GENETICALLY ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL IS ASSOCIATED WITH AORTIC VALVE CALCIFICATION AND INCIDENT AORTIC STENOSIS: A MENDELIAN RANDOMIZATION STUDY

2014 ◽  
Vol 30 (10) ◽  
pp. S257
Author(s):  
G. Thanassoulis ◽  
K. Luk ◽  
C. Schulz ◽  
J. Engert ◽  
R. Do ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol ◽  
Aortic Valve Calcification ◽  
Valve Calcification

scholarly journals Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis

JAMA ◽  
2014 ◽  
Vol 312 (17) ◽  
pp. 1764 ◽  
Author(s):  
J. Gustav Smith ◽  
Kevin Luk ◽  
Christina-Alexandra Schulz ◽  
James C. Engert ◽  
Ron Do ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Genetic Variants ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

Abstract 47: Genetically Elevated Low-Density Lipoprotein Cholesterol is Associated with Aortic Valve Calcification and Incident Aortic Stenosis

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
George Thanassoulis ◽  
Kevin Luk ◽  
Christina A Schulz ◽  
James Engert ◽  
David Owens ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Low Density ◽  
Low Density Lipoprotein Cholesterol

Background: Although plasma low density lipoprotein cholesterol (LDL-C) appears to be a causative factor in animal models of aortic valve (AV) disease, randomized trials with cholesterol lowering therapies in established disease have failed to reduce progression. We sought to evaluate whether life-long genetic elevations in LDL-C, high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) are associated with AV disease. Methods: Using 144 single nucleotide polymorphisms associated with LDL-C, HDL-C or TG in genomewide association studies (GWAS), we constructed three separate genetic risk scores (GRS). We estimated the association between each GRS and (1) the presence of AV calcium determined by computed tomography in 6942 participants of white European ancestry from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium using summary level GWAS data and; (2) incidence of aortic stenosis in 28,585 participants from the Malmo Diet and Cancer Study (MDCS) over a mean follow-up time of 15.8 years. Results: The LDL-C GRS, but not the HDL-C or the TG GRS, was associated with presence of AV calcium (OR per predicted mmol/L LDL-C, 1.38 95% CI 1.09-1.74; p=0.007). The LDL-C GRS was also associated with incident aortic stenosis (HR per mmol/L LDL-C, 3.04 (1.34-6.91, p=0.008). In sensitivity analyses excluding SNPs also associated with HDL-C or TG to reduce pleiotropy, the LDL-C GRS remained associated with AV calcium (OR per predicted mmol/L LDL-C 1.39 95% CI 1.04-1.90; p=0.03) and aortic stenosis (HR per mmol/L LDL-C 3.85, 95% CI 1.37-10.79, p=0.01). Further analyses to exclude residual pleiotropic effects of HDL-C and TG, did not materially change these findings. Conclusions: Genetic predisposition to increased LDL-C is associated with presence of AV calcium and incidence of aortic stenosis, providing novel supportive evidence that LDL-C is a causal factor for the development of AV disease. Earlier intervention to reduce LDL-C merits further investigation to prevent AV disease.

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.

Abstract 2655: Correlates Of Aortic Valve Calcification In Aortic Stenosis: Insights From The Astronomer Study

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kwan Chan ◽  
James Tam ◽  
Randall Sochowski ◽  
Jean Dumesnil ◽  
Peter Giannoccaro ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Common Finding ◽  
Aortic Valve Calcification ◽  
Cholesterol Lowering ◽  
Valve Calcification ◽  
Increased Risk ◽  
Male Sex

Aortic valve calcification (AVC), a common finding in aortic stenosis (AS), is a predictor of rapid AS progression and increased risk of cardiac events. We evaluated clinical, echocardiographic and biochemical correlates of AVC to gain insight into pathogenesis and to identify potential targets for intervention. Methods: The ASTRONOMER study (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin) is a randomized trial to assess cholesterol lowering using rosuvastatin on AS progression in mild to moderate AS. Patients with indication for cholesterol lowering were excluded. Severity of AVC was classified as none, mild, moderate and severe according to published criteria. Results: 272 patients (167 men, 105 women; mean age 58.1±13.6 years) have been enrolled with peak and mean AV gradients 41±11 and 23±8 mmHg respectively. Patients with none or mild AVC were compared with patients with moderate or severe AVC (Table ). ACE-I= angiotensin converting enzyme inhibitor, BAV=bicuspid aortic valve, BP=blood pressure, HDL-C=high-density lipoprotein cholesterol, LDL-C= low-density lipoprotein cholesterol, MAC=mitral annular calcification. Regression analysis showed that AVC was associated with age (p<0.001), male sex (p=0.01), systolic BP (p=0.002), LDL-C (p=0.05), MAC (p=0.01) and tricuspid AV (p=0.001). With adjustment for age, correlates of AVC were male sex with odds ratio (OD) 2.04, p<0.01, systolic BP (OD=1.02, p=0.096), and LDL-C (OD 1.44, p=0.077). Conclusions: In patients with AS, age and male sex are the main correlates of AVC. After adjusting for age, AVC is not associated with AV morphology but appears to be related to male sex, BP and LDL-C. Thus BP and LDL-C are promising modifiable targets to prevent AVC which in turn should reduce AS progression.

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
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