg-Hansen ◽  
Stefan Stender ◽  
Ruth Frikke-Schmidt ◽  
Børge G. Nordestgaard
Keyword(s):  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Risk Of Cancer

scholarly journals Evaluating lipid-lowering drug targets for Parkinson disease prevention with Mendelian randomization

2020 ◽  
Author(s):  
Dylan M. Williams ◽  
Sara Bandres-Ciga ◽  
Karl Heilbron ◽  
David Hinds ◽  
Alastair J Noyce ◽  
...  
Keyword(s):  
Protective Effect ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Genome Wide Association Studies ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

AbstractObjectiveTo examine whether long-term exposure to statins and other lipid-lowering drugs may affect PD risk – either beneficially or adversely – using Mendelian randomization (MR).MethodsMR analyses were based on variants in genes encoding the targets of several approved or emerging drug classes that reduce circulating low-density lipoprotein cholesterol (LDL-C) or triglycerides. Variants were weighted by their associations with differences in circulating LDL-C, triglycerides or apolipoprotein B (ApoB) using data from genome-wide association studies of lipids (N = 14,004 to 295,826). MR models indexing the effects of modulating each drug target on PD risk were then estimated from genetic associations with PD case-control status (N = 37,688 cases and 981,372 controls).ResultsEstimates for statin exposure were incompatible with drug use increasing PD risk, but were not precise enough to confirm a protective effect: odds ratio for PD per standard deviation (SD) reduction in low-density lipoprotein cholesterol = 0.83; 95% confidence interval (CI): 0.65, 1.07. Findings for other LDL-lowering targets were also close to the null. Among triglyceride-lowering targets, variants indexing Apolipoprotein-A5 / Apolipoprotein-C3 modulation suggested a protective effect (OR per SD lower triglycerides = 0.84; 95% CI = 0.80, 0.89), whereas others were null.InterpretationThis genetic evidence does not support findings from large observational studies which suggest that statin exposure could alter risk of PD. Our overall pattern of results suggest peripheral lipid transport may not influence PD etiology, but this does not necessarily exclude effects of statins or the modulation of apolipoproteins A5/C3 via other mechanisms.

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