Biology subjects

Arsenault, B. J.

Publications and source records attributed to Arsenault, B. J..

3 recordsLinked to original sources

bioRxiv2019

Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

BackgroundElevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether genetically-determined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality.\n\nMethodsWe determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or fathers age of death [≥]90 or mother still alive and older than 93 or mothers age of death [≥]93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study.\n\nResultsIn the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7x10-8). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels <50 mg/dL, those with Lp(a) levels [≥]50 mg/dL had an increased hazard ratio (HR) for all-cause (HR=1.17, 95% CI=1.08-1.27) and cardiovascular (HR=1.54, 95% CI=1.37-1.72) mortality. Compared to individuals with Lp(a) levels below the 50th percentile of the Lp(a) distribution (in whom event rates were 29.8% and 11.3%, respectively for all-cause and cardiovascular mortality), those with Lp(a) levels equal or above the 95th percentile of the population distribution ([≥]70 mg/dL) had HRs of 1.22 (95% CI=1.09-1.37, event rate 37.5%) and 1.71 (95% CI=1.46-2.00, event rate 20.0%), for all-cause mortality and cardiovascular mortality, respectively.\n\nConclusionsResults of this study suggest a potentially causal effect of Lp(a) on human longevity, support the use of parental lifespan as a tool to study the genetic determinants of human longevity, and provide a rationale for a trial of Lp(a)-lowering therapy in individuals with high Lp(a) levels.

genetics↗

bioRxiv2019

Genetic inhibition of PCSK9, atherogenic lipoprotein concentrations, and calcific aortic valve stenosis

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces plasma concentrations of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)]. Atherogenic lipoprotein levels have been linked with calcific aortic valve stenosis (CAVS). Our objectives were to determine the association between variants in PCSK9 and lipoprotein-lipid levels, coronary artery disease (CAD) and CAVS, and to evaluate if PCSK9 could be implicated in aortic valve interstitial cells (VICs) calcification. MethodsWe built a genetic risk score weight for LDL-C levels (wGRS) using 10 independent PCSK9 single nucleotide polymorphisms and determined its association with lipoprotein-lipid levels in 9692 participants of the EPIC-Norfolk study. We investigated the association between the wGRS and CAD and CAVS in the UK Biobank, as well as the association between the PCSK9 R46L variant and CAVS in a meta-analysis of published prospective, population-based studies (Copenhagen studies, 1463 cases/101,620 controls) and unpublished studies (UK Biobank, 1350 cases/349,043 controls, Malmo Diet and Cancer study, 682 cases/5963 controls and EPIC-Norfolk study, 508 cases/20,421 controls). We evaluated PCSK9 expression and localization in explanted aortic valves by capillary Western blot and immunohistochemistry in patients with and without CAVS. Von Kossa staining was used to visualize aortic leaflet calcium deposits. PCSK9 expression under oxidative stress conditions in VICs was assessed. ResultsThe wGRS was significantly associated with lower LDL-C and apoB (p<0.001), but not with Lp(a). In the UK Biobank, the association of PCSK9 variants with CAD were positively correlated with their effects on apoB levels. CAVS was less prevalent in carriers of the PCSK9 R46L variant [odds ratio=0.71 (95% confidence interval, 0.57-0.88), p<0.001]. PCSK9 expression was elevated in the aortic valves of patients with aortic sclerosis and CAVS compared to controls. In calcified leaflets, PCSK9 co-localized with calcium deposits. PCSK9 expression was induced by oxidative stress in VICs. ConclusionGenetic inhibition of PCSK9 is associated with lifelong reductions in the levels of non-Lp(a) apoB-containing lipoproteins as well as lower odds of CAD and CAVS. PCSK9 is abundant in fibrotic and calcified aortic leaflets. Oxidative stress increases PCSK9 expression in VICs. These results provide a rationale for performing randomized clinical trials of PCSK9 inhibition in CAVS.

genetics↗

bioRxiv2019

Genetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis

To date, only two replicated loci, LPA and PALMD, have been identified as causal genes for calcific aortic valve stenosis (CAVS) using genome-wide and transcriptome-wide association study (TWAS). To identify additional susceptibility genes for CAVS, we performed a GWAS meta-analysis totaling 5,115 cases and 354,072 controls of European descent. Four loci achieved genome-wide significance, including two new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating an eQTL study of 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Association results at the genome-wide scale showed genetic correlation with coronary artery disease and cardiovascular risk factors. Our study highlights three new loci implicating inflammation, mineralization and blood vessel integrity in CAVS pathogenesis and supports shared genetic etiology with cardiovascular traits.

genomics↗