biostudies-literatureSmith JGIntramural NIH HHSNCATS NIH HHSNCRR NIH HHSNIDDK NIH HHSNIA NIH HHSNHLBI NIH HHSNovo Nordisk FondenCIHR1764-71https://www.ebi.ac.uk/biostudies/studies/S-EPMC4280258biostudies-literatureUnknown312(17)IMPORTANCE:Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE:To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS:Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n?=?6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n?=?1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n?=?2527), Age Gene/Environment Study-Reykjavik (2000-2012; n?=?3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n?=?28,461). MAIN OUTCOMES AND MEASURES:Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS:The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n?=?2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n?=?473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n?=?205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P?=?.02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P?=?.007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P?=?.02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P?=?.03) and aortic stenosis (P?=?.009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P?=?.02). CONCLUSIONS AND RELEVANCE:Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.JAMAAssociation of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.PMC4280258N01 AG012100R01 HL071205N01-HC-25195MOP-119380N01-HC-95161N01-HC-95162N01-HC-65226N01-HC-95163N01-HC-95164N01 HC095169N01HC95159N01-HC-95160N01 HC025195N01-HC-95159R01-HL-071205NNF14OC0011049UL1 RR024156R01 HL071739N01HC25195T32 HL007208R01 HL071259UL1 TR000124R01 HL071258KL2 TR002317R01 HL071051N01 HC095159R01 HL071251R01 HL071250N01AG12100R01 HL071252N01-HC-95169N02HL64278N01-HC-95165N01-HC-95166N01-HC-95167R01-HL-071259N01-HC-95168R01-HL-071258N02 HL64278R01-HL-071252MOP-126033P30 DK063491N01HC65226R01-HL-071051N01 HC065226R01-HL-071251R01-HL-071250Cupples LAHindy GRotter JIKerr KFOrho-Melander MGudnason VBudoff MJRich SSchulz CASmith JGOwens DSAlmgren PPeloso GMSmith AVPost WSThanassoulis GKathiresan SDufresne LO'Donnell CJWong QLuk KCohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Extracoronary Calcium Working GroupRukh GHarris TBEngert JCDo RfalseAssociation of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.IMPORTANCE:Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. OBJECTIVE:To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. DESIGN, SETTING, AND PARTICIPANTS:Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n?=?6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n?=?1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n?=?2527), Age Gene/Environment Study-Reykjavik (2000-2012; n?=?3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n?=?28,461). MAIN OUTCOMES AND MEASURES:Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS. RESULTS:The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n?=?2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n?=?473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n?=?205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P?=?.02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P?=?.007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P?=?.02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P?=?.03) and aortic stenosis (P?=?.009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P?=?.02). CONCLUSIONS AND RELEVANCE:Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.2014-01-01T00:00:00Z2014 Nov2020-10-29T11:13:23Z2019-03-27T01:42:30ZS-EPMC42802582534473410.1001/jama.2014.13959